Re: 우울증을 치료하는 장내유익균 대사산물..

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Microb Cell. 2019 Oct 7; 6(10): 454–481.

Published online 2019 Sep 27. doi: 10.15698/mic2019.10.693

PMCID: PMC6780009

PMID: 31646148

Gut microbial metabolites in depression: understanding the biochemical mechanisms

Giorgia Caspani,1 Sidney Kennedy,2,3,4,5 Jane A. Foster,6,* and Jonathan Swann1

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Abstract

Gastrointestinal and central function are intrinsically connected by the gut microbiota, an ecosystem that has co-evolved with the host to expand its biotransformational capabilities and interact with host physiological processes by means of its metabolic products. Abnormalities in this microbiota-gut-brain axis have emerged as a key component in the pathophysiology of depression, leading to more research attempting to understand the neuroactive potential of the products of gut microbial metabolism.

This review explores the potential for the gut microbiota to contribute to depression and focuses on the role that microbially-derived molecules – neurotransmitters, short-chain fatty acids, indoles, bile acids, choline metabolites, lactate and vitamins – play in the context of emotional behavior. The future of gut-brain axis research lies is moving away from association, towards the mechanisms underlying the relationship between the gut bacteria and depressive behavior. We propose that direct and indirect mechanisms exist through which gut microbial metabolites affect depressive behavior: these include (i) direct stimulation of central receptors, (ii) peripheral stimulation of neural, endocrine, and immune mediators, and (iii) epigenetic regulation of histone acetylation and DNA methylation. Elucidating these mechanisms is essential to expand our understanding of the etiology of depression, and to develop new strategies to harness the beneficial psychotropic effects of these molecules. Overall, the review highlights the potential for dietary interventions to represent such novel therapeutic strategies for major depressive disorder.

장과 중추 기능은 

숙주와 함께 진화하여 생체 변형 능력을 확장하고 

대사 산물을 통해 숙주의 생리적 과정과 상호 작용하는 생태계인 장내 미생물에 의해 

본질적으로 연결되어 있습니다. 

이 미생물총-장-뇌 축의 이상은 우울증의 병태 생리학에서 핵심적인 요소로 부상하면서 장내 미생물 대사 산물의 신경 활성 가능성을 이해하려는 연구로 이어지고 있습니다. 

이 리뷰에서는 

장내 미생물이 우울증에 기여할 수 있는 잠재력을 탐구하고 

미생물 유래 분자(신경전달물질, 단쇄 지방산, 인돌, 담즙산, 콜린 대사산물, 젖산염 및 비타민)가 

정서적 행동의 맥락에서 수행하는 역할에 중점을 둡니다. 

장-뇌 축 연구의 미래는 

연관성에서 벗어나 장내 세균과 우울한 행동 사이의 관계의 근본적인 메커니즘으로 나아가고 있습니다. 

우리는 장내 미생물 대사 산물이 

우울한 행동에 영향을 미치는 직간접적인 메커니즘이 존재한다고 제안합니다: 

(i) 중추 수용체의 직접 자극, 

(ii) 신경, 내분비 및 면역 매개체의 말초 자극, 

(iii) 히스톤 아세틸화 및 DNA 메틸화의 후성 유전학적 조절 등이 여기에 포함됩니다. 

이러한 메커니즘을 규명하는 것은 우울증의 원인에 대한 이해를 넓히고 이러한 분자의 유익한 향정신성 효과를 활용할 수 있는 새로운 전략을 개발하는 데 필수적입니다. 전반적으로 이 리뷰는 주요 우울 장애에 대한 새로운 치료 전략으로 식이 개입의 잠재력을 강조합니다.

Keywords: microbiome, indole, tryptophan, bile acids, lactate, vitamins, mental health

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THE GUT MICROBIOME CONTRIBUTES TO DEPRESSIVE BEHAVIOR

With an estimated three to four million different genes in the collective genomes of the gut microbiota [1] there is approximately 100 to 150 times more genetic information in the human microbiome than the human genome. Many of these genes encode proteins that perform metabolic functions and produce metabolites exclusive to the microbiome. The host encounters these metabolites in the gut, where they can exert local effects in the gastrointestinal (GI) environment or at the gut wall. Alternatively, these microbial metabolites can be absorbed, enter the systemic circulation and reach distant organs, including the brain. At these host sites, microbial metabolites can serve as ligands for host receptors with downstream effects on host gene expression‎ and function. In addition, these microbial metabolites can integrate into host metabolic pathways altering their activity (Figure 1).

장내 미생물 총 유전체에는 

약 300만~400만 개의 서로 다른 유전자가 있는 것으로 추정되며[1], 

인간 유전체보다 약 100~150배 많은 유전 정보가 장내 미생물 군집에 존재합니다. 

이러한 유전자 중 다수는 

대사 기능을 수행하는 단백질을 암호화하고 

마이크로바이옴 전용 대사산물을 생성합니다. 

숙주는 장에서 이러한 대사산물을 만나 

위장(GI) 환경이나 장 벽에서 

국소적인 효과를 발휘할 수 있습니다. 

또는 이러한 미생물 대사산물이 흡수되어 

전신 순환계로 들어가 

뇌를 포함한 먼 장기에 도달할 수도 있습니다. 

이러한 숙주 부위에서 미생물 대사산물은 숙주 수용체의 리간드로 작용하여 숙주 유전자 발현과 기능에 영향을 미칠 수 있습니다. 또한 이러한 미생물 대사산물은 숙주 대사 경로에 통합되어 활동을 변화시킬 수 있습니다(그림 1).

Figure 1

FIGURE 1: Bioactive molecules originating from microbial metabolism are thought to modulate emotional behavior through several mechanisms:

(1) Activation of afferent vagal nerve fibers.

(2) Stimulation of the mucosal immune system or of circulatory immune cells after translocation from the gut into the circulation.

(3) Absorption into the bloodstream, and biochemical interaction with a number of distal organs. In the brain, such metabolites may be able to activate receptors on neurons or glia, modulate neuronal excitability, and change expression‎ patterns by means of epigenetic mechanisms.

(1) 구심성 미주 신경 섬유의 활성화.

(2) 장에서 순환계로 전위된 후 점막 면역계 또는 순환계 면역 세포의 자극.

(3) 혈류로의 흡수 및 여러 원위 기관과의 생화학적 상호 작용. 

뇌에서 이러한 대사산물은 

뉴런이나 신경교세포의 수용체를 활성화하고, 

신경세포 흥분성을 조절하며, 

후성유전학적 메커니즘을 통해 발현 패턴을 변화시킬 수 있습니다.

Colonization of the human gut by the microbiota is an evolutionary-driven process that impacts host physiology, for example, by priming the immune system and aiding the breakdown of otherwise indigestible fibers, and also by driving brain development and shaping behavior [2]. It is now well established that a bidirectional communication network exists between the gut and the brain, termed the gut-brain axis [3], of which the microbiota and its metabolic output are a major component. Colonization of the gut by the microbiota and central nervous system (CNS) development have extensively overlapping critical developmental windows. As a result, early-life perturbations in the maturation of the microbiota can result in deficits in neurogenesis, axonal and dendritic growth and synaptogenesis, which can negatively impact on later mental health [4]. Indeed, compared to specific pathogen-free and conventional mice, germ-free mice exhibited an exaggerated hypothalamic pituitary adrenal (HPA) axis response to restraint stress, characterized by elevated plasma adrenocorticotropic hormone (ACTH) and corticosterone as well as reduced cortical and hippocampal expression‎ of brain-derived neurotrophic factor (BDNF) [5]. Fecal inoculation from specific pathogen-free donor mice reversed these stress-associated physiological alterations only when administered at early developmental stages. This suggests that early-life colonization by the gut microbiota is essential for the normal development of the HPA axis and of the neuroendocrine response to stress [5] and supports the notion that a limited, early critical window exists in which gut microbial stimulation shapes normal brain development [2].

미생물에 의한 장내 미생물 군집화는 

면역 체계를 활성화하고 

소화가 잘 안 되는 섬유질 분해를 돕고 

뇌 발달과 행동 형성을 촉진하는 등 

숙주 생리학에 영향을 미치는 진화론적 과정입니다[2]. 

장과 뇌 사이에 장-뇌 축[3]이라고 불리는 양방향 통신 네트워크가 존재하며, 

장내 미생물과 그 대사 산물이 주요 구성 요소라는 사실은 이제 잘 알려져 있습니다. 

장내 미생물 군집과 중추신경계(CNS) 발달은 

중요한 발달 시기가 광범위하게 겹칩니다. 

그 결과, 

미생물 군집의 성숙에 초기 교란이 발생하면 

신경 발생, 

축삭 및 수상돌기 성장, 

시냅스 형성에 결함이 생겨 

나중에 정신 건강에 부정적인 영향을 미칠 수 있습니다 [4]. 

실제로 특정 병원체가 없는 일반 마우스와 비교했을 때, 세균이 없는 마우스는 억제 스트레스에 대한 시상하부 뇌하수체 부신(HPA) 축 반응이 과장된 것으로 나타났는데, 이는 혈장 부신피질 자극 호르몬(ACTH)과 코르티코스테론의 상승과 뇌유래 신경 영양 인자(BDNF)의 피질 및 해마 발현 감소로 특징지어집니다 [5]. 특정 병원체가 없는 기증자 마우스의 분변 접종은 초기 발달 단계에 투여했을 때만 이러한 스트레스 관련 생리적 변화를 역전시켰습니다. 이는 장내 미생물에 의한 생후 초기 식민지화가 HPA 축의 정상적인 발달과 스트레스에 대한 신경내분비 반응에 필수적이며[5], 장내 미생물 자극이 정상적인 뇌 발달을 형성하는 제한적이고 초기 중요한 기간이 존재한다는 개념을 뒷받침합니다[2].

Major depressive disorder (MDD) has become the leading cause of disability globally and is associated with death and suicide, more often than any other mental or physical disorder. The symptomatology of MDD includes prolonged feelings of low mood, worthlessness or guilt, anhedonia, sleep and appetite disturbances, fatigue, slowed movements and speech, and suicidal thoughts [6]. In addition to CNS abnormalities, patients with depression also exhibit alterations in metabolic, immune and endocrine systems. There is growing evidence associating the gut microbiota in the pathophysiology of depression. Several taxonomic association studies in humans have observed differences in the fecal microbiota composition of MDD patients compared to healthy subjects [7–10]. These studies identified variation in the phyla Bacteroidetes, Proteobacteria, Actinobacteria and Firmicutes, and in the genera Enterobacteriaceae, Alistipes, Faecalibacterium, Bifidobacterium and Blautia, although contradicting results were found regarding the direction of the associations detected between disease and bacterial taxa. Valles-Colomer and colleagues [11] used a module-based analytical approach of fecal metagenomes to link microbiota neuroactive capacity with depressive symptoms. This study showed a positive association between quality of life indicators and the genera Faecalibacterium and Coprococcus, as well as a negative association between the abundance of Coprococcus spp. and Dialister with depression after controlling for antidepressant use. Psychological stress can change the composition of the gut microbiota [12], and in turn, microbiota abnormalities can influence emotional behavior [13]. Germ-free rodent studies have begun to interrogate the causative role of microbiome abnormalities in the etiology of depression. Alongside the appearance of anhedonia and anxiety-like behavior, the oral gavage of fecal microbiota from MDD patients to antibiotic-treated rats induced decreased gut microbiota richness and diversity and elevated plasma kynurenine and kynurenine/tryptophan ratio [14], highlighting the potential to transfer depressive-like behavioral and physiological traits via the microbiota.

Tryptophan metabolism along the serotonin (also known as 5-hydroxytryptamine or 5-HT), kynurenine and indole pathways can be influenced by the gut microbiota. The bacterial enzyme tryptophanase is responsible for the conversion of tryptophan into indole, which can give rise to a range of neuroactive signaling molecules. Additionally, tryptophan can be metabolized into 5-HT, via aromatic amino acid decarboxylase (AAAD) activity, or kynurenine by the enzymes tryptophan-2,3-dioxygenase (TDO) or the ubiquitous indoleamine-2,3-dioxygenase (IDO). Lipopolysaccharides (LPS), an inflammatory cell wall component from Gram negative bacteria, can induce the expression‎ of IDO, increasing the conversion of tryptophan to kynurenine (reflected in the kynurenine:tryptophan ratio). The reduction in Firmicutes and the subsequent decrease in short-chain fatty acid synthesis observed in MDD patients has been linked to increased inflammation [15], and cytokines are also known to promote tryptophan utilization for kynurenine synthesis via IDO activity. This pathway gives rise to the neurotoxic metabolite quinolinic acid, and reduces central serotonergic availability [16]. Much of the mechanistic evidence of the involvement of the gut microbiota in depression comes from research on germ-free or on microbiota-depleted animals. Germ-free rodent models show substantial behavioral and molecular abnormalities (Table 1), represented by reduced anxiety and changes in central levels of several neurotransmitters, both of which could be rescued following colonization with a conventional microbiota early in life [17, 18]. Depletion of the gut microbiota by antibiotic administration was also found to induce depressive-like behaviors in adult rats, as well as altered central 5-HT availability and other depression-related physiological changes [19].

주요우울장애(MDD)는 

전 세계적으로 장애의 주요 원인이 되고 있으며 

다른 어떤 정신적 또는 신체적 장애보다 사망 및 자살과 더 자주 연관되어 있습니다. 

주요 우울장애의 증상으로는 

장기간의 기분 저하, 무가치감 또는 죄책감, 무감동증, 수면 및 식욕 장애, 피로, 움직임 및 언어 둔화, 자살 충동 등이 있습니다[6]. 

우울증 환자는 

중추신경계 이상 외에도 

대사, 면역, 내분비계에도 변화가 나타납니다. 

장내 미생물이 우울증의 병태생리와 관련이 있다는 증거가 점점 늘어나고 있습니다. 

인간을 대상으로 한 여러 분류학적 연관성 연구에서 건강한 피험자와 비교하여 MDD 환자의 분변 미생물 구성에 차이가 있음을 관찰했습니다[7-10]. 

이러한 연구에서는 

박테로이데테스, 

프로테오박테리아, 

액티노박테리아 및 

펌미쿠테스 문과 장내 세균과, 

알리스티페스, 

페칼리박테리움, 

비피도박테리움 및 블라우티아 속의 변이를 확인했지만 

질병과 세균 분류군 간에 발견된 연관성의 방향에 대해서는 상반된 결과가 발견되었습니다. 

Valles-Colomer와 동료들[11]은 분변 메타게놈의 모듈 기반 분석 접근법을 사용하여 미생물군집의 신경 활성 능력과 우울 증상을 연결했습니다. 

이 연구에서는 

삶의 질 지표와 

페칼리박테리움 및 코프로코커스 속 사이에 긍정적인 연관성이 있는 것으로 나타났으며, 

항우울제 사용을 통제한 후 코프로코커스 속과 다이알리스터의 풍부함과 우울증 사이에 부정적인 연관성이 있는 것으로 나타났습니다. 

심리적 스트레스는 

장내 미생물총의 구성을 변화시킬 수 있으며[12], 

결과적으로 미생물총의 이상은 정서적 행동에 영향을 미칠 수 있습니다[13]. 

무균 설치류 연구를 통해 우울증의 원인에서 마이크로바이옴 이상이 어떤 역할을 하는지 규명하기 시작했습니다. 우울증 환자의 분변 미생물을 항생제 치료를 받은 쥐에게 경구 투여하면 무감동 및 불안과 유사한 행동과 함께 장내 미생물의 풍부도와 다양성이 감소하고 혈장 키누레닌과 키누레닌/트립토판 비율이 증가하여[14] 미생물을 통해 우울과 유사한 행동 및 생리적 특성이 전달될 가능성이 있음을 강조했습니다. 

세로토닌(5-하이드록시트립타민 또는 5-HT라고도 함), 

키누레닌 및 

인돌 경로에 따른 트립토판 대사는 

장내 미생물에 의해 영향을 받을 수 있습니다. 

박테리아 효소인 트립토파나아제는 

트립토판을 인돌로 전환하여 

다양한 신경 활성 신호 분자를 생성할 수 있습니다. 

또한 트립토판은 

방향족 아미노산 탈카르복실효소(AAAD) 활성을 통해 

5-HT로 대사되거나 

트립토판-2,3-다이옥시게나제(TDO) 또는 유비쿼터스 인돌아민-2,3-다이옥시게나제(IDO) 효소에 의해 

키누레닌으로 대사될 수 있습니다. 

그람 음성균의 염증성 세포벽 성분인 리포다당류(LPS)는 

IDO의 발현을 유도하여 

트립토판을 키누레닌으로 전환(키누레닌:트립토판 비율에 반영)을 증가시킬 수 있습니다. 

MDD 환자에서 관찰되는 

피르미쿠테스의 감소와 

그에 따른 단쇄 지방산 합성의 감소는 

염증 증가와 관련이 있으며[15], 

사이토카인은 

IDO 활성을 통해 키누레닌 합성을 위한 트립토판 활용을 촉진하는 것으로 알려져 있습니다. 

이 경로는 신경독성 대사산물인 퀴놀린산을 생성하고 

중추 세로토닌 가용성을 감소시킵니다[16]. 

장내 미생물이 우울증에 관여한다는 역학적 증거의 대부분은 세균이 없거나 미생물이 고갈된 동물에 대한 연구에서 나왔습니다. 무균 설치류 모델은 불안감 감소와 여러 신경전달물질의 중추 수준 변화로 대표되는 상당한 행동 및 분자적 이상을 보이며(표 1), 이는 모두 생애 초기에 기존 미생물 군집으로 회복될 수 있습니다[17, 18]. 

항생제 투여에 의한 장내 미생물의 고갈은 

성인 쥐에서 우울증과 유사한 행동을 유발하고

 중추 5-HT 가용성 및 기타 우울증 관련 생리적 변화를 변화시키는 것으로 밝혀졌습니다 [19].

TABLE 1.

Studies investigating the effect of a lack of microbiota on neurotransmitter systems.

ModelSpecies or strainBehavioral outcomesMolecular mechanismsReference

GF	Adult male BALB/c mice (7–9 weeks)	-	Biologically inactive and conjugated form of colonic norepinephrine and dopamine in GF mice (compared to the biologically active, free form in conventional mice); reduced intestinal norepinephrine and dopamine rescued by microbiota recolonisation	[45]
GF	Male Swiss Webster mice (8–10 weeks)	-	altered blood concentrations of indole derivatives (including ↑ tryptophan and ↓5-HT), phenyl derivatives (including ↑ tyrosine) and other metabolites in GF compared to conventional mice	[32]
GF	Male BALB/c mice (7 weeks)	-	Altered cerebral metabolome (including ↓ tryptophan and tyrosine, but ↑ dopamine and N-acetylaspartatic acid) of germ-free mice compared to Ex-GF mice, which were inoculated with suspension of feces from SPF mice; reduced GABA in faeces and blood (but not in brain) rescued by microbiota recolonisation	[46]
GF	Male and female Swiss Webster mice	↑ anxiety phenotype normalised by conventionalisation	↓ immune response and ↑ HPA axis reactivity in GF mice; ↓ BDNF expression‎ in hippocampus; ↑ hippocampal 5-HT and 5-HIAA in males only; ↑ plasma tryptophan availability and ↓ kynurenine:tryptophan ratio in males (restored by colonisation); ↑ hippocampal 5-HT and 5-HIAA not normalised by conventionalisation	[49]
GF	Male mice (8-10 week)	↓ anxiety-like behavior	↑norepinephrine, Dopamine, and 5-HT turnover in the Striatum; Altered Expression‎ of Synaptic Plasticity-Related Genes; Colonization of GF Mice Reduces Protein Expression‎ of Synaptophysin and PSD-95 in Striatum	[2]
GF	C57Bl/6J mice	-	↓ circulatory and faecal (colonic ECs) 5-HT in GF compared to SPF mice; colonisation of GF mice with SPF microbiota restores serotonergic abnormalities, elevates TPH1 expression‎ and decreases SLC6A4 expression‎.	[48]
GF	BALB/c mice	-	Altered intestinal concentration of several metabolites (including ↓ GABA in GF compared to colonised mice)	[53]
GF	Male Swiss Webster mice (12–14 weeks)	-	Altered levels of microbial metabolites in serum of GF compared to conventional mice, including ↓serum concentrations of dopamine and tyramine and of trans - 2-aminomethylcyclopropanecarboxylic acid, a cyclopropane analog of GABA	[52]

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5-HIAA: 5-Hydroxyindoleacetic Acid; 5-HT: 5-Hydroxytryptamine; BDNF: Brain-Derived Neurotrophic Factor; GABA: Gamma-Aminobutyric Acid; GF: Germ-Free; HPA: Hypothalamic-Pituitary-Adrenal; PSD-95: Postsynaptic Density Protein 95; SLC6A4: Serotonin Transporter; SPF: Specific Pathogen Free; TPH-1: Tryptophan Hydroxylase 1.

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PATHWAYS OF MICROBIOTA-GUT-BRAIN-COMMUNICATION

The gut microbiota and its metabolic products can affect central physiological and pathological processes through several proposed mechanisms. Neural communication between the gut and the brain is mainly mediated by intestinal afferent fibers of the vagus nerve. Vagal stimulation by the gut microbiota or its metabolites is relayed to the nucleus tractus solitarius, and then transmitted to the thalamus, hypothalamus, locus coeruleus, amygdala and periaqueductal grey [3]. Electrical stimulation of the vagus nerve by the gut microbiota can alter the concentrations of neurotransmitters like 5-HT, γ-aminobutyric acid (GABA) and glutamate in the brain of both rodents and humans [20]. Additionally, rodent studies have shown that the anxiety and depressive phenotype that is normally induced by an immune challenge can be prevented by vagotomy [21, 22], supporting the role played by the vagus nerve in stress reactivity and emotional regulation.

장내 미생물과 그 대사 산물은 

몇 가지 제안된 메커니즘을 통해 

중추 생리적 및 병리학적 과정에 영향을 미칠 수 있습니다. 

장과 뇌 사이의 신경 통신은 

주로 미주 신경의 장 구심성 섬유에 의해 매개됩니다. 

장내 미생물 또는 그 대사 산물에 의한 미주 자극은 

솔리타리우스 핵으로 전달된 다음 

시상, 시상하부, 코에룰루스, 편도체 및 시교차로로 전달됩니다 [3]. 

장내 미생물에 의한 미주신경의 전기 자극은 

설치류와 인간 모두의 뇌에서 

5-HT, 

γ- 아미노부티르산(GABA), 

글루타메이트와 같은 신경전달물질의 농도를 변화시킬 수 있습니다[20]. 

또한 설치류 연구에 따르면 일반적으로 면역 도전에 의해 유발되는 불안과 우울 표현형은 미주신경 절제술로 예방할 수 있으며[21, 22], 이는 스트레스 반응성과 감정 조절에서 미주신경의 역할을 뒷받침합니다.

The immune system represents a major component of gut-to-brain communication. While central immune cells and low levels of inflammatory mediators exert a variety of physiological roles in the brain (ranging from sleep to memory formation), sustained neuroinflammation has deleterious effects on brain function and has been associated with a variety of neuropsychiatric disorders [23]. The gut microbiota has important roles in shaping immune function throughout life. In early life, it directs normal development of central immune cells, like microglia and astrocytes [24]; in adulthood, it sets a chronic physiological state of low-grade inflammation [25], as the bacterial antigens present in the intestinal tract stimulate cytokine release by intestinal macrophages and T cells [26]. Peptidoglycans derived from bacterial cell walls have been measured in the brain, where they activate central pattern-recognition receptors to stimulate the innate immune system and alter behavior [27]. These observations are consistent with a role for immune molecules in the CNS independent of infection or immune stimulation, but actually a component of normal healthy brain function.

면역 체계는 

장과 뇌 사이의 의사소통의 주요 구성 요소입니다. 

중추 면역 세포와 낮은 수준의 염증 매개체는 

뇌에서 다양한 생리적 역할(수면에서 기억 형성까지)을 수행하지만, 

지속적인 신경 염증은 

뇌 기능에 해로운 영향을 미치며 다양한 신경 정신과 질환과 관련이 있습니다 [23]. 

장내 미생물은 

일생 동안 면역 기능을 형성하는 데 중요한 역할을 합니다. 

생애 초기에는 

미세아교세포 및 성상세포와 같은 중추 면역 세포의 정상적인 발달을 유도하고[24], 

성인기에는 장에 존재하는 박테리아 항원이 

장 대식세포와 

T 세포의 사이토카인 방출을 자극하여 

만성 생리적 염증 상태[25]를 형성합니다[26]. 

박테리아 세포벽에서 추출한 펩티도글리칸은

 뇌에서 측정되어 중추 패턴 인식 수용체를 활성화하여 

선천성 면역 체계를 자극하고 행동을 변화시킵니다[27]. 

이러한 관찰은 

감염이나 면역 자극과는 무관하지만 

실제로는 정상적인 건강한 뇌 기능의 구성 요소인 CNS에서 면역 분자의 역할과 일치합니다.

The gut microbiota is also central to brain function in the context of an immune challenge. LPS can trigger the release of the cytokine IL-18 [28]. Parenteral administration of LPS to healthy individuals induced immune system activation accompanied with mild depressive and cognitive symptoms [29]. Significantly, LPS translocation into the brain is suggested to be under the control of propionate, a gut microbial metabolite that modulates blood-brain barrier (BBB) permeability [30]. Pro-inflammatory cytokines in the GI tract can also modulate central stress circuitry by stimulating the vagus nerve and activating the HPA axis [31]. Stress and dietary patterns such as the Western diet can contribute to neuroinflammation by increasing the permeability of the intestinal wall, a pathological state referred to as “leaky gut”. This allows the translocation of bacteria and LPS from the intestinal lumen into the bloodstream and the CNS [25].

장내 미생물은 또한 

면역 도전의 맥락에서 뇌 기능의 중심입니다. 

LPS는 

사이토카인 IL-18의 방출을 유발할 수 있습니다[28]. 

건강한 사람에게 LPS를 비경구 투여하면 

경미한 우울증 및 인지 증상과 함께 면역계 활성화가 유도되었습니다 [29]. 

중요한 것은 뇌로의 LPS 전위는 

혈액뇌장벽(BBB) 투과성을 조절하는 장내 미생물 대사산물인 

프로피오네이트의 제어하에 있는 것으로 추정된다는 점입니다[30]. 

위장관 내 전 염증성 사이토카인은 

미주 신경을 자극하고 

HPA 축을 활성화하여 

중추 스트레스 회로를 조절할 수도 있습니다[31]. 

서구식 식단과 같은 스트레스와 식이 패턴은

장벽의 투과성을 증가시켜

신경 염증을 유발할 수 있으며,

이는 "새는 장 증후군"이라고 하는 병리학적인 상태입니다.

이로 인해 장 내강에서

혈류와 중추신경계로

박테리아와 LPS가 전이될 수 있습니다[25].

Finally, direct biochemical signaling can take place by means of bioactive molecules of bacterial origin. Extensive studies in germ-free and antibiotic-treated rodents have highlighted the diverse biochemical output of the microbiome. This diversity is a product of the chemically heterogeneous substrate entering the gut from both the diet and host secretions as well as from the expansive metabolic repertoire of the microbiome [32]. Metabolites produced in the gut by the bacterial fermentation of dietary components can be absorbed in the bloodstream and interact with enzymes and receptors expressed by the host, contributing to both physiological and pathological processes in the host [33]. To date, evidence suggests that microbiota-derived acetate can act remotely to influence neural function [34]. Neurotransmitters, short-chain fatty acids (SCFAs), bile acids, choline metabolites, lactate and vitamins are products of gut microbial metabolism that can directly or indirectly influence central processes and, when dysregulated, contribute to neuropathology [25]. This review will focus on the potential of these metabolite classes to alter biochemical processes underlying gut-to-brain communication, and describe the role played by these microbial metabolites in the pathophysiology of depression.

마지막으로, 

박테리아 유래의 생리활성 분자를 통해 

직접적인 생화학적 신호가 발생할 수 있습니다. 

무균 및 항생제 치료를 받은 설치류를 대상으로 한 광범위한 연구에서 마이크로바이옴의 다양한 생화학적 산출물이 강조되었습니다. 이러한 다양성은 마이크로바이옴의 광범위한 대사 레퍼토리뿐만 아니라 식이 및 숙주 분비물에서 장으로 유입되는 화학적으로 이질적인 기질의 산물입니다[32]. 

식이 성분의 박테리아 발효에 의해 

장에서 생성된 대사 산물은 

혈류로 흡수되어 

숙주가 발현하는 효소 및 수용체와 상호 작용하여 

숙주의 생리적 및 병리학적 과정에 기여할 수 있습니다 [33]. 

현재까지 미생물총 유래 아세테이트가 원격으로 작용하여 신경 기능에 영향을 미칠 수 있다는 증거가 제시되고 있습니다[34]. 

신경전달물질, 

단쇄지방산(SCFA), 

담즙산, 

콜린 대사산물, 

젖산염 및 

비타민은 

장내 미생물 대사의 산물로 중추 과정에 직간접적으로 영향을 미칠 수 있으며, 

조절 장애가 발생하면 신경 병리에 기여할 수 있습니다 [25]. 

이 리뷰에서는 이러한 대사산물이 장과 뇌 사이의 소통의 기초가 되는 생화학적 과정을 변화시킬 수 있는 가능성에 초점을 맞추고, 우울증의 병태생리에서 이러한 미생물 대사산물이 수행하는 역할을 설명합니다.

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NEUROACTIVE MICROBIAL METABOLITES AND THEIR ROLE IN DEPRESSION

Neurotransmitters

The majority of central neurotransmitters are also present in the GI tract, where they exert local effects ranging from modulating gut motility and secretion to cell signaling [35, 36]. Members of the gut microbiota can synthesize neurotransmitters: Lactobacilli and Bifidobacteria produce GABA [37–41]; Escherichia coli (E. coli) produce 5-HT and dopamine [42, 43]; Lactobacilli produce acetylcholine [44], and many more microbial taxa contribute to the synthesis and release of other molecules with neuroactive properties. In fact, gut microbiota absence is associated with significant reductions in intestinal levels of neurotransmitters like norepinephrine [45], 5-HT [32], and GABA [46]. While recolonization can re-establish normal neurotransmitter concentrations, it is not clear if this restoration of neurotransmission is due to bacterially derived products or due to stimulation of neurotransmitter producing host intestinal cells [47]. An example of the latter is 5-HT, whose intestinal concentrations are maintained by enterochromaffin cells, which express the enzyme tryptophan hydroxylase upon stimulation by gut metabolites such as SCFAs and secondary bile acids [48].

대부분의 중추 신경 전달 물질은 

위장관에도 존재하며, 

장 운동성 및 분비 조절부터 세포 신호 전달에 이르기까지 

다양한 국소 효과를 발휘합니다 [35, 36]. 

장내 미생물총의 구성원은 

신경전달물질을 합성할 수 있습니다: 

유산균과 비피도박테리아는 

GABA를 생성하고[37-41], 

대장균은 5-HT와 도파민을 생성하며[42, 43], 

락토바실리는 아세틸콜린을 생성하고[44], 

그 외에도 많은 미생물 분류군이 신경 활성 특성을 가진 다른 분자의 합성 및 방출에 기여하고 있습니다. 

실제로 장내 미생물의 부재는 

노르에피네프린[45], 

5-HT[32], 

GABA[46]와 같은 신경전달물질의 장내 수치가 현저히 감소하는 것과 관련이 있습니다. 

재식민화가 정상적인 신경전달물질 농도를 회복시킬 수 있지만, 이러한 신경전달물질의 회복이 박테리아 유래 물질 때문인지 아니면 신경전달물질을 생산하는 숙주 장 세포의 자극 때문인지는 명확하지 않습니다[47].

후자의 예로

5-HT는

장내 크로마핀 세포에 의해 장내 농도가 유지되는데,

이 세포는 SCFA 및 이차 담즙산과 같은 장 대사 산물에 의해 자극을 받으면

트립토판 하이드 록실 라제 효소를 발현합니다 [48].

It is now established that peripheral production of neurotransmitters by the gut microbiome may alter brain chemistry and influence behavior (Table 2). While there is no evidence that gut-derived neurotransmitters reach the brain, these compounds may influence CNS signaling by co-feeding of other commensal bacteria and modulation of local host gut physiology upon absorption into the bloodstream. For example, Clarke et al. [49] showed that male germ-free mice exhibit anxiety-like behaviors as well as altered neurotransmitter (5-HT and 5-hydroxyindole acetic acid (5-HIAA)) abundance in the hippocampus. These central alterations were accompanied by an elevation in plasma tryptophan concentrations, suggesting that the peripheral tryptophan metabolism is influenced by microbiota, that also influence CNS neurotransmitter systems. While abnormal anxiety behavior was normalized by conventionalization in adulthood, the neurochemical imbalances in male germ-free mice persisted, indicating the profound effects of the gut microbiota on the development of neurotransmission [49]. The concentrations of dopamine and norepinephrine were also increased in the brains of germ-free mice in a separate study [17]. Additionally, a study chronically administering L. rhamnosus to mice reported changes in GABAA and GABAB receptor expression‎ as well as in the levels of brain activity, accompanied by a reduction in anxiety and depression-like symptoms [50]. Similarly, the GABA-producing L. brevis FPA3709 had an antidepressant effect when administered to rats [51]. Lower circulating concentrations of 5-HT [32, 48], dopamine [52] and GABA [53] have been observed in germ-free mice. This finding suggests that the gut microbiota may modulate neurotransmission via the bloodstream. Although enhancing 5-HT production in the gut does not result in an increase in central concentrations [47], central concentrations of 5-HT can be enhanced by increasing the concentrations of its precursor tryptophan in the GI tract [16, 54]. These findings have an important relevance in the context of depression, as they demonstrate the possibility of modulating central serotonergic neurotransmission through non-invasive interventions that target the gut microbiome.

장내 미생물에 의한 신경전달물질의 말초 생산이 

뇌 화학을 변화시키고 

행동에 영향을 미칠 수 있다는 사실이 밝혀졌습니다(표 2). 

장에서 유래한 신경전달물질이 뇌에 도달한다는 증거는 없지만, 

이러한 화합물은 다른 공생 박테리아의 공생과 혈류 흡수 시 

국소 숙주 장 생리학의 조절을 통해

 CNS 신호에 영향을 미칠 수 있습니다. 

예를 들어, 클라크 등[49]은 세균이 없는 수컷 마우스가 해마에서 신경전달물질(5-HT 및 5-하이드록시인돌 아세트산(5-HIAA))의 풍부함뿐만 아니라 불안과 유사한 행동을 보인다는 것을 보여주었습니다. 이러한 중추 변화는 혈장 트립토판 농도의 상승을 동반했으며, 이는 말초 트립토판 대사가 미생물의 영향을 받아 중추 신경 전달 물질 시스템에도 영향을 미친다는 것을 시사합니다. 

비정상적인 불안 행동은 성인이 되어 정상화되었지만, 수컷 무균 생쥐의 신경 화학적 불균형은 지속되어 장내 미생물이 신경 전달 발달에 미치는 중대한 영향을 나타냅니다 [49]. 별도의 연구에서 무균 생쥐의 뇌에서 도파민과 노르에피네프린의 농도도 증가했습니다[17]. 또한, 쥐에게 L. 람노수스를 만성적으로 투여한 연구에서는 불안 및 우울증 유사 증상의 감소와 함께 뇌 활동 수준뿐만 아니라 GABAA 및 GABAB 수용체 발현의 변화가 보고되었습니다 [50]. 마찬가지로, GABA를 생성하는 L. 브레비스 FPA3709를 쥐에게 투여했을 때 항우울 효과가 나타났습니다 [51]. 무균 마우스에서 5-HT [32, 48], 도파민 [52] 및 GABA [53]의 순환 농도가 낮아지는 것이 관찰되었습니다. 이 발견은 장내 미생물이 혈류를 통한 신경 전달을 조절할 수 있음을 시사합니다. 장에서 5-HT 생산을 강화한다고 해서 중추 농도가 증가하지는 않지만[47], 위장관 내 전구체 트립토판의 농도를 증가시킴으로써 5-HT의 중추 농도를 높일 수 있습니다[16, 54]. 이러한 연구 결과는 장내 미생물을 표적으로 하는 비침습적 개입을 통해 중추 세로토닌 신경전달을 조절할 수 있다는 가능성을 보여 주므로 우울증과 관련하여 중요한 의미를 갖습니다.

TABLE 2.

Studies investigating the effects of treatment with microbial cultures on neurotransmission and behavior.

TreatmentSpecies or strainBehavioral outcomesMolecular mechanismsReference

L. rhamnosus (109 cfu daily for 28 days)	Adult male BALB/c mice (10–11 weeks)	↓ anxiety and depressive-like behavior in OFT, SIH, EPM, fear conditioning (contextual and cued), and FST after L. rhamnosus chronic adnimistration; vagotomy prevented the anxiolytic and antidepressant effects of L. rhamnosus	Changes in expression‎ of GABAAα2 and GABAB1b mRNA after L. rhamnosus chronic administration; vagotomy alone was sufficient to increase GABAAα2 mRNA in the hippocampus but prevented further changes induced by L. rhamnosus	[55]
B. infantis (daily for 14 days)	Sprague-Dawley rats	no effect on depressive-like behavior	↓ inflammatory markers (IFN-γ, TNF-α and IL-6 cytokines); ↑ plasma tryptophan and kynurenic acid; ↓concentrations of 5-HIAA (frontal cortex) and DOPAC (amygdaloid cortex)	[58]
L. rhamnosus (1 × 109 cfu daily for 4 weeks)	male BALB/c mice	↓ in anxiety and depression-related behaviors	↑ glutamate + glutamine and ↑ total N-acetyl aspartate + N-acetyl aspartyl glutamic acid at 2 weeks; ↑ GABA at 4 weeks	[50]
L. brevis FPA 3709 (48-h fermented black soybean milk at a dosage of 35 mg/kg b.w. including 2.5 mg GABA/kg b.w. for 28 days)	Male Sprague-Dawley rats	↓ in depressive behavior in FST comparable to the effect of fluoxetine	-	[51]

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5-HIAA: 5-Hydroxyindoleacetic Acid; cfu: Colony-Forming Unit; DOPAC: 3,4-Dihydroxyphenylacetic Acid; FST: Forced Swim Test; EPM: Elevated Plus Maze; GABA: Gamma-Aminobutyric Acid; IFN-γ: Interferon Gamma; IL-6: Interleukin-6; OFT; Open Field Test; SIH: Stress-Induced Hyperthermia; TNF-α: Tumor Necrosis Factor Alpha.

Microbial metabolites can also have an impact on central neurotransmission by activating afferent nerve fibers. The involvement of the vagus nerve in gut-brain communication was demonstrated by Bravo et al. [55]. This work showed that administration of probiotics like L. rhamnosus had anxiolytic and antidepressant effects and induced significant changes in GABA receptor expression‎ in the brain of normal, but not vagotomized, mice [55]. Neurotransmitters produced in the gut may also influence brain function through the modulation of the immune system. There have been reports of 5-HT activating cells of the immune system [56], and of GABA dampening intestinal inflammation [57]. Upon chronic administration of the probiotic B. infantis, naïve rats displayed an attenuation of inflammatory markers such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) [58]. Since a concomitant increase in circulating tryptophan and kynurenic acid and decrease in central 5-HIAA and 3,4-dihydroxyphenylacetic acid (DOPAC) were described, the dampening of the inflammatory response may be ascribed to a change in neurotransmitter production and availability [58]. Alternatively, neurotransmitters produced by the gut microbiota can inhibit cytokine production through local stimulation of the vagus nerve [59].

미생물 대사 산물은 

구심성 신경 섬유를 활성화하여 

중추 신경 전달에도 영향을 미칠 수 있습니다. 

장과 뇌의 소통에 미주 신경이 관여한다는 사실은 브라보 등[55]에 의해 입증되었습니다. 이 연구에 따르면 L. 람노수스와 같은 프로바이오틱스를 투여하면 불안 완화 및 항우울 효과가 있으며, 미주신경이 없는 정상 쥐의 뇌에서 GABA 수용체 발현에 상당한 변화를 유도하는 것으로 나타났습니다[55].

장에서 생성되는 신경전달물질은

면역 체계의 조절을 통해 뇌 기능에도 영향을 미칠 수 있습니다.

5-HT가

면역계의 세포를 활성화하고[56],

GABA가

장내 염증을 완화한다는 보고가 있습니다[57].

프로바이오틱스 B. 인판티스를 만성적으로 투여한 결과, 순진한 쥐에서 인터페론-γ(IFN-γ), 종양괴사인자-α(TNF-α), 인터루킨-6(IL-6)와 같은 염증 마커가 감소하는 것으로 나타났습니다 [58]. 순환 트립토판과 키누레닉산의 수반되는 증가와 중추 5-HIAA 및 3,4-디하이드록시페닐아세트산(DOPAC)의 감소가 설명되었으므로 염증 반응의 감쇠는 신경전달물질 생산 및 가용성의 변화로 인한 것일 수 있습니다[58].

또는

장내 미생물에 의해 생성된 신경전달물질이

미주 신경의 국소 자극을 통해

사이토카인 생성을 억제할 수 있습니다 [59].

These studies suggest that neurotransmitters produced, either directly or indirectly, by gut bacteria may influence emotional behavior by binding specific receptors in the CNS, or peripheral receptors on neural or immune cells. A wider range of bacterially-derived, bioactive, transmitter-like molecules may exist whose effects on depressive symptoms have not been investigated to the same extent as classic neurotransmitters. These molecules include histamine, gasotransmitters (e.g. nitric oxide, ammonia), neuropeptides, endocannabinoids, steroids [60], and it is likely that more will be identified in the future. This communication between bacterial and host metabolism of neurotransmitters is bidirectional in nature: in addition to synthesizing neurotransmitters that are able to alter host physiology, gut microbes can also respond to neurotransmitters produced by the host, which influence bacterial growth and development [61].

이러한 연구는 

장내 세균이 직간접적으로 생산하는 신경전달물질이 

중추신경계의 특정 수용체 또는 

신경 또는 면역 세포의 말초 수용체와 결합하여 

정서적 행동에 영향을 미칠 수 있음을 시사합니다. 

우울증 증상에 미치는 영향이 기존의 신경전달물질과 같은 정도로 조사되지 않은 더 광범위한 박테리아 유래의 생리활성, 전달물질 유사 분자가 존재할 수 있습니다. 

이러한 분자에는 

히스타민, 

가스 전달 물질(예: 산화질소, 암모니아), 

신경 펩타이드, 

엔도카나비노이드, 

스테로이드[60]가 포함되며, 

앞으로 더 많은 분자가 밝혀질 것으로 예상됩니다. 

박테리아와 숙주의 신경전달물질 대사는 

본질적으로 양방향으로 이루어지며, 

장내 미생물은 

숙주의 생리를 변화시킬 수 있는 신경전달물질을 합성하는 것 외에도 

숙주가 생성하는 신경전달물질에 반응하여 

박테리아의 성장과 발달에 영향을 줄 수 있습니다[61].

SCFAs

SCFAs are small organic compounds produced in the cecum and colon by anaerobic fermentation of predominantly indigestible dietary carbohydrates that cross-feed other bacteria and are readily absorbed in the large bowel [62]. SCFAs are involved in digestive, immune and central function, although different accounts on their impact on behavior exist. Administration of the three most abundant SCFAs (acetate, butyrate and propionate) was shown to alleviate symptoms of depression in mice [63]. In support of their involvement with the etiology of depression, a depletion of butyrate, acetate and propionate was reported in MDD patients [8, 10, 64, 65], and a high abundance of butyrate-producing bacteria, like Faecalibacterium and Coprococcus spp., was detected in subjects with higher quality of life indicators [11]. The genera Faecalibacterium and Coprococcus are Gram-positive, anaerobic bacteria which ferment dietary fibers to produce SCFAs. Faecalibacteria are one of the most abundant gut microbial genera, with important immunological functions and clinical relevance for a variety of diseases, including MDD [8].

SCFAs are able to bind and activate the G protein-coupled receptors GPR43 (free fatty acid receptor 2 (FFAR2)) and GPR41 (FFAR3), as well as the less common CPR164 and GPR109a (also known as OR51E1 and HCAR2 respectively) [66]. These receptors are ubiquitously expressed by several organs in the body, including enteroendocrine cells, adipocytes, immune cells and neurons [66], suggesting that SCFAs may alter behavior by direct stimulation of neural pathways, or through the indirect central effect of neuroendocrine and immune activation.

SCFA는 

주로 소화가 잘 되지 않는 식이 탄수화물이 

혐기성 발효를 통해 맹장과 결장에서 생성되는 작은 유기 화합물로, 

다른 박테리아의 먹이가 되며 대장에서 쉽게 흡수됩니다[62]. 

SCFA는 

소화, 면역 및 중추 기능에 관여하지만, 

행동에 미치는 영향에 대한 다양한 설명이 존재합니다. 

가장 풍부한 세 가지 

SCFA(아세테이트, 부티레이트, 프로피오네이트)를 투여하면 

생쥐의 우울증 증상이 완화되는 것으로 나타났습니다 [63]. 

우울증의 원인과 관련이 있다는 것을 뒷받침하는 연구 결과로는 

MDD 환자에서 

부티레이트, 아세테이트 및 프로피오네이트의 고갈이 보고되었으며[8, 10, 64, 65], 

삶의 질 지표가 높은 대상자에서 

Faecalibacterium 및 Coprococcus spp.와 같은 부티레이트 생성 박테리아가 많이 검출되었습니다[11]. 

페칼리박테리움과 코프로코커스 속은 

그람 양성 혐기성 박테리아로 

식이 섬유를 발효시켜 SCFA를 생성합니다. 

페이칼리박테리아는 

가장 풍부한 장내 미생물 속 중 하나로, 

면역학적 기능이 중요하고 

MDD를 비롯한 다양한 질병과 임상적 관련성이 있습니다[8].

SCFA는 

G 단백질 결합 수용체 GPR43(유리 지방산 수용체 2(FFAR2)) 및

 GPR41(FFAR3)뿐만 아니라 

덜 일반적인 CPR164 및 GPR109a(각각 OR51E1 및 HCAR2라고도 함) [66]와 결합하고 

활성화할 수 있습니다. 

이러한 수용체는 

장내 내분비 세포, 

지방 세포, 

면역 세포 및 뉴런을 포함한 신체의 여러 기관에서 편재적으로 발현되며[66], 

이는 SCFA가 신경 경로의 직접적인 자극 또는 

신경 내분비 및 면역 활성화의 간접적인 중추 효과를 통해 행동을 변화시킬 수 있음을 시사합니다.

Locally, SCFAs promote gut health by modulating energy regulation, glucose metabolism and lipid homeostasis [67] and regulate intestinal barrier integrity by enhancing the expression‎ of tight junctions (particularly butyrate, see [68]). By binding to FFAR2, SCFAs control feeding behavior by stimulating the production of the anorexigenic hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) by enteroendocrine cells [69–71], and of leptin by adipocytes [72]. As previously stated, SCFAs also contribute to the synthesis and release of peripheral neurotransmitters (like 5-HT and acetylcholine) by enterochromaffin cells, in a process that is thought to be mediated by OR51E1 [73], and norepinephrine by sympathetic neurons, via stimulation of FFAR2 and FFAR3 [74]. Recent work has demonstrated the presence of FFAR3 in the mouse vagal ganglia [75], suggesting a role for SCFAs in establishing visceral reflexes. The ability of SCFAs to activate vagal fibers and induce activity in the hypothalamus has been implicated as the neural basis of their central anorexigenic effect [76]. In addition to their local action in the gut and in the peripheral nervous system, SCFAs can act directly on central receptors due to their ability to diffuse passively or actively (via monocarboxylate transporters) across the BBB [77, 78]. SCFAs like acetate can directly modulate appetite by binding to and activating receptors in the hypothalamus [34]. Interestingly, appetite suppression by propionate involves the attenuation of neural activity in regions of the brain reward system (i.e. caudate and nucleus accumbens) [79], a circuitry that is also dysfunctional in patients with depression [80]. Since no change in circulatory concentrations of PYY or GLP-1 were observed, it is likely that signaling via the vagus nerve or central receptors is responsible for the central effects of propionate. In addition, in vitro studies show both propionate and butyrate, but not acetate, can modulate the permeability of the BBB, protecting against the increased permeability caused by LPS [30].

국소적으로 SCFA는 

에너지 조절, 

포도당 대사 및 지질 항상성을 조절하여 

장 건강을 증진하고[67], 

긴밀한 접합부(특히 부티레이트, [68] 참조)의 발현을 강화하여 

장 장벽의 완전성을 조절합니다. 

SCFA는 

FFAR2에 결합하여 

장내 내분비 세포에 의한 식욕 자극 호르몬인 

글루카곤 유사 펩타이드-1(GLP-1)과 

펩타이드 YY(PYY)의 생성을 자극하고[69-71], 

지방 세포에 의한 렙틴의 생성을 촉진함으로써 

섭식 행동을 조절합니다[72]. 

앞서 언급한 바와 같이, 

SCFA는 

또한 장내 크로마핀 세포에 의한 

말초 신경전달물질(예: 5-HT 및 아세틸콜린)의 합성 및 방출에 기여하며, 

이 과정에서 OR51E1[73]과 교감 신경세포에 의한 노르에피네프린이 

FFAR2 및 FFAR3의 자극을 통해 매개하는 것으로 생각되는 과정[74]을 거치게 됩니다. 

최근 연구에 따르면 

마우스 미주신경절에 FFAR3가 존재한다는 사실이 입증되어[75] 

내장 반사를 확립하는 데 있어 

SCFA의 역할을 시사합니다. 

SCFA가 

미주 섬유를 활성화하고 

시상하부의 활동을 유도하는 능력은 

중추적 식욕 억제 효과의 신경학적 근거로 여겨져 왔습니다 [76]. 

장과 말초 신경계에서 국소적으로 작용하는 것 외에도 

SCFA는 

BBB를 통해 수동적 또는 능동적으로(모노카복실레이트 수송체를 통해) 확산하는 능력으로 인해 

중추 수용체에 직접 작용할 수 있습니다 [77, 78]. 

아세테이트와 같은 SCFA는 

시상하부의 수용체에 결합하고 활성화하여 

식욕을 직접적으로 조절할 수 있습니다 [34]. 

흥미롭게도 

프로피오네이트에 의한 식욕 억제는 

뇌 보상 시스템 영역(즉, 꼬리핵과 핵핵)의 신경 활동 약화를 수반하며[79], 

이는 우울증 환자에서도 기능 장애를 보이는 회로입니다[80]. 

PYY 또는 GLP-1의 순환 농도에는 변화가 관찰되지 않았으므로 미주 신경 또는 중추 수용체를 통한 신호 전달이 프로피오네이트의 중추 효과를 담당하는 것으로 보입니다. 

또한, 시험관 내 연구에 따르면 

프로피오네이트와 부티레이트는 

아세테이트가 아닌 BBB의 투과성을 조절하여 

LPS로 인한 투과성 증가로부터 보호할 수 있습니다[30].

Binding of SCFAs to FFAR2, FFAR3, GPR109a and Olfr78 receptors expressed by immune cells contributes to the development and function of the immune system [81]. For example, microglia abnormalities in germ-free mice can be reversed by SCFA administration in a FFAR2-dependent manner [82]. The observation that SCFAs generally dampen inflammation [83, 84] suggests that the antidepressant effects of SCFAs may be partly accounted for by their anti-inflammatory properties. However, while butyrate was shown to suppress neuroinflammation by acting on microglial GPR109a receptors [68], propionic acid was shown to activate microglia and induce reactive astrogliosis in rats [85] and to promote immune cell recruitment in a FFAR3-mediated pathway [86]. These observations suggest a complex relationship between SCFAs and immune function. Moreover, while central butyrate promotes neurogenesis and angiogenesis [87, 88] and contributes to tight junction expression‎ and BBB structural integrity [68], intraventricular infusions of propionate contributed to mitochondrial dysfunction and oxidative stress by inducing lipid peroxidation, protein carbonylation and metabolic alterations in the rat brain [85, 89, 90]. However, it must be noted that many of these preclinical studies used supraphysiological doses of propionate and that, while intraventricular injections elicited a strong effect on the brain, such changes do not occur if SCFAs were administered peripherally.

SCFAs are strong epigenetic modulators that can control the accessibility of genetic material for DNA methylation and inhibition of histone deacetylation. A rodent study revealed the DNA methylation properties of sodium butyrate, the salt form of butyric acid [91]. This mechanism is dependent on ten-eleven translocation (TET) proteins, which catalyze the hydroxylation of cytosine residue (5mC) into 5-hydroxymethylcytosine (5hmC). 5hmC can then mediate active DNA demethylation. While depressed mice exhibited low levels of the TET methylcytosine dioxygenase 1 (TET1), mice treated with sodium butyrate showed a normalization in 5-hydroxymethylation levels by TET1, resulting in BDNF gene overexpression‎ [91]. Depression is often characterized by altered histone deacetylase (HDAC) activity, and several studies have demonstrated the epigenetic potential of different antidepressant medications [92]. Butyrate has been identified as a HDAC inhibitor for HDAC1, HDAC2 and HDAC7 [93], and its systemic administration induced histone acetylation in the hippocampus and frontal cortex in mice [94]. The beneficial effect of sodium butyrate on mood was shown in rodent models of depression either alone [95–97] or in conjunction with antidepressant drugs [94, 98]. For example, repeated injections of sodium butyrate reversed the LPS-induced activation of microglia and depressed mood in mice [99]. This antidepressant effect was mediated by the acetylation of hippocampal histones H3 and H4, which reduced the expression‎ of Iba1, a marker of microglia activation [99]. Alternatively, Sun et al. [100] found that the beneficial effects of sodium butyrate on depressive behavior were mediated by an increase in 5-HT concentrations, reversal of hippocampal neuronal abnormalities, increased BDNF expression‎, and an upregulation of tight junction expression‎ at the BBB [100]. In line with these findings, sodium butyrate was reported to promote the expression‎ of dopamine, adrenaline, and other neurotransmitter genes in a rat pheochromocytoma cell line [101]. Other investigations demonstrated that further effects of HDAC inhibition by butyrate included a reduction in neuroinflammation through modulation of microglia activation [102] and an enhancement in N-methyl-D-aspartate (NMDA) receptor activity [103].

면역 세포에 의해 발현되는 

FFAR2, FFAR3, GPR109a 및 Olfr78 수용체에 대한 SCFA의 결합은 

면역 체계의 발달과 기능에 기여합니다 [81]. 

예를 들어, 무균 마우스의 미세아교세포 이상은 FFAR2에 의존적인 방식으로 SCFA를 투여함으로써 역전될 수 있습니다 [82]. 

SCFA가 일반적으로 염증을 완화한다는 관찰 결과[83, 84]는 

SCFA의 항우울 효과가 부분적으로 

항염증 특성에 의해 설명될 수 있음을 시사합니다. 

그러나 

부티레이트는 

미세아교세포 GPR109a 수용체에 작용하여 

신경 염증을 억제하는 것으로 나타난 반면[68], 

프로피온산은 미세아교세포를 활성화하고 

쥐의 반응성 성상교세포증[85]을 유도하고 

FFAR3 매개 경로에서 면역 세포 모집을 촉진하는 것으로 나타났습니다[86]. 

이러한 관찰 결과는 SCFA와 면역 기능 사이의 복잡한 관계를 시사합니다. 

또한, 중추 부티레이트는 

신경 생성과 혈관 생성을 촉진하고[87, 88] 

타이트 접합 발현과 

BBB 구조적 완전성에 기여하는 반면[68], 

뇌실 내 프로피오네이트 주입은 쥐 뇌에서 지질 과산화, 단백질 탄산화 및 대사 변화를 유도하여 미토콘드리아 기능 장애와 산화 스트레스에 기여했습니다[85, 89, 90]. 

그러나 이러한 전임상 연구의 대부분은 생리학적 용량을 초과하는 프로피오네이트 용량을 사용했으며 뇌실 내 주사가 뇌에 강력한 영향을 미치는 반면, SCFA를 말초로 투여한 경우에는 이러한 변화가 발생하지 않는다는 점에 유의해야 합니다.

SCFA는 

DNA 메틸화 및 히스톤 탈아세틸화 억제를 위한 

유전 물질의 접근성을 제어할 수 있는 

강력한 후성유전학적 조절제입니다. 

설치류를 대상으로 한 연구에서 부티르산의 염 형태인 부티레이트 나트륨의 DNA 메틸화 특성이 밝혀졌습니다[91]. 이 메커니즘은 시토신 잔류물(5mC)을 5-하이드록시메틸시토신(5hmC)으로 하이드 록실화하는 것을 촉매하는 10-11번 전위(TET) 단백질에 의존합니다. 그런 다음 5hmC는 활성 DNA 탈메틸화를 매개할 수 있습니다. 우울한 마우스는 TET 메틸시토신 디옥시게나제 1(TET1)의 수치가 낮았지만, 부티레이트 나트륨으로 치료한 마우스는 TET1에 의한 5-하이드록시메틸화 수준이 정상화되어 BDNF 유전자가 과발현되는 것으로 나타났습니다[91]. 우울증은 종종 히스톤 탈아세틸화 효소(HDAC) 활성의 변화를 특징으로 하며, 여러 연구에서 다양한 항우울제의 후성유전학적 잠재력이 입증되었습니다 [92]. 

부티레이트는 

HDAC1, HDAC2 및 HDAC7에 대한 HDAC 억제제로 확인되었으며 [93], 

전신 투여 시 생쥐의 해마와 전두엽 피질에서 히스톤 아세틸화를 유도했습니다 [94]. 

부티레이트 나트륨이 기분에 미치는 유익한 효과는 설치류 우울증 모델에서 단독으로 [95-97] 또는 항우울제와 함께 [94, 98] 투여했을 때 나타났습니다. 예를 들어, 부티레이트 나트륨을 반복적으로 주사하면 쥐에서 LPS에 의한 미세아교세포의 활성화와 우울한 기분이 역전되었습니다 [99]. 이 항우울 효과는 해마 히스톤 H3 및 H4의 아세틸화에 의해 매개되었으며, 이는 미세아교세포 활성화의 마커인 Iba1의 발현을 감소시켰습니다 [99]. 또는 Sun 등[100]은 부티레이트 나트륨이 우울 행동에 미치는 유익한 효과는 5-HT 농도의 증가, 해마 신경세포 이상 반전, BDNF 발현 증가, BBB에서의 긴밀한 접합부 발현의 상향 조절에 의해 매개된다는 사실을 발견했습니다 [100]. 이러한 연구 결과에 따라 부티레이트 나트륨은 쥐 갈색세포종 세포주에서 도파민, 아드레날린 및 기타 신경전달물질 유전자의 발현을 촉진하는 것으로 보고되었습니다 [101]. 

다른 연구에서는 

부티레이트에 의한 HDAC 억제의 추가 효과로 

미세아교세포 활성화 조절을 통한 

신경염증 감소 [102] 및 

N-메틸-D-아스파르트산염(NMDA) 수용체 활성 향상 [103]이 입증되었습니다.

The SCFA propionate also acts as a HDAC inhibitor [104], and intrarectal administration of sodium propionate was shown to improve despair behavior in rats [105]. The antidepressant effect of propionate was accompanied by an increase in norepinephrine, dopamine, tryptophan, 5-HIAA and 3-hydroxyanthranilic acid (3-HAA) in the prefrontal cortex, although no change was detected in 5-HT and 3-hydroxykynurenine (3-HK). The known ability of propionate (shared with butyrate) to promote dopamine and norepinephrine synthesis by enhancing the transcription of the tyrosine hydroxylase gene [101], may be the mechanism underlying these molecular and behavioral effects. Both butyrate and propionate may also contribute to dopaminergic function by inhibiting the expression‎ of dopamine-β-hydroxylase, which catalyzes the conversion of dopamine into norepinephrine. Thus, the opposite effects of SCFAs on behavior may be explained by their action via independent mechanisms: for example, Li et al. [105] found that while butyrate modulated the expression‎ of 5-HT (with slow-onset but long-term antidepressant action), propionate altered the expression‎ of norepinephrine (with fast-acting, but short-term antidepressant action). However, propionate is also able to modulate serotonergic function by increasing the expression‎ of tryptophan hydroxylase (TPH) [101], responsible for the conversion of tryptophan to 5-HT. This finding is significant for unveiling the link between neuroinflammation and neurotransmitter production, as an increased TPH turnover induces an accumulation of kynurenine and neurotoxic metabolites like 3-HK [105]. Since altered tryptophan–kynurenine metabolism is characteristic of depression [106], this observation suggests that serotonergic function may be linked to anti-inflammatory mechanisms. Indeed, oral administration of propionate was shown to result in a decrease in the neurotransmitters GABA, 5-HT, and dopamine, as well as in a range of biomolecular alterations which included increased oxidative stress (indicated by lipid peroxidation), altered energy metabolism, and higher pro-inflammatory markers like IL-6, TNF-α, IFN-γ, heat shock protein 70 and caspase 3 [107]. Several additional studies suggested that modulation of mood by SCFAs can occur via mechanisms involving the immune system, but the findings are contradictory. While butyrate has established anti-inflammatory effects including the inhibition of pro-inflammatory gene expression‎ [108–110], propionate has been reported to have both anti- [111] and pro-inflammatory properties [112–114].

SCFA 프로피오네이트는 

또한 HDAC 억제제로도 작용하며[104], 

프로피오네이트 나트륨의 직장 내 투여는 쥐의 절망 행동을 개선하는 것으로 나타났습니다 [105]. 

프로피오네이트의 항우울 효과는 

전전두엽 피질에서 

노르에피네프린, 도파민, 트립토판, 5-HIAA 및 3-하이드록시안트라닐산(3-HAA)의 증가를 동반했지만 

5-HT와 3-하이드록시키누레닌(3-HK)에서는 변화가 발견되지 않았습니다. 

프로피오네이트(부티레이트와 공유)가 

티로신 하이드 록실 라제 유전자의 전사를 강화하여 

도파민 및 노르에피네프린 합성을 촉진하는 것으로 알려진 능력[101]이 

이러한 분자 및 행동 효과의 기저에 있는 메커니즘일 수 있습니다. 

부티레이트와 프로피오네이트는 

또한 도파민의 노르에피네프린 전환을 촉매하는 

도파민-β-하이드록실라제의 발현을 억제하여 

도파민 기능에 기여할 수 있습니다. 

예를 들어, Li 등[105]은 

부티레이트가 5-HT의 발현을 조절하는 반면(느리게 시작되지만 장기적인 항우울 작용), 

프로피오네이트는 

노르에피네프린의 발현을 변화시키는(빠르게 작용하지만 단기간의 항우울 작용) 

독립적인 메커니즘을 통해 행동에 대한 SCFA의 반대 효과를 설명할 수 있다는 사실을 발견했습니다. 

그러나 프로피오네이트는 또한 

트립토판을 5-HT로 전환하는 트립토판 하이드 록실 라제 (TPH) [101]의 발현을 증가시켜 

세로토닌 기능을 조절할 수 있습니다. 

이 발견은 

신경염증과 신경전달물질 생성 사이의 연관성을 밝히는 데 중요한데, 

TPH 회전율 증가는 

키누레닌과 3-HK 같은 신경독성 대사물질의 축적을 유도하기 때문입니다 [105]. 

트립토판-키누레닌 대사의 변화는 

우울증의 특징이므로[106], 

이 관찰은 세로토닌 기능이 항염증 메커니즘과 관련이 있을 수 있음을 시사합니다. 

실제로 

프로피오네이트의 경구 투여는 

신경전달물질인 

GABA,

 5-HT, 

도파민의 감소뿐만 아니라 

산화 스트레스 증가(지질 과산화로 표시됨), 

에너지 대사 변화, 

IL-6, TNF-α, IFN-γ, 열충격 단백질 70 및 카스파제 3 [107] 같은 

전염증 마커 증가를 포함한 다양한 생체 분자 변화를 초래하는 것으로 나타났습니다. 

여러 추가 연구에 따르면 SCFA에 의한 기분 조절은 면역 체계와 관련된 메커니즘을 통해 발생할 수 있지만, 그 결과는 모순적입니다. 부티레이트는 전 염증성 유전자 발현 억제를 포함한 항염증 효과가 입증된 반면[108-110], 프로피오네이트는 항[111] 및 전 염증성[112-114] 특성을 모두 가지고 있는 것으로 보고되었습니다.

Despite this evidence (Table 3), results supporting the antidepressant potential of SCFAs are not consistent enough to be translated into medical practice. For example, cecal isobutyrate is reduced in response to administration of probiotics with antidepressant efficacy [115], and some studies have failed to detect significant abnormalities in the abundance of butyrate in MDD patients [116, 117] or animal models of depression [105] compared to controls. Such discrepancies may be partly due to the highly volatile nature of SCFA and to their sensitivity to the conditions of storage and tissue extraction [118], which can affect quantification and hinder comparable results across studies. In addition, controversies exist regarding the appropriate control for studies that administer SCFA in the form of salt. Although the ideal control for this experimental model should be sodium matched, some behavioral and/or physiological effects cannot be excluded [63], especially in the light of recent findings showing that a diet high in salt alters gut microbiota composition and reduces butyrate production [119]. As for propionate, its dysregulation in animal models of depression has been consistently demonstrated [64, 105], but its neurotoxic effects and the behavioral deficits elicited at excessive doses imply that more in-depth knowledge of the underlying mechanisms are required before a targeted intervention can be developed.

이러한 증거에도 불구하고(표 3), 

SCFA의 항우울제 잠재력을 뒷받침하는 결과는 

의료 현장에 적용하기에 충분히 일관적이지 않습니다. 

예를 들어, 

항우울 효과가 있는 프로바이오틱스를 투여하면 

맹장 이소부티레이트가 감소하고[115], 

일부 연구에서는 대조군과 비교하여 MDD 환자[116, 117] 또는 우울증 동물 모델[105]에서 부티레이트의 풍부도에 유의미한 이상을 발견하지 못했습니다. 

이러한 불일치는 부분적으로 

SCFA의 휘발성이 높고 보관 및 조직 추출 조건에 민감하기 때문일 수 있으며[118], 

이는 정량화에 영향을 미치고 연구 간 비교 가능한 결과를 방해할 수 있습니다. 

또한 소금 형태로 SCFA를 투여하는 연구에 대한 적절한 대조군에 대한 논란도 존재합니다. 이 실험 모델의 이상적인 대조군은 나트륨과 일치해야 하지만, 특히 염분이 높은 식단이 장내 미생물 구성을 변화시키고 부티레이트 생산을 감소시킨다는 최근 연구 결과에 비추어 볼 때[63] 일부 행동 및/또는 생리적 영향을 배제할 수 없습니다[119]. 프로피오네이트의 경우, 우울증 동물 모델에서 조절 장애가 지속적으로 입증되었지만[64, 105], 신경 독성 효과와 과도한 용량에서 유발되는 행동 결함은 표적 개입을 개발하기 전에 기본 메커니즘에 대한 더 심층적인 지식이 필요하다는 것을 시사합니다.

TABLE 3.

Studies investigating the effects of SCFAs on depressive-like behavior.

TreatmentSpecies or strainModelBehavioral outcomesMolecular mechanismsReference

Sodium butyrate (100 mg/kg or 1.2 g/kg; ip; 1 or 21 days)	129SvEv x C57BI/6 mice (F1 crosses)	-	↑ immobility time and ↑ latency to consume peanut butter chips in the novel environment after acute treatment with SB100; no effect of chronic treatment	↑ acH4/H3 and acH3/H3 protein in HP after acute SB 100 and/or 1.2 treatment, respectively;↓ acH4/H3 (no changes in acH3/H3) in HP after chronic SB100 administration	[95]
Sodium butyrate (1.2 g/kg ip; 1 or 7 days)	Sprague-Dawley rats	-	↓ immobility time in rats after repeated (but not acute) SB administration; no changes in OFT	↑ Ttr and ↓ Slc8a3, Casr, Htr2a, Tcf12 and no changes in Sin3a, Gnrhr, Crhr2, Bdnf, Slc8a2 gene expression‎ in hippocampus after repeated SB treatment; ↑ levels of acH4-associated DNA at the Ttr promotor region in HP of rats repeated treated with SB; ↑ Ttr and no changes in acH3/H3, acH4/H4 protein level in HP after repeated SB administration	[97]
Sodium butyrate (0.3 g/kg ot 0.6 g/kg)	ICR mice	CRS	↓ anhedonia, time spent in dark and immobility time after SB0.6 administration in CRS-treated mice	SB0.6 reverses CRS-induced decrease in acH3 level in HP	[96]
Fluoxetine (10 mg/kg; oral) + Sodium butyrate (300 mg/kg; ip) for 21 days	Sprague-Dawley rats (2 months)	-	↓ time spent in social grooming and frequency of pouncing and ↑ immobility time and immobility events in PNFlx rats; ↑ latency to approach center and ↓ time spent in the center and path length in the center in PNFlx animals; postnatal treatment with SB and adult fluoxetine (AFlx) treatment prevented the PNFlx-evoked behavioral changes	↑ Hdac4, Ppp2r2b, Gal, Dcx, Kcnh2, Grm8, ElkI and ↓mTOR, Gnai1, Prkcc, HcnI, Notch3 and Avpr2 mRNA levels in HP of PNFlx rats;co-administration of SB prevented the PNFlx-evoked dysregulation of Hdac4 and mTOR, but not Gnai1, Prkcc and HcnI in HP; AFlx administration did no alter hippocampal expression‎ of Hdac4, mTOR, Gnai1, HcnIand Prkcc; ↑ acetylation of H3 and H4 at the Hdac4 promoter and ↑ HDAC4 enrichment in Gnai1 and mTOR promoter in HP of PNFlx rats and normalization after adult fluoxetine treatment; ↓ mTOR protein level in HP of PNFlx rats and no changes after AFlx treatment	[98]
Sodium butyrate (0.4 g/kg; ip) twice a day for 23 days	Male FRL and FSL rats (3 months)	-	chronic NaB-treatment rescued the FSL depression-like phenotype; ↓ immobility time	The FSL-NaB group exhibited ↑ Tet1 mRNA (and protein); ↓ Dnmt1 mRNA (but not protein) levels in the FSL-NaB group; ↓ 5hmC levels at the Bdnf P4 locus; hypermethylation of Bdnf P4 compared to FRL-Veh; the NaB-dependent increase in 5hmC levels in Bdnf P4 of FSL was associated with DNA hypomethylation at the same locus; NaB-dependent increase in TET1 and 5hmC levels in the FSL group was associated with a Bdnf P4 overexpression‎	[91]
Sodium butyrate (500 mg/kg, i.p.) twice a day for 7 days	Wistar rats (2 months)	maternal deprivation or CMS	↓depressive-like behavior in FST	↑ tricarboxylic acid cycle anzyme (succinate dehydrogenase and malate dehydrogenase) and mitochondrial chain complexes (I, II, II-III and IV) activity in the striatum	[103]
Propionate	Sprague-Dawley rats	CUMS	Improved performance at the SPT and OFT; short-term antidepressant-like effects.	Restored plasma levels of propionic acid; ↑NE, DA, TRP, 5-HIAA, and 3-HAA in the PFC (no effects on 5-HT and 3-HK) were not; ↓ turnover of TRP to KYN (calculated as KYN/TRP) and ↓turnover of DA to HVA (calculated as HVA/DA); ↑ abundance of DOPAC and 3-MT, but no change in HVA; no effect on turnover of 5-HT to 5-HIAA (calculated as 5-HIAA/5-HT); ↑turnover of KYN to 3-HK	[105]
Sodium butyrate (200 mg/kg) or fluoxetine (20 mg/kg)	Male C57BL/B6 mice	CUMS	↑ sucrose intake in SPT; ↑ locomotor activities in OFT; decreases immobility time in TST and FST	decreases histological abnormalities in hippocampal neurons; ↑ BDNF expression‎; ↑ Occludin and ZO-1 protein levels	[100]
Sodium butyrate (1.2 g/kg or 0.2 g/kg, i.p.); fluoxetine (10 mg/kg, i.p.)+ SB (0.6 mg/kg, i.p.) acutely of chronically (28 days)	male and female C57BL/6J mice (9-22 weeks)	-	improved performance at the TST	↑ histone acetylation in the brain; ↑ BDNF in mouse frontal cortex	[94]

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3-HAA: 3-Hydroxyanthranilic Acid; 3-HK: 3-Hydroxyanthranilic Acid; 3-MT: 3-Methoxytyramine; 5-HIAA: 5-Hydroxyindoleacetic Acid; 5hmc: 5-Hydroxymethylcytosine; 5-HT: 5-Hydroxytryptamine; Ach4/H3: Acetylated Histone H3/4; Avpr2: Arginine Vasopressin Receptor 2; Casr: Calcium-Sensing Receptor; CMS: Chronic Mild Stress; Crhr2: Corticotropin Releasing Hormone Receptor 2; CRS: Chronic Restraint Stress; CUMS: Chronic Unpredictable Mild Stress; DA: Dopamine; Dcx: Dublecortin; Dnmt1: DNA (Cytosine-5)-Methyltransferase 1; DOPAC: 3,4-Dihydroxyphenylacetic Acid; Elkl: ETS Domain-Containing Protein; FRL: Flinders Sensitive Line; FSL: Flinders Resistant Line; FST: Forced Swim Test; Gal: Galanin; Gnai1: G Protein Subunit Alpha I1; Gnrhr: Gonadotropin Releasing Hormone Receptor; Grm8: Glutamate Metabotropic Receptor 8; Hcnl: Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 1; Hdac4: Histone Deacetylase 4; Htr2a: 5-Hydroxytryptamine Receptor 2A; HVA: Homovanillic Acid; Kcnh2: Potassium Voltage-Gated Channel Subfamily H Member 2; KYN: Kynurenine; Mtor: Mammalian Target of Rapamycin; NE: Norepinephrine; Notch3: Neurogenic Locus Notch Homolog Protein 3; OFT: Open Field Test; PFC: Prefrontal Cortex; Ppp2r2b: Protein Phosphatase 2 Regulatory Subunit Beta; Prkcc: Protein Kinase C Gamma; Sin3a: SIN3 Transcription Regulator Family Member A; Slc8a3: Solute Carrier Family 8 Member A3; SPT: Sucrose Preference Test; Tcf12: Transcription Factor 7-Like 2; TET1: Ten-Eleven Translocation 1; TRP: Tryptophan; TST: Tail Suspention Test; Ttr: Transthyretin; ZO-1: Zonula Occludens-1.

For example, there is still a lack of consensus regarding the mode of action and receptor specificity of SCFAs. In addition, it remains unclear how well the microbial production of SCFAs in the gut parallels CNS availability. It is known that lumen concentrations of SCFAs are highly variable among individuals, and can range between 20-140 mM depending (among other factors) on fiber content of the diet, microbiota composition, rate of absorption and site of measurement in the gut [120, 121]. Absorbed by colonocytes, SCFAs are transported to the liver and then enter the systemic circulation in much lower concentrations (0.1–10 mM) [122, 123]. Although it remains unclear how well the microbial production of SCFAs in the gut relates to CNS availability, rodent studies have shown that ~3% of acetate administered intravenously reaches the CNS [34], suggesting that only a small proportion of the SCFAs absorbed from the gut reaches the brain. Increasing bacterial production of SCFAs by means of higher fiber intake (reviewed in [124, 125]) and pre- or probiotics use [126, 127] have been shown to effectively enhance the concentrations of SCFAs in the gut. The question remains as to whether direct SCFA supplementation is more effective than strategies targeting the gut microbiota. While direct supplementation with SCFAs may overcome problems related to competition of probiotic strains with resident bacterial strains, care has to be taken to elucidate the effects of SCFA depending on whether it is administered acutely (i.e. via supplementation) or chronically (i.e. via microbial production). Thus, the best strategy to implement the known beneficial effects of SCFAs on mood has still to be elucidated.

예를 들어, SCFA의 작용 방식과 수용체 특이성에 대한 합의가 아직 부족합니다. 또한 장내 미생물의 SCFA 생산이 CNS 가용성과 얼마나 잘 일치하는지도 아직 불분명합니다. 

SCFA의 내강 농도는 

개인마다 매우 다양하며, 

식이 섬유 함량, 미생물 구성, 흡수 속도 및 장내 측정 부위에 따라 (다른 요인에 따라) 

20-140mM 사이일 수 있는 것으로 알려져 있습니다 [120, 121]. 

대장세포에 흡수된 SCFA는 간으로 운반된 후 훨씬 낮은 농도(0.1~10mM)로 전신 순환계로 유입됩니다[122, 123]. 

장내 미생물의 SCFA 생산이 CNS 가용성과 얼마나 관련이 있는지는 아직 명확하지 않지만, 

설치류 연구에 따르면 정맥으로 투여된 아세테이트의 약 3%가 

CNS에 도달하는 것으로 나타났는데[34],

 이는 장에서 흡수된 SCFA의 일부만이 뇌에 도달한다는 것을 시사합니다. 

섬유질 섭취를 늘리고([124, 125]에서 검토됨) 

프리바이오틱스 또는 

프로바이오틱스 사용[126, 127]을 통해 SCFA의 박테리아 생산을 늘리면 

장내 SCFA 농도를 효과적으로 높일 수 있는 것으로 나타났습니다. 

장내 미생물을 대상으로 하는 전략보다 

SCFA를 직접 보충하는 것이 더 효과적인지에 대한 의문이 남아 있습니다. 

SCFA를 직접 보충하면 

프로바이오틱 균주와 상주 세균 균주와의 경쟁과 관련된 문제를 극복할 수 있지만, 

급성(즉, 보충제를 통해) 또는 

만성(즉, 미생물 생산을 통해) 투여 여부에 따라 SCFA의 효과를 규명하는 데 주의를 기울여야 합니다. 

따라서 SCFA가 기분에 미치는 유익한 효과를 구현하기 위한 최선의 전략은 아직 밝혀지지 않았습니다.

Tryptophan metabolites

Tryptophan is an essential amino acid involved in protein synthesis [128]. Its metabolic breakdown by host (TDO and IDO) and bacterial enzymes (tryptophanase) give rise to neuroactive molecules with established mood-modulating properties, including 5-HT, kynurenine and indole. It is well-established that dietary intake of tryptophan can modulate central concentrations of 5-HT in humans [129, 130], and that tryptophan depletion exacerbates depressive symptoms in healthy individual at risk for depression [131, 132], as well as remitted [133–135] and currently depressed patients [136, 137]. However, less than 5% of tryptophan is converted into 5-HT along the methoxyindoles pathway by the enzyme tryptophan hydroxylase; the remaining 95% is metabolized along the kynurenine pathway by the enzymes TDO and IDO. Kynurenine can be further metabolized into kynurenic acid (KYNA) or, alternatively, into quinolinic and picolinic acids via the nicotinamide adenine dinucleotide (NAD) pathway. KYNA is an NMDA and α7 nicotinic acetylcholine receptor antagonist; quinolinic and picolinic acids are NMDA agonists with neurotoxic and pro-depressant effects [138]. Over-stimulation of the kynurenine pathway leads to increased lipid peroxidation and inflammation, due to quinolinic and picolinic acids and free radical generation (3-hydroxykynurenine and 3-hydroxyanthranilic acid) [139, 140]. Conversely, production of stress hormones (i.e. cortisol) and pro-inflammatory cytokines (i.e. interferons, TNF-α, interleukins) stimulate TDO and IDO formation respectively, enhancing kynurenine output at the expenses of 5-HT synthesis. In turn, the weakening of the inhibitory feedback of 5-HT on cortisol production contributes to the worsening of this cycle [141]. Therefore, disturbances in tryptophan metabolism (i.e. the shunt of tryptophan from 5-HT to kynurenine synthesis) may be partly responsible for the mood, cognitive and sleep disturbances typical of depression [141].

트립토판 대사산물

트립토판은 

단백질 합성에 관여하는 필수 아미노산입니다[128]. 

숙주(TDO 및 IDO)와 

박테리아 효소(트립토파나제)에 의해 대사 분해되면 

5-HT, 

키누레닌, 

인돌 등 기분 조절 특성이 확립된 신경 활성 분자가 생성됩니다. 

트립토판의 식이 섭취가 

인간의 5-HT 중심 농도를 조절할 수 있으며[129, 130], 

트립토판 고갈이 

우울증 위험에 처한 건강한 개인[131, 132]과 

우울증 완화[133-135] 및 

현재 우울증 환자[136, 137]의 우울 증상을 악화시킨다는 사실은 잘 알려져 있습니다. 

그러나 

트립토판의 5% 미만은 

트립토판 하이드 록실 라제 효소에 의해 메톡시인돌 경로를 따라 

5-HT로 전환되고, 

나머지 95%는 TDO 및 IDO 효소에 의해 키누레닌 경로를 따라 대사됩니다. 

키누레닌은 

니코틴아미드 아데닌 디뉴클레오티드(NAD) 경로를 통해 

키누레닌산(KYNA)으로 추가 대사되거나 

퀴놀린산 및 

피콜린산으로 대사될 수 있습니다. 

KYNA는 

NMDA 및 α7 니코틴 아세틸콜린 수용체 길항제이며, 

퀴놀린산과 피콜린산은 

신경독성 및 항우울 효과가 있는 NMDA 작용제입니다[138]. 

키누레닌 경로를 과도하게 자극하면 

퀴놀린산과 피콜린산 및 자유 라디칼 생성(3-하이드록시 키누레닌 및 3-하이드록시 안트라닐산)으로 인해 

지질 과산화와 염증이 증가합니다[139, 140]. 

반대로 

스트레스 호르몬(예: 코르티솔)과 

전 염증성 사이토카인(예: 인터페론, TNF-α, 인터루킨)의 생산은 

각각 TDO와 IDO 형성을 자극하여 

5-HT 합성을 희생하면서 키누레닌 생산량을 증가시킵니다. 

결과적으로 

코르티솔 생산에 대한 5-HT의 억제 피드백이 약화되면

이 주기가 악화됩니다 [141].

따라서

트립토판 대사 장애(즉, 트립토판이 5-HT에서 키누레닌 합성으로 전환되는 것)는

우울증의 전형적인 기분, 인지 및 수면 장애를 부분적으로 일으킬 수 있습니다 [141].

The mechanisms that control the uptake of tryptophan into the brain are not fully understood: these include the proportion of circulatory tryptophan that is bound to albumin (which is unable to cross the BBB), as well as the competition with other neutral amino acids for its transport through the BBB [142], but other factors are likely to be involved. Studies on germ-free animals have demonstrated the role of the microbiome in mediating the behavioral effects of tryptophan metabolism, suggesting a potential additional mechanism. Upon colonization of these animals with tryptophan-metabolizing bacteria, a decrease in tryptophan and an increase in hippocampal 5-HT concentrations was noted, accompanied by reduced anxiety-like behaviors [2, 49]. Studies have shown that the metabolic activity of the gut microbiota on dietary tryptophan produces biologically active signaling molecules, such as indole and its derivatives. Indole is an aromatic amino acid produced through the microbial metabolism of tryptophan by bacteria expressing the enzyme tryptophanase (e.g. E. coli [143] and other strains [144]). In microbial communities, indole is used as a quorum-sensing signal to coordinate collective behaviors like spore formation, plasmid stability and drug resistance [144]. Moreover, it plays an important role in gut physiology as it stimulates enteroendocrine L cells to secrete GLP-1 [145] and regulates gut barrier permeability [146]. In addition, oxindole and isatin (2,3-dioxoindole), products of indole oxidation and conjugation respectively, have been described as neuroactive signaling molecules able to modulate motor function and emotional behavior. Oxindole is a strong inhibitor of motor activity, and it is known to result in loss of the righting reflex, hypotension, and reversible coma [147]. Isatin increases water intake and decreases food intake. A rodent study using antagonists selective to specific receptors highlighted the possibility of these effects being mediated by the 5-HT3 receptor and the dopamine D2 receptor [148]. The action of isatin on 5-HT3 and atrial natriuretic peptide (ANP) receptors may also be responsible for the negative effect of this compound on memory formation [149].

트립토판이 

뇌로 흡수되는 메커니즘은 완전히 이해되지 않았습니다. 

여기에는 알부민에 결합된 

순환 트립토판의 비율(BBB를 통과할 수 없음)과 

다른 중성 아미노산과의 BBB 통과 경쟁이 포함되지만[142], 

다른 요인도 관여할 가능성이 높습니다. 

세균이 없는 동물에 대한 연구에서는 트립토판 대사의 행동 효과를 매개하는 미생물 군집의 역할이 입증되어 잠재적인 추가 메커니즘이 있음을 시사했습니다. 이러한 동물에 트립토판 대사 박테리아를 식민지화하면 트립토판이 감소하고 해마 5-HT 농도가 증가하며 불안과 유사한 행동이 감소하는 것으로 나타났습니다 [2, 49]. 

연구에 따르면 

식이 트립토판에 대한 장내 미생물의 대사 활동은 

인돌 및 그 유도체와 같은 생물학적 활성 신호 분자를 생성하는 것으로 나타났습니다. 

인돌은 

트립토파나제 효소를 발현하는 박테리아(예: 대장균 [143] 및 기타 균주 [144])가 

트립토판의 미생물 대사를 통해 생성하는 

방향족 아미노산입니다. 

미생물 군집에서 인돌은 

포자 형성, 플라스미드 안정성 및 약물 내성과 같은 

집단 행동을 조정하기 위한 쿼럼 감지 신호로 사용됩니다 [144]. 

또한 장내 내분비 L 세포를 자극하여 G

LP-1을 분비하고[145] 장 장벽 투과성을 조절하기 때문에 

장 생리학에서 중요한 역할을 합니다[146]. 

또한 

인돌 산화 및 접합의 산물인 옥신돌과 이사틴(2,3-디옥소인돌)은 

각각 운동 기능과 정서적 행동을 조절할 수 있는 신경 활성 신호 분자로 설명되고 있습니다. 

옥신돌은 운동 활동의 강력한 억제제이며, 

직립 반사, 저혈압 및 가역적 혼수 상태를 초래하는 것으로 알려져 있습니다[147]. 

이사틴은 

수분 섭취를 증가시키고 

음식 섭취를 감소시킵니다. 특정 수용체에 선택적으로 작용하는 길항제를 사용한 설치류 연구에서는 이러한 효과가 5-HT3 수용체와 도파민 D2 수용체에 의해 매개될 가능성이 강조되었습니다 [148]. 5-HT3 및 심방 나트륨 이뇨 펩타이드(ANP) 수용체에 대한 이사틴의 작용은 이 화합물이 기억 형성에 미치는 부정적인 영향의 원인이 될 수도 있습니다 [149].

Additionally, isatin is an endogenous monoamine oxidase (MAO) B inhibitor and a benzodiazepine receptor antagonist. As such, it has an established anxiogenic profile in both mice and rats [150, 151], and in turn, its production is drastically increased in conditions of stress. However, it is important to state that modifications in the chemical structure of indole and derivatives have been reported to drastically change the behavioral properties of these compounds, and even confer some antidepressant actions [152].

또한, 이사틴은 

내인성 모노아민 산화효소(MAO) B 억제제이자 

벤조디아제핀 수용체 길항제입니다. 

따라서 생쥐와 쥐 모두에서 불안 유발 프로필이 확립되어 있으며[150, 151], 스트레스를 받는 조건에서 그 생산이 급격히 증가합니다. 그러나 인돌과 유도체의 화학 구조를 변형하면 이러한 화합물의 행동 특성이 크게 변화하고 심지어 항우울제 작용을 하는 것으로 보고되고 있습니다[152].

Based on research studies investigating the behavioral effects of indole and its metabolites, several pathways may mediate the neuroactive potential of indoles (Table 4). Enhanced tryptophan catabolism into indoles may mimic the reversible effect of a tryptophan-deficient diet, which is also associated with reduced 5-HT availability and increased neuroinflammation [153]. Other mechanisms may include direct effects of indole metabolites on central receptors, activation of the vagus nerve by gut bacteria or their metabolites, and stimulation of a neuroinflammatory state. A study by Jaglin et al. [154] showed how the effects of indole on physiology and behavior were mediated by different pathways depending on whether they were administered chronically or acutely. Acute administration of indole in the rat cecum caused a significant reduction in locomotion and an accumulation of indole metabolites in the brain, suggesting a possible direct role on central receptors. In contrast, chronic exposure to indole, achieved by the colonization of germ-free rats with E. coli, exacerbated anxiety-like and helplessness (i.e. depression-like) behaviors, but had no effect on motor activity [154]. In contrast to acutely administered animals, these colonized rats did not exhibit increased oxindole and isatin in the brain, nor increased circulatory corticosterone. These findings suggest that the behavioral alterations induced by chronic indole production (via colonization with indole-producing E. coli) are not mediated by the action of indole or its metabolites on central receptors or on the HPA axis [154]. A reduction in eye blinking frequency was detected, suggesting the involvement of the vagus nerve in eliciting the anxiogenic and depressive-like behaviors described [154].

인돌과 그 대사 산물의 행동 효과를 조사한 연구에 따르면, 

인돌의 신경 활성 잠재력을 매개하는 경로는 여러 가지가 있습니다(표 4). 

인돌로의 

트립토판 이화 작용이 강화되면 

트립토판 결핍 식단의 가역적 효과를 모방할 수 있으며, 

이는 5-HT 가용성 감소 및 신경염증 증가와도 관련이 있습니다[153]. 

다른 메커니즘으로는 

인돌 대사산물이 중추 수용체에 미치는 직접적인 영향, 

장내 박테리아 또는 그 대사산물에 의한 

미주 신경 활성화, 

신경 염증 상태 자극 등이 있을 수 있습니다. 

Jaglin 등[154]의 연구에 따르면 인돌의 생리와 행동에 대한 영향이 만성적으로 투여되는지 급성적으로 투여되는지에 따라 다른 경로를 통해 매개되는 것으로 나타났습니다. 쥐 맹장에 인돌을 급성 투여하면 운동성이 현저히 감소하고 뇌에 인돌 대사 산물이 축적되어 중추 수용체에 직접적인 역할을 할 수 있음을 시사합니다. 반면, 무균 쥐에 대장균을 집락화하여 인돌에 만성적으로 노출시키면 불안과 무력감(즉, 우울증과 유사한) 행동이 악화되었지만 운동 활동에는 영향을 미치지 않았습니다[154]. 급성 투여 동물과 달리 대장균에 감염된 쥐는 뇌에서 옥신돌과 이사틴이 증가하거나 순환 코르티코스테론이 증가하지 않았습니다. 이러한 결과는 만성 인돌 생산(인돌 생산 대장균 식민지화를 통한)에 의해 유도된 행동 변화가 인돌 또는 그 대사물질이 중추 수용체나 HPA 축에 작용하여 매개되지 않음을 시사합니다[154]. 눈 깜박임 빈도의 감소가 감지되어 미주 신경이 설명한 불안 및 우울 유사 행동을 유발하는 데 관여한다는 것을 시사합니다 [154].

TABLE 4.

Studies investigating the effects of indole metabolites on depressive-like behavior.

TreatmentSpecies or strainModelBehavioral outcomesMolecular mechanismsReference

Isatin (15 mg/kg i.p. in mice and 20 mg/kg i.p. in rats); yohimbine (2 mg/kg i.p. in mice and 2.5 mg/kg i.p. in rats)	Male Charles Foster rats and Wistar mice	-	↑anxiety in the OFT and EPM in mice, and the SIT in rats, comparable to yohimbine. ↓anxiolytic effects of diazepam in the OFT	-	[150]
Isatin (0–160 mg/kg i.p.)	Male Sprague-Dawley rats (90-100 days)	-	↑immobility in the OFT and FST	-	[151]
Oxindole or isatin (50 or 100 mg/kg, i.p.) or indole (500 mg/kg intra-cecal administration); inoculation with 1 mL of BW25113 or JW3686 bacterial cultures	F344 male rats (2–2.5 months)	Conventional, SPF and GF	Acute intra-cecal administration of indole induced ↓motor activity and ↑ concentrations of oxindole and isatin in the brain. Chronic overproduction of indole by colonization with E. coli caused no change in motor activity and no detectable oxindole or isatin in the brain but ↑ helplessness in the TST and ↑anxiety in the novelty test, EPM and OFT.	↑eye blinking frequency and ↑c-Fos protein expression‎ in the dorsal vagal complex	[154]
Tryptophan-depleted diet with or without tryptophan supplementation; I3S, IPA, IAld or indole supplementation	female C57BL/6J mice (WT and GFAP AhR-deficient)	EAE	-	↑Ccl2 and Nos2 expression‎ in astrocytes in tryptophan depleted group, reverted by supplementation; administration of I3S, IPA, IAld activates AhR and ↓Ccl2 and Nos2 expression‎	[153]

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AhR: Aryl Hydrocarbon Receptor; Ccl2: C-C Motif Chemokine Ligand 2; EAE: Experimental Autoimmune Encephalomyelitis; EPM: Elevated Plus Maze; FST: Forced Swim Test; GF: Germ Free; GFAP: Glial Fibrillary Acidic Protein; I3S: Indoxyl-3-sulfate; IAld: Indole-3-aldehyde; IPA: Indole-3-propionic acid; Nos2: Nitric Oxide Synthase 2; OFT: Open Field Test; SIT: Social Interaction Test; SPF: Specific Pathogen Free; WT: Wild Type.

Indole and its derivatives (e.g. indoxyl-3-sulfate (I3S), indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld)) are able to activate the aryl hydrocarbon receptor (AhR) [153, 155], with a subsequent inhibitory effect on neuroinflammation.

Rothhammer et al. [153] showed in mice that were either supplemented with indole and related compounds or treated with tryptophanase, that neuroinflammation was reduced via activation of the AhR on astrocytes. This was attributed to increased expression‎ of suppressor of cytokine signaling 2 (Socs2), and a subsequent inhibition of the transcription factor NF-kB.

Our understanding of the physiological and pathological role of indoles is hindered by the existence of a high number of indole derivatives, with diverse and dynamic actions. For example, IAld triggers the release of the anti-inflammatory cytokine IL-22 [156], IPA regulates intestinal barrier function via pregnane X receptor (PXR) [157] and is protective against DNA damage, lipid peroxidation and amyloid-β deposition in the brain [158, 159], and I3S is cytotoxic and triggers free radical production [160]. Additionally, there is a very small number of studies aimed at investigating the effect of these bioactive compounds on behavior. Given the tight link between tryptophan metabolism and mood, it is important to investigate the role of these molecules in order to understand the underlying mechanisms of this disease.

로스해머 등[153]은 

인돌 및 관련 화합물을 보충하거나 

트립토파나제로 처리한 쥐를 대상으로 성상교세포에서 AhR의 활성화를 통해 

신경 염증이 감소한다는 것을 보여주었습니다. 

이는 사이토카인 신호 전달 억제제 2(Socs2)의 발현 증가와 

그에 따른 전사인자 NF-kB의 억제에 기인하는 것으로 밝혀졌습니다.

인돌의 생리적 및 병리학적 역할에 대한 이해는 

다양하고 역동적인 작용을 하는 수많은 인돌 유도체가 존재하기 때문에 방해를 받고 있습니다. 

예를 들어, IAld는 항염증성 사이토카인 IL-22의 방출을 유발하고[156], IPA는 임신인 X 수용체(PXR)를 통해 장 장벽 기능을 조절하며[157], 뇌의 DNA 손상, 지질 과산화 및 아밀로이드-β 침착으로부터 보호하며[158, 159], I3S는 세포 독성이며 활성 산소 생성을 유발하는[160] 등입니다. 또한 이러한 생리 활성 화합물이 행동에 미치는 영향을 조사하기 위한 연구는 매우 적습니다. 트립토판 대사와 기분 사이의 긴밀한 연관성을 고려할 때, 이 질환의 근본적인 메커니즘을 이해하기 위해서는 이러한 분자의 역할을 조사하는 것이 중요합니다.

Lactate

Lactate is an organic acid arising from both mammalian host processes and the fermentation of dietary fibers by lactic acid bacteria (e.g., L. lactis, L. gasseri, and L. reuteri), Bifidobacteria and Proteobacteria [161]. Lactate can be converted by several bacterial species to SCFAs contributing to the overall pool. Although present in the gut at low levels, lactate is absorbed into the bloodstream [162] and can cross the BBB [163]. Lactate has an established role in central signaling: in the brain, it is used as an energy substrate by neurons (due to its ability to be metabolized into glutamate) [164], it contributes to synaptic plasticity, and underlies memory formation [165, 166]. Both rodent and human studies support an association between depression and lactate abnormalities (Table 5). Increased concentrations of urinary lactate were measured in patients suffering from severe MDD compared to controls [167]. Interestingly, compared to conventionally colonized mice, germ-free mice exhibit elevated hippocampal concentrations of lactate, but decreased concentrations in the frontal cortex. In contrast, germ-free rats exhibit higher frontal concentrations of lactate than conventional rats [168].

젖산염은 

포유류 숙주 과정과 유산균(예: L. 락티스, L. 가세리, L. 루테리), 

비피도박테리아 및 프로테오박테리아에 의한 

식이 섬유의 발효 과정에서 발생하는 

유기산입니다[161]. 

젖산염은 

여러 박테리아 종에 의해 전체 풀에 기여하는 

SCFA로 전환될 수 있습니다. 

젖산염은 

장내에서 낮은 수준으로 존재하지만 

혈류로 흡수되어[162] BBB를 통과할 수 있습니다[163]. 

젖산염은 

뇌에서 뉴런의 에너지 기질로 사용되며(글루타메이트로 대사되는 능력으로 인해)[164], 

시냅스 가소성에 기여하고 

기억 형성의 기초가 됩니다[165, 166] 등 중앙 신호 전달에서 중요한 역할을 합니다. 

설치류와 인간 연구 모두 

우울증과 젖산염 이상 사이의 연관성을 뒷받침합니다(표 5). 

중증 MDD를 앓고 있는 환자에서 대조군에 비해 요 젖산염 농도가 증가된 것으로 측정되었습니다[167]. 흥미롭게도, 세균이 없는 쥐는 기존의 식민지화된 쥐에 비해 해마의 젖산염 농도는 증가했지만 전두피질의 농도는 감소한 것으로 나타났습니다. 반면, 세균이 없는 쥐는 기존 쥐보다 전두엽의 젖산염 농도가 더 높았습니다[168].

TABLE 5.

Studies investigating the effects of lactate on depressive-like behavior.

TreatmentSpecies or strainModelBehavioral outcomesMolecular mechanismsReference

L-lactate (1 g/kg, ip, either acute or chronic (daily for 3 weeks))	C57Bl/6 mice (8-10 weeks)	corticosterone model of depression (for chronic experiment only)	Chronic treatment ↓ immobility in the FST to a similar extent as desipramine; chronic treatment abolished the increased immobility induced by corticosterone treatment in the FST and TST, reversed the corticosterone-induced decrease in saccharin consumption and decreased the immobility time in the open-space forced swim model of depression to a similar extent as desipramine	Acute effects: ↓ GSK3α and GSK3β in the hippocampus; ↓ phospho-CREB levels in the hippocampus; ↑hippocampal Arc, COX-2 and NOS1 mRNA expression‎; ↓COX-2 mRNA in the hippocampus. Chronic effects: ↑mRNA and protein levels encoding the regulator of serotonin receptors p11, the astrocytic marker S100β1 and the transcription factor Hes534 in the hippocampus of animals subjected to the open-space FST compared with vehicle-treated animals; ↓expression‎ of PDE4D and NOS1 both at the mRNA and protein levels in the hippocampus of animals subjected to the open-space FST compared with vehicle-treated animals.	[174]
Lactate (during experimental stress period) or lactate + CI-994 (after experimental stress period)	male C57Bl/6 mice (8-10 weeks)	CSDS	Before the establihsment of depression: Reverses social avoidance and anxiety. After the establihsment of depression: reduced depression-like behavior	Before the establihsment of depression: Restores hippocampal class I HDAC2/3 levels and activity. After the establihsment of depression: hippocampal class II HDAC5 deactivation	[173]

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Arc: Activity-Regulated Cytoskeleton-Associated Protein; COX-2: Cyclooxygenase 2; CREB: Camp Response Element-Binding Protein; CSDS: Chronic Social Defeat Stress; FST: Forced-Swim Test; GSK3α/β: Glycogen synthase kinase 3 alpha/beta; HDAC2/3/5: Histone Deacetylase 2/3/5; NOS1: Nitric Oxide Synthase 1; PDE4D: Camp-Specific 3′,5′-Cyclic Phosphodiesterase 4D; TST: Tail Suspention Test.

A potential mechanism through which lactate can modulate emotional behavior is through direct activation of the receptor GPR81 (also known as hydroxycarboxylic acid receptor 1 or HCA1), expressed in the hippocampus, neocortex and cerebellum [169]. The involvement of GPR81 in mood disorders has been suggested by Shoblock et al. [170]. However, through GPR81 activation, lactate modulates lipid and glucose metabolism, exerts an anti-inflammatory effect (also mediated by ARRB2) [171], and inhibits GABAergic neurotransmission [172].

젖산염이 

정서적 행동을 조절할 수 있는 잠재적 메커니즘은 

해마, 신피질 및 소뇌에서 발현되는 수용체 

GPR81(하이드 록시 카르 복실 산 수용체 1 또는 HCA1이라고도 함)의 

직접적인 활성화를 통해서입니다 [169]. 

기분 장애에 대한 GPR81의 관여는 Shoblock 등에 의해 제안되었습니다 [170]. 그러나 젖산염은 GPR81 활성화를 통해 지질 및 포도당 대사를 조절하고 항염증 효과(ARRB2에 의해 매개됨)를 발휘하며[171] GABAergic 신경전달을 억제합니다[172].

An alternative, and significantly more explored, mechanism explaining the effect of lactate on depressive behavior is epigenetic regulation of depression-related genes. An interesting study by Karnib et al. (2019) revealed that lactate has both protective and reversing effects against depression, and that these processes occur via distinct epigenetic mechanisms on HDACs [173]. In this experiment, chronic lactate administration immediately before a 10-day social defeat challenge protected against the resulting social avoidance and anxiety behaviors observed in control mice. Lactate-treated mice exhibited increased levels and activity of the class I HDAC2/3 in the hippocampus [173]. In a second group of mice, which were not given lactate during the social stress challenge period, and that exhibited depressive-like symptoms, lactate had an antidepressant effect as shown by the rescue of social avoidance behavior. After the establishment of depression, the effect of lactate was not mediated by HDAC2/3; instead, it was mediated by a reduction in HDAC5 levels [173].

젖산염이 우울한 행동에 미치는 영향을 설명하는 '

또 다른 메커니즘으로

우울증 관련 유전자의 후성유전학적 조절을 들 수 있습니다.

Karnib 등(2019)의 흥미로운 연구에 따르면

젖산염은 우울증에 대한 보호 효과와 역전 효과가 있으며,

이러한 과정은 HDAC에 대한

뚜렷한 후성유전학적 메커니즘을 통해 발생한다는 사실이 밝혀졌습니다 [173].

이 실험에서 10일간의 사회적 패배 과제 직전에 만성 젖산염을 투여하면 대조군 마우스에서 관찰된 사회적 회피 및 불안 행동으로부터 보호되는 것으로 나타났습니다. 젖산염을 처리한 마우스는 해마에서 클래스 I HDAC2/3의 수준과 활동이 증가했습니다 [173]. 사회적 스트레스 도전 기간 동안 젖산염을 투여하지 않고 우울증과 유사한 증상을 보인 두 번째 마우스 그룹에서는 사회적 회피 행동이 회복되는 것으로 나타나 젖산염이 항우울제 효과를 나타냈습니다. 우울증이 확립된 후 젖산염의 효과는 HDAC2/3에 의해 매개되지 않았으며, 대신 HDAC5 수준의 감소에 의해 매개되었습니다 [173].

Carrard et al. (2018) also demonstrated the antidepressant effect of acute and chronic intraperitoneal injections of L-lactate in a corticosterone mouse model of depression. These behavioral effects followed an increase in the hippocampal concentrations of L-lactate, and were dependent on changes in the expression‎ of several genes implicated in the pathophysiology of depression: GSK-α, GSK-β and CREB phosphorylation levels were significantly decreased, while the expression‎ of Arc was increased and COX-2 and NOS1 decreased [174]. In addition to changes in the expression‎ of depression-related or plasticity-related genes (GSK-α, GSK-β, CREB, Arc, COX-2 and NOS1), the behavioral effects of lactate were mediated by an increase in hippocampal p11 (regulator of 5-HT receptors), S100 β (astrocytic marker), Hes5 (transcription vector) and a decrease in cAMP-specific phosphodiesterase-4D (PDE4D) and NOS1 mRNA and protein levels [174].

Carrard 등(2018)은 

또한 우울증의 코르티코스테론 마우스 모델에서 

급성 및 만성 L-락테이트 복강 내 주사의 항우울 효과를 입증했습니다. 

이러한 행동 효과는 해마의 L-락테이트 농도 증가에 따른 것으로, 우울증의 병태생리에 관여하는 여러 유전자의 발현 변화에 따라 달라지는 것으로 나타났습니다: GSK-α, GSK-β 및 CREB 인산화 수준은 현저히 감소한 반면 Arc의 발현은 증가하고 COX-2 및 NOS1은 감소했습니다 [174]. 

우울증 관련 또는 가소성 관련 유전자(GSK-α, GSK-β, CREB, Arc, COX-2 및 NOS1)의 발현 변화 외에도 젖산염의 행동 효과는 해마 p11(5-HT 수용체의 조절자), S100 β(성상세포 마커), Hes5(전사 벡터)의 증가와 cAMP 특이 포스포디에스 테라제-4D(PDE4D) 및 NOS1 mRNA 및 단백질 수준의 감소로 매개되었습니다[174].

Since lactate can also be synthetized by astrocytes on neuronal demand as a byproduct of glycolysis [175], it remains difficult to assess the net effect of microbial metabolism on central levels of lactate and mood. A simple way to isolate the contribution of the gut microbiome in the relationship between lactate production and depressive behavior would be using germ-free rodents; to the best of our knowledge, this has not been investigated to date. However, the well-established interchange of lactate between the periphery and the CNS [163] points towards a role of the gut microbiota in mediating the antidepressant effects of lactate. In support of this statement, the beneficial effects of exercise on mood have been hypothesized to be due to gut microbiota-mediated changes in the production of lactate [176, 177].

젖산염은 

해당 과정의 부산물로서 

신경 세포의 요구에 따라 

성상 세포에서 합성될 수도 있기 때문에[175], 

미생물 대사가 젖산염과 기분의 중추 수준에 미치는 순 효과를 평가하기는 여전히 어렵습니다. 

젖산염 생산과 우울한 행동 사이의 관계에서 

장내 미생물 군집의 기여도를 분리하는 간단한 방법은

 무균 설치류를 사용하는 것이지만, 우리가 아는 한 현재까지 이에 대한 조사는 이루어지지 않았습니다. 그러나 말초와 중추신경계 사이의 젖산염 교환이 잘 확립되어 있다는 사실[163]은 젖산염의 항우울 효과를 매개하는 장내 미생물의 역할을 시사합니다. 이러한 주장을 뒷받침하는 근거로, 운동이 기분에 미치는 유익한 효과는 장내 미생물이 젖산염 생성을 매개하는 변화 때문이라는 가설이 제기되었습니다[176, 177].

Bile acids

Bile acids are cholesterol-derived steroid acids synthesized in the liver, secreted into the small intestine and absorbed in the ileum. The two primary bile acids (in humans and rats), cholic acid (CA) and chenodeoxycholic acid (CDCA), undergo further structural modifications in the gut by means of the gut microbiota, which convert them into secondary and tertiary bile acids [178]. Bile acids have local detergent properties that enables them to emulsify lipophilic molecules and, in turn, facilitate nutrient digestion and absorption. However, they can also act as signaling molecules to modulate feeding behavior and in turn, control glucose homeostasis, lipid metabolism and energy expenditure [179]. Their signaling pathways are initiated by their binding to the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5) [180].

담즙산은 

간에서 합성되어 소장으로 분비되고 

회장에 흡수되는 

콜레스테롤 유래 스테로이드산입니다. 

사람과 쥐의 두 가지 주요 담즙산인 

콜산(CA)과 케노데옥시콜산(CDCA)은 

장내 미생물에 의해 장에서 추가적인 구조적 변형을 거쳐 

이차 및 3차 담즙산으로 전환됩니다[178]. 

담즙산은 

친유성 분자를 유화시켜 

영양소의 소화와 흡수를 촉진하는 국소 세제 특성을 가지고 있습니다. 

그러나 

담즙산은 

섭식 행동을 조절하고 

포도당 항상성, 

지질 대사 및 에너지 소비를 조절하는 신호 분자로도 작용할 수 있습니다[179]. 

이들의 신호 경로는 파네소이드 X 수용체(FXR)와 다케다 G 단백질 결합 수용체 5(TGR5)에 결합함으로써 시작됩니다[180].

The FXR is a nuclear receptor that is involved in the synthesis, secretion and transport of bile acids [181], as well as in the modulation of CREB activity [182]. Through its inhibitory control of the transcription factor CREB, bile acids can repress the transcription of several genes, including BDNF. Since the first reports of FXR expression‎ in the brain [180, 183], the possibility has been explored that BDNF abnormalities found in the brains of depressed individuals may be accounted for, in part, by altered bile acid activity. Supportive of this hypothesis, the chronic unpredictable mild stress (CUMS) rodent model of depression exhibits enhanced hippocampal FXR expression‎, and in turn, FXR overexpression‎ in the rat hippocampus is sufficient to induce depressive-like behavior in naïve animals [184]. These behavioral changes were mirrored by a significant decrease in BDNF expression‎ in the hippocampus of rats overexpressing FXR. In contrast, FXR knockdown in naïve rats had a strong antidepressant effect as measured by the forced-swim and tail suspension tests, and prevented the occurrence of CUMS-associated behavioral (depressive-like symptoms) and molecular (decreased BDNF expression‎) abnormalities [184]. The antidepressant effect of FXR genetic deletion was confirmed in an independent study, which also reported altered glutamatergic, GABAergic, serotonergic, and noradrenergic neurotransmission in the hippocampus and cerebellum of FXR knockout mice, while no change was detected in the prefrontal cortex [185]. Deletion of FXR also led to disrupted bile acid metabolism and to increased bile acid abundance both peripherally and centrally [185, 186]. Different rodent models of depression have reported increased abundance of bile acids in urine and plasma [187], as well as in the fecal metabolic phenotype [188]. Su et al. [189], instead, reported an upregulation in serum glycocholic acid, but a decrease in cholic acid in chronic variable stress (CVS)-induced depression rats. These abnormalities were associated with a reduced abundance of Peptostreptococcaceae incertaesedis [188], supporting a link with altered microbiota function.

FXR은 

담즙산의 합성, 분비 및 수송에 관여하는 핵 수용체이며[181], 

CREB 활성의 조절에도 관여합니다[182]. 

담즙산은 전사인자 CREB의 억제 조절을 통해 BDNF를 포함한 여러 유전자의 전사를 억제할 수 있습니다. 

뇌에서 FXR 발현이 처음 보고된 이후[180, 183], 

우울증 환자의 뇌에서 발견되는 BDNF 이상이 

부분적으로 담즙산 활동의 변화로 인해 설명될 수 있다는 가능성이 탐구되었습니다. 

이 가설을 뒷받침하는 만성 예측 불가능한 가벼운 스트레스(CUMS) 우울증 설치류 모델에서는 해마의 FXR 발현이 강화되고, 결과적으로 쥐 해마에서의 FXR 과발현은 순진한 동물에서 우울증과 유사한 행동을 유도하기에 충분합니다[184]. 이러한 행동 변화는 FXR을 과발현한 쥐의 해마에서 BDNF 발현의 현저한 감소로 반영되었습니다. 

반면, 순진한 쥐의 FXR 녹다운은 강제 수영 및 꼬리 현수 실험으로 측정한 결과 강력한 항우울 효과를 보였으며, CUMS와 관련된 행동(우울 유사 증상) 및 분자(BDNF 발현 감소) 이상 발생을 예방했습니다[184]. FXR 유전자 결실의 항우울 효과는 독립적인 연구에서도 확인되었는데, 이 연구에서는 FXR 녹아웃 마우스의 해마와 소뇌에서 글루타머성, GABA성, 세로토닌성 및 노르아드레날린성 신경전달이 변화된 반면 전전두엽 피질에서는 변화가 발견되지 않았다고 보고했습니다 [185]. 또한 FXR의 결실은 담즙산 대사를 방해하고 말초와 중추 모두에서 담즙산 농도를 증가시켰습니다 [185, 186]. 다른 설치류 우울증 모델에서는 소변과 혈장 [187], 대변 대사 표현형 [188]에서 담즙산 농도가 증가한다고 보고했습니다. Su 등[189]은 만성 가변 스트레스(CVS)로 유발된 우울증 쥐에서 혈청 글리코콜산은 증가하지만 콜산은 감소하는 것으로 보고했습니다. 이러한 이상은 펩토스트렙토코커스 인세르타에시디스의 감소와 관련이 있으며[188], 이는 미생물총 기능 변화와의 연관성을 뒷받침합니다.

Moreover, bile acids may contribute to major depression by disrupting tight junction expression‎, leading to permeabilization of both intestinal and central epithelial cells [190]. Chenodeoxycholic acid or deoxycholic acid injections permealized the BBB in naïve rats [190]. When investigated in rat brain microvascular endothelial cells, increased BBB permeability upon administration of chenodeoxycholic acid or deoxycholic acid was found to be mediated by occludin phosphorylation in a Rac-1-dependent and FXR-independent fashion [190]. Enhanced permeabilization of intestinal epithelial barrier in human Caco-2 monolayers was associated with phosphorylation of the epithelial growth factor (EGF) receptor and dephosphorylation of the tight junction occludin. This occurred in response to administration of the hydrophobic bile acids cholic acid, chenodeoxycholic acid and deoxycholic acid, but not the hydrophilic bile acid ursodeoxycholic acid [191]. These findings suggest that the effect of bile acids may be to some extent dependent on their chemical and physical properties, which in turn, relies upon microbial-mediated modification of these compounds.

또한 담즙산은 

장 및 중추 상피 세포의 투과성을 방해하여 

긴밀한 접합부 발현을 방해함으로써 

주요 우울증에 기여할 수 있습니다 [190]. 

체노데옥시콜산 또는 데옥시콜산 주사는 순진한 쥐의 BBB를 투과성화했습니다[190]. 쥐의 뇌 미세혈관 내피 세포에서 조사한 결과, 체노데옥시콜산 또는 데옥시콜산 투여 시 BBB 투과성 증가는 Rac-1 의존적 및 FXR 독립적 방식으로 오클루딘 인산화에 의해 매개되는 것으로 밝혀졌습니다 [190]. 인간 Caco-2 단층에서 장 상피 장벽의 투과성 강화는 상피 성장 인자(EGF) 수용체의 인산화 및 타이트 접합부 오클루딘의 탈인산화와 관련이 있었습니다. 이는 소수성 담즙산인 콜산, 체노데옥시콜산 및 데옥시콜산의 투여에 대한 반응에서 발생했지만 친수성 담즙산인 우르소데옥시콜산은 그렇지 않았습니다 [191]. 이러한 결과는 담즙산의 영향이 화학적 및 물리적 특성에 어느 정도 의존할 수 있으며, 이는 다시 이러한 화합물의 미생물 매개 변형에 의존할 수 있음을 시사합니다.

Another factor that may influence the behavioral outcome of bile acids is the receptor that mediates the response (Table 6). Binding of the TGR5 receptor by the secondary bile acid tauroursodeoxycholic acid (TUDCA) ameliorates the depressive phenotype of CUS mice by dampening neuroinflammation (TNF-α and IL-6), as well as oxido-nitrosative and endoplasmic reticulum stress [192]. This is consistent with previous reports of the neuroprotective effects of TUDCA in microglia [193]. Additionally, some bile acids, like lithocholic acid can stimulate central PXR and vitamin D receptor (VDR) [194], which have well-established antidepressant effects [195, 196]. Thus, the impact of bile acids on depressive behavior may be dependent on the specific receptor that they act upon, with FXR mediating pro-depressive phenotype, and PXR, VDR and TGR5 mediating their antidepressant action. This hypothesis has yet to be formally tested.

담즙산의 행동 결과에 영향을 미칠 수 있는 또 다른 요인은 

반응을 매개하는 수용체입니다(표 6). 

이차 담즙산 타우르소데옥시콜산(TUDCA)에 의한 TGR5 수용체의 결합은 신경염증(TNF-α 및 IL-6)과 산화 질소 및 소포체 스트레스를 완화하여 CUS 마우스의 우울한 표현형을 개선합니다[192]. 이는 미세아교세포에서 TUDCA의 신경 보호 효과에 대한 이전 보고와 일치합니다 [193]. 또한, 리토콜산과 같은 일부 담즙산은 항우울 효과가 잘 확립된 중추 PXR 및 비타민 D 수용체(VDR)를 자극할 수 있으며[194][195, 196], 이는 항우울 효과가 있습니다. 따라서 담즙산이 우울 행동에 미치는 영향은 담즙산이 작용하는 특정 수용체에 따라 달라질 수 있으며, FXR은 친우울 표현형을 매개하고 PXR, VDR 및 TGR5는 항우울 작용을 매개할 수 있습니다. 이 가설은 아직 공식적으로 검증되지 않았습니다.

TABLE 6.

Studies investigating the effects of bile acids on depressive-like behavior.

TreatmentSpecies or strainModelBehavioral outcomesMolecular mechanismsReference

FXR knockout mice	C57BL/6 (4-5 months)	-	↓ immobility time in TST but not in FST (improved depressive-like symptoms); ↑ motor activity; impaired memory.	↓ hippocampal GAD65 and ↑ cerebral GAT1; changes in bile acid concentrations in serum (taurodehydrocholic acid, taurocholic acid, deoxycholic acid, glycocholic acid, tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid) and brain (taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid)	[185]
FXR overexpression‎ (LV-FXR-EGFP)	Male Sprague-Dawley rats (7 weeks)	-	Exacerbates depressive-like behavior in the FST, TST and SPT in naïve rats	No change in hippocampal expression‎ of CREB and CRTC2; ↓ expression‎ of BDNF in hippocampus.	[184]
FXR knockdown (LV-FXR-shRNA-EGFP)	Male Sprague-Dawley rats (7 weeks)	CUMS	Prevents depressive-like behavior in the FST, TST and SPT.	Restores decrease in hippocampal BDNF expression‎.	[184]
Chronic TUDCA (100, 200 mg/kg; ip) or fluoxetine (20 mg/kg; ip) or TUDCA + fluoxetine co-treatment for 10 days	Male C57BL/6J mice (8-10 weeks)	CUS	TUDCA (at 200 mg/kg) ↓ immobile time in TS and FST; ↑ crossing numbers in the OFT; ↑ sucrose intake in SPT compared to vehicle	TUDCA (at 200 mg/kg) ↓ TNFα and IL-6 in hippocampus and PFC	[192]

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BDNF: Brain-Derived Neurotrophic Factor; CREB: Camp Response Element-Binding Protein; CRTC2: CREB-Regulated Transcription Coactivator 2; CUMS: Chronic Unpredictable Mild Stress; CUS: Chronic Unpredictable Stress; FST: Forced-Swim Test; FXR: Farnesoid X Receptor; GAD65: Glutamic Acid Decarboxylase 65; GAT1: GABA Transporter 1; IL-6: Interleukin-6; OFT: Open Field Test; SPT: Sucrose Preference Test; Tnfα: Tumor Necrosis Factor Alpha; TST: Tail Suspension Test; TUDCA: Tauroursodeoxycholic Acid.

Choline metabolites

Choline is an essential nutrient mainly obtained from dietary lecithin and carnitine, but in humans, small amounts of choline can also be synthesized in the liver [197]. Choline has structural, epigenetic and cell signaling functions. It is involved in the synthesis of acetylcholine and it is a precursor of the cell membrane components phosphatidylcholine and sphingomyelin. Although not a bacterial product per se, choline is broken down by the action the gut microbiota into a range of metabolites, including trimethylglycine (betaine) and trimethylamine (TMA). In the liver, flavin monooxygenase, a family of xenobiotic-metabolizing enzymes, can further convert TMA into trimethylamine-N-oxide (TMAO) [198]. The role of the gut microbiota in choline metabolism is demonstrated by the positive association found between the plasma levels of TMA and TMAO with the microbial order Clostridiales, the genus Ruminococcus, and the taxon Lachnospiraceae, and the negative association with proportions of S24-7, an abundant family from Bacteroidetes, in mice [199]. In a CUMS rat model, depression was associated with increased TMA but decreased TMAO levels [200]. Since choline metabolism by the gut microbiota can deplete choline stores available for the host, excessive choline-utilizing bacteria can mimic the effects of choline deficiency, such as increased occurrence of metabolic diseases, higher cardiovascular risk, as well as altered behavior [201]. For example, reduced choline availability in the hippocampus and basal ganglia was reported in MDD patients [202, 203]. Reduced circulatory choline [117, 204], but elevated plasma TMAO [204] were also found in patients with depressive symptoms. However, this evidence is far from conclusive, as increased central concentrations of choline have been reported in depressed adults [195, 205, 206] as well as children and adolescents [207–209]. Moreover, the choline metabolites dimethylamine, dimethylglycine, and TMAO were found to be significantly lower in the urine of MDD subject compared to controls [210]. It is apparent that contradictory evidence exists with regards to the role of these microbial metabolites in the context of depression. The finding that urinary choline concentrations were lower in moderate MDD, but higher in severe MDD compared to matched control [211] hints to the complexity of choline metabolism in relation to depressive behavior.

콜린은 

주로 식이 레시틴과 

카르니틴에서 얻는 필수 영양소이지만, 

사람의 경우 간에서도 소량의 콜린이 합성될 수 있습니다[197]. 

콜린은 

구조적, 후성유전학적, 세포 신호 전달 기능을 가지고 있습니다. 

콜린은 

아세틸콜린 합성에 관여하며 

세포막 성분인 포스파티딜콜린과 스핑고마이엘린의 전구체입니다. 

콜린 자체는 

박테리아의 산물은 아니지만 

장내 미생물의 작용에 의해 

트리메틸글리신(베타인)과 트리메틸아민(TMA)을 포함한 

다양한 대사산물로 분해됩니다. 

간에서 이종 생물 대사 효소 계열인 플라빈 모노옥시게나제는

 TMA를 트리메틸아민-N-옥사이드(TMAO)로 추가 전환할 수 있습니다[198]. 

콜린 대사에서 장내 미생물의 역할은 

TMA와 TMAO의 혈장 수준과 

클로스트리듐속, 루미노코커스속, 라크노스피라세아목의 미생물 분류군 사이의 긍정적인 연관성 및 생쥐의 박테로이데테아과에 속하는 S24-7의 비율과의 부정적인 연관성을 통해 입증되었습니다 [199]. 

CUMS 쥐 모델에서 우울증은 TMA 증가와 관련이 있지만 TMAO 수치는 감소했습니다[200]. 장내 미생물에 의한 콜린 대사는 숙주가 사용할 수 있는 콜린 저장소를 고갈시킬 수 있으므로 과도한 콜린 활용 박테리아는 대사 질환 발생 증가, 심혈관 위험 증가, 행동 변화와 같은 콜린 결핍의 영향을 모방할 수 있습니다 [201]. 

예를 들어, 

해마와 기저핵의 콜린 가용성 감소는 

MDD 환자에서 보고되었습니다[202, 203]. 

우울 증상이 있는 환자에서도 

순환 콜린 감소[117, 204]와 혈장 TMAO 증가[204]가 발견되었습니다. 

그러나 우울한 성인[195, 205, 206]과 소아 및 청소년[207-209]에서도 콜린의 중추 농도 증가가 보고되었기 때문에 이러한 증거는 결정적이지 않습니다. 또한, 콜린 대사산물인 디메틸아민, 디메틸글리신, TMAO는 대조군에 비해 MDD 환자의 소변에서 유의하게 낮은 것으로 나타났습니다[210]. 우울증의 맥락에서 이러한 미생물 대사 산물의 역할과 관련하여 모순되는 증거가 존재한다는 것이 분명합니다. 중등도 MDD에서는 소변 콜린 농도가 낮았지만, 대조군에 비해 중증 MDD에서는 더 높았다는 결과는[211] 우울 행동과 관련된 콜린 대사의 복잡성을 암시합니다.

Thus, different mechanisms may exist through which choline and its metabolites influence emotional behavior. One of these potential modes of action is DNA methylation. Romano et al. [201] showed that bacterial consumption of choline reduced the availability of methyl donors and altered global DNA methylation patterns in both the adult mice and their offspring, in line with previous reports of maternal choline deficiency inducing diminished hippocampal DNA methylation and neurodevelopmental abnormalities in the offspring [212]. Choline contributes to DNA methylation by modulating the production of the methyl donor S-adenosylmethionine (SAM) [201]. In a rat model of early-life stress, supplementation of choline and betaine and other methyl donors was successful in reversing depressive-like behavior [213]. In humans, betaine exhibited a positive effect on mood by promoting the DNA methylation of SAM: in subjects with mild MDD, adjunctive treatment of SAM with betaine showed higher antidepressant efficacy than treatment with SAM alone [214].

따라서 

콜린과 그 대사 산물이 정서적 행동에 영향을 미치는 다양한 메커니즘이 존재할 수 있습니다. 

이러한 잠재적 작용 방식 중 하나는 

DNA 메틸화입니다. 

로마노 등[201]은 박테리아의 콜린 섭취가 성체 생쥐와 그 자손 모두에서 메틸 공여자의 가용성을 감소시키고 전체 DNA 메틸화 패턴을 변화시켰으며, 이는 모체 콜린 결핍이 자손의 해마 DNA 메틸화 감소 및 신경 발달 이상을 유도한다는 이전 보고와 일치한다고 밝혔습니다 [212]. 콜린은 메틸 공여체인 S-아데노실메티오닌(SAM)의 생성을 조절하여 DNA 메틸화에 기여합니다[201]. 초기 스트레스 쥐 모델에서 콜린과 베타인 및 기타 메틸 공여체를 보충하면 우울증과 유사한 행동을 역전시키는 데 성공했습니다 [213]. 사람의 경우, 베타인은 SAM의 DNA 메틸화를 촉진하여 기분에 긍정적인 영향을 미치는 것으로 나타났습니다: 경증 MDD 환자의 경우, SAM을 베타인과 함께 보조적으로 치료하면 SAM 단독 치료보다 더 높은 항우울제 효능을 보였습니다 [214].

An alternative mechanism involves the modulation of neurotransmission. Oral ingestion of choline increases its concentrations in the brain [215], suggesting that dietary choline can contribute to acetylcholine synthesis. This suggests that abnormal choline metabolism may promote depressive behavior by altering the availability of choline destined for acetylcholine synthesis. In fact, the neurotransmitter acetylcholine is present in significantly higher concentrations in MDD patients than in healthy subjects [216]. Since choline can reach the CNS via active transport across the BBB [217], excessive choline in the periphery may have a significant impact on mood and behavior.

또 다른 메커니즘은 

신경 전달을 조절하는 것입니다. 

콜린을 

경구 섭취하면 

뇌의 콜린 농도가 증가하는데[215], 

이는 식이 콜린이 아세틸콜린 합성에 기여할 수 있음을 시사합니다. 

이는 비정상적인 콜린 대사가 

아세틸콜린 합성을 위한 콜린의 가용성을 변화시킴으로써 

우울한 행동을 촉진할 수 있음을 시사합니다. 

실제로 

신경전달물질인 아세틸콜린은 

건강한 사람보다 MDD 환자에게서 

훨씬 더 높은 농도로 존재합니다[216]. 

콜린은

 BBB를 통한 활성 수송을 통해 중추신경계에 도달할 수 있기 때문에[217], 

말초의 과도한 콜린은 기분과 행동에 상당한 영향을 미칠 수 있습니다.

There remains uncertainty regarding the impact of choline metabolites on behavior (Table 7). While choline deficiency may be detrimental for mental health due to insufficient DNA methylation, excessive choline may contribute to depressive pathology by leading to enhanced acetylcholine synthesis. In addition, the extent to which the gut microbiota impacts on choline metabolism remains unknown, since clinical trials have shown that TMAO levels do not respond to prebiotic administration [218–220].

콜린 대사산물이 행동에 미치는 영향에 대해서는 아직 불확실성이 남아 있습니다(표 7). 

콜린 결핍은 

불충분한 DNA 메틸화로 인해 정신 건강에 해로울 수 있지만, 

과도한 콜린은 아세틸콜린 합성을 촉진하여 우울한 병리를 유발할 수 있습니다. 

또한 장내 미생물이 콜린 대사에 어느 정도 영향을 미치는지는 아직 밝혀지지 않았는데, 임상시험 결과 프리바이오틱스 투여에 TMAO 수치가 반응하지 않는 것으로 나타났습니다[218-220].

TABLE 7.

Studies investigating the effects of choline metabolites on depressive-like behavior.

TreatmentSpecies or strainModelBehavioral outcomesMolecular mechanismsReference

Methyl donor supplementation (choline, betaine, folate, vitamin B12) for 18 weeks

Wistar rats

ELS (maternal separation)

↓depressive behavior in the Porsolt FST

normalisation of total and HDL-cholesterol; ↑total DNA methylation and ↑hippocampal (not hypothalamic) expression‎ of the insulin receptor

[213]

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HDL: High-Density Lipoprotein; FST: Forced Swim Test.

Vitamins (folate)

Most bacteria in the gut, such as Lactobacillus and Bifidobacterium, synthesize vitamins (particularly B-group vitamins and vitamin K) as part of their metabolic processes in the large intestine, and humans rely heavily on the gut microbiota for their production [221]. Vitamins are essential micronutrients with ubiquitous roles in a great number of physiological processes in several organs in the human body, including the brain. Fat-soluble vitamins (such as vitamins A, D, E, and K) make up the cell membrane, while water-soluble vitamins (including the vitamin B family and vitamin C) are enzymatic co-factors for a wide number of physiological reactions [221]. Active transporters are responsible for their transport across the BBB [222]. In the CNS, their role extends from energy homeostasis to neurotransmitter production [223], meaning that vitamin deficiencies can have a significant negative impact on neurological function (e.g. neural tube defects during fetal development). Folic acid, or vitamin B9, is a vitamin of microbial origin that has been extensively implicated in the pathology of depression (Table 8), with one third of depressed patients exhibiting a folate deficiency [224]. Its biosynthesis by the gut microbiota requires the C-N binding of 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) – obtained from guanosine triphosphate (GTP) - and p-aminobenzoic acid (pABA) – a product of the pentose phosphate pathway [225].

락토바실러스와 비피도박테리움과 같은 대부분의 장내 세균은 

대장에서 대사 과정의 일부로 

비타민(특히 비타민 B군과 비타민 K)을 합성하며, 

인간은 장내 미생물에 크게 의존하여 비타민을 생산합니다[221]. 

비타민은 뇌를 비롯한 인체의 여러 기관에서 수많은 생리적 과정에 필수적인 역할을 하는 필수 미량 영양소입니다. 

지용성 비타민(예: 비타민 A, D, E, K)은 

세포막을 구성하는 반면 

수용성 비타민(비타민 B군 및 비타민 C 포함)은 

다양한 생리적 반응의 효소 보조 인자입니다[221]. 

활성 수송체는 BBB를 가로지르는 수송을 담당합니다[222]. 중추신경계에서 이들의 역할은 에너지 항상성에서 신경전달물질 생산에 이르기까지 광범위하며[223], 이는 비타민 결핍이 신경 기능(예: 태아 발달 중 신경관 결손)에 심각한 부정적인 영향을 미칠 수 있다는 것을 의미합니다. 

엽산 또는 비타민 B9는 

미생물 유래 비타민으로 우울증의 병리와 광범위하게 연관되어 있으며(표 8), 

우울증 환자의 1/3이 엽산 결핍증을 보입니다[224]. 

장내 미생물에 의한 생합성을 위해서는 

구아노신 삼인산(GTP)에서 얻은 6-하이드록시메틸-7,8-디하이드롭테린 파이로인산(DHPPP)과 펜토스 인산 경로의 산물인 p-아미노벤조산(pABA)의 C-N 결합이 필요합니다 [225].

TABLE 8.

Studies investigating the effects of folate on depressive-like behavior.

TreatmentSpecies or strainModelBehavioral outcomesMolecular mechanismsReference

Folic acid (75 mg/kg)	Male Sprague-Dawley rats	CUMS	Improvement of depression-like behaviors as assessed in FST, TST and OFT	↑5-HT, BDNF and GluR1 expression‎; changes in synaptic organisation in the brain	[227]
Folic acid (p.o. and i.c.v.) + PCPA (100 mg/kg) or fluoxetine (10 mg/kg, p.o.) or WAY100635 (0.1 mg/kg, s.c.) or ketanserin (5 mg/kg) or yohimbine (1 mg/kg, i.p.)	Male and female Swiss mice	-	↓immobility time in the FST; no effect on locomotor activity; PCPA blocked the decrease in immobility time elicited by folic acid; co-administration of a subeffective fluoxetine produced a synergistic effect with a subeffective dose of folic acid; WAY100635 significantly blocked the decrease in immobility time in the FST elicited by full dose of folic acid; WAY100635 produced a synergistic effect with a subeffective dose of folic acid; ketanserin blocked the decrease in immobility time in the FST elicited by folic acid; yohimbine was also able to prevent the anti-immobility effect the folic acid	-	[226]
folic acid (10 nmol/site, i.c.v.) + naloxone (1 mg/kg, i.p.) or naltrindole (3 mg/kg, i.p.) or naloxonazine (10 mg/kg, i.p.) or naloxone methiodide (1 mg/kg, s.c.)	Male and female Swiss mice	-	Naloxone, naltrindole, naloxonazine, but not naloxone methiodide, prevented the antidepressant-like effect of folic acid in the FST; folic acid + morphine had a synergistic anti-depressant effect in the FST (but no effect on locomotion); naloxone reversed the anti-depressant properties of folic acid + MK-801	-	[232]
Folate-depleted vs folate-supplemented diets	Adult male and female Wistar Kyoto rats	ELS (maternal separation)	dietary methyl donor supplementation induced ↑ exploratory behavior in the OFT, exhibit ↑social behavior and ↓ immobile time in the FST	↑DNA methylation in the hippocampus of mice exposed to maternal separation; ↑brain methionine levels in rats supplemented with methyl donors	[234]
Methyl donor supplementation (choline, betaine, folate, vitamin B12) for 18 weeks	Wistar rats	ELS (maternal separation)	↓depressive behavior in the Porsolt FST	normalisation of total and HDL-cholesterol; ↑total DNA methylation and ↑hippocampal (not hypothalamic) expression‎ of the insulin receptor	[213]
Folic acid (5 or 10 nmol/i.c.v.; 25, 50 or 75 mg/kg p.o.), or fluoxetine (20 or 25 mg/kg) or 17-β estradiol (10 or 20 μg/rat); combination of folic acid (2.5 nmol/i.c.v.; or 25.0 mg/kg, p.o.) + fluoxetine (15.0 mg/kg); combination of folic acid (2.5 nmol/i.c.v.; or 25.0 mg/kg, p.o.) + 17-β estradiol (5 μg/rat)	Female Wistar rats	ovariectomized	↓ immobility in the FST; antidepressant effects were not achieved if ketanserin was admnistered.	-	[228]

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5-HT: 5-Hydroxytryptamine; BDNF: Brain-Derived Neurotrophic Factor; CUMS: Chronic Unpredictable Mild Stress; ELS: Early-Life Stres; FST: Forced-Swim Test; GluR1: Glutamate Receptor 1; HDL: High-Density Lipoprotein; MK-801: Non-Competitive NMDA Receptor Antagonist; OFT: Open Field Test; PCPA: Para-Chlorophenylalanine; TST: Tail Suspension Test; WAY100635: 5-HT1A Receptor Antagonist And Full D4 Receptor Agonist.

Folate has an established antidepressant effect in animal models of depression [226–228], with some clinical studies suggesting its potential as antidepressant augmentation therapy in humans [229, 230]. Using a series of pharmacological inhibitors, Brocardo et al. [226] showed that the antidepressant effects of folic acid were dependent of serotonergic (5-HT1A and 5-HT2A/2C receptors) and noradrenergic (α1- and α2-adrenoceptors) activity in mice. The finding that serotonergic and noradrenergic antagonists prevented the antidepressant effects of folic acid supports the possibility that a mechanism of action is represented by an enhancement of monoaminergic production. Folic acid can synthesize tetrahydrobiopterin (BH4), which in turns act as a cofactor for the conversion of phenylalanine and tryptophan into the neurotransmitters dopamine, norepinephrine, and 5-HT [231]. With a similar design, the same group demonstrated that the antidepressant action of folic acid was mediated by the opioid system, as treatment of the mice with different opioid receptor antagonists prevented the folate-induced reduction in immobility time in the forced swim test [232]. The authors also proposed that the action of folic acid may involve inhibition of NMDA receptors [232].

엽산은 

우울증 동물 모델에서 항우울 효과가 입증되었으며[226-228], 

일부 임상 연구에서는 인간에 대한 항우울증 증강 요법으로서의 가능성을 제시하고 있습니다[229, 230]. 

일련의 약리학적 억제제를 사용하여 Brocardo 등[226]은 

엽산의 항우울 효과가 

생쥐의 세로토닌(5-HT1A 및 5-HT2A/2C 수용체) 및 

노르아드레날린(α1- 및 α2- 아드레날린 수용체) 활성에 의존한다는 것을 보여주었습니다. 

세로토닌 및 

노르아드레날린 길항제가 

엽산의 항우울 효과를 방해한다는 발견은 

엽산의 작용 메커니즘이 단아민 생성의 향상으로 대표될 가능성을 뒷받침합니다. 

엽산은 

테트라하이드로비옵테린(BH4)을 합성할 수 있으며, 

이는 페닐알라닌과 트립토판을 

신경 전달 물질인 도파민, 노르에피네프린, 5-HT로 전환하는 보조 인자로 작용합니다[231]. 

유사한 설계를 통해 같은 그룹은 다른 오피오이드 수용체 길항제로 쥐를 치료하면 강제 수영 테스트에서 엽산으로 인한 부동 시간 감소가 방지됨에 따라 엽산의 항우울 작용이 오피오이드 시스템에 의해 매개된다는 것을 입증했습니다 [232]. 저자들은 또한 엽산의 작용이 NMDA 수용체의 억제를 포함할 수 있다고 제안했습니다 [232].

In addition to increased central 5-HT concentrations, folic acid can also induce an increase in BDNF and GluR1 expression‎ in the hippocampus and association cortex, concurrent with a normalization in serum corticosterone concentration, mitochondria structure and spine synapse numbers that were altered in the CUMS model of depression [227]. Due to its involvement in the synthesis of DNA, RNA and proteins and in DNA methylation reactions [233], folate may exert these changes via epigenetics mechanisms. A diet rich in methyl donors such as folic acid has beneficial effects on exploratory behavior, social interaction and depressive-like behavior in rats [213, 234]. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF), converts homocysteine into methionine, which is used for the production of the methyl group donor SAM. In turn, SAM has been demonstrated to have antidepressant properties [235] via DNA methylation of phospholipids [236, 237], with extensive consequences on neurotransmission [238]. Despite the marked improvement in depressive behavior obtained in animal studies, clinical trials have highlighted great heterogeneity and do not provide strong evidence on the benefits of the use of folate as and adjunctive strategy for depression [239].

엽산은 

중추 5-HT 농도 증가 외에도 

해마 및 연합 피질에서 BDNF 및 GluR1 발현의 증가를 유도할 수 있으며, 

동시에 혈청 코르티코스테론 농도, 

미토콘드리아 구조 및 척추 시냅스 수의 정상화와 함께 

우울증의 CUMS 모델에서 변경된 [227] 척추 시냅스 수를 정상화할 수 있습니다. 

엽산은 

DNA, RNA 및 단백질의 합성과 

DNA 메틸화 반응에 관여하기 때문에[233] 

후성유전학 메커니즘을 통해 이러한 변화를 일으킬 수 있습니다. 

엽산과 같은 메틸 공여체가 풍부한 식단은 쥐의 탐색 행동, 사회적 상호 작용 및 우울증과 유사한 행동에 유익한 영향을 미칩니다[213, 234]. 엽산의 활성 대사산물인 5-메틸테트라하이드로엽산(5-MTHF)은 호모시스테인을 메티오닌으로 전환하여 메틸기 기증자인 SAM을 생성하는 데 사용됩니다. 결과적으로 SAM은 인지질의 DNA 메틸화[236, 237]를 통해 신경전달에 광범위한 영향을 미치는 항우울제[235]로 작용하는 것으로 입증되었습니다[238]. 동물 실험에서 얻은 우울 행동의 현저한 개선에도 불구하고 임상 시험에서는 큰 이질성이 강조되었으며 우울증에 대한 보조 전략으로서 엽산 사용의 이점에 대한 강력한 증거를 제공하지 못했습니다 [239].

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FUTURE DIRECTIONS

Almost one third of depressed patients do not respond to treatment long-term [240]. The known impact of the microbiome on pathways involved in depression, as well as evidence linking abnormal microbiota and depressive behavior [14], suggest that targeting the gut microbiota may be an attractive strategy to improve depression-related pathological features. A strong advantage of this approach is the accessibility of the microbiome to nutritional modulation. In fact, administration of the probiotics Bifidobacterium infantis, Lactobacillus rhamnosus, Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 have proved effective in normalizing the gut microbiome and alleviating anxiety- and depression-like symptoms in both rodents [55, 58] and healthy humans [241].

우울증 환자의 

거의 1/3이 장기간 치료에 반응하지 않습니다[240]. 

우울증과 관련된 경로에 대한 

마이크로바이옴의 알려진 영향과 비정상적인 미생물군과 

우울한 행동을 연결하는 증거[14]는 

장내 미생물을 표적으로 삼는 것이 

우울증 관련 병리적 특징을 개선하는 매력적인 전략이 될 수 있음을 시사합니다. 

이 접근법의 강력한 장점은 

영양 조절에 대한 마이크로바이옴의 접근성이라는 점입니다. 

실제로 

프로바이오틱스인 

비피도박테리움 인판티스, 

락토바실러스 람노서스, 

락토바실러스 헬베티쿠스 R0052, 

비피도박테리움 롱검 R0175의 투여는 설치류[55, 58]와 건강한 사람[241] 모두에서 장내 미생물군을 정상화하고 불안 및 우울증 유사 증상을 완화하는 데 효과적인 것으로 입증된 바 있습니다.

However, the complexity of the microbiota and its biochemical exchange with the host need to be better understood before this trans-kingdom communication can be harnessed to ameliorate neurological disorders. The contradictory findings reported across several studies may be reflective of this complexity. Components of the gut microbiota are in a dynamic state of equilibrium, dependent on substrate availability, exposure to antimicrobial compounds and competition with other bacterial strains. In vitro, the production of neuroactive metabolites by probiotics can be affected by nutrient availability [61]. Similarly, an intricate interplay exists between human and bacterial metabolism, as well as among the metabolic pathways reviewed. For example, intestinal neurotransmitter production is intrinsically linked to the abundance of SCFAs and bile acids in the gut, and inflammatory molecules like nitrate promote metabolism of choline by choline-utilizing bacteria [242], suggesting that the psychotropic effect of a specific metabolite may be tightly dependent on the presence of other metabolites. Another challenge encountered by gut-brain axis research is the ability to discriminate between peripheral production of neuroactive metabolites by the gut microbiota, and host production of the same metabolites in the brain. This makes it challenging to understand the extent to which the observed effect on depressive behavior can be ascribed to gut microbial metabolism per se (as compared to host central metabolism).

그러나 미생물 군집의 복잡성과 숙주와의 생화학적 교류가 신경 장애를 개선하는 데 활용되기 위해서는 이러한 왕국 간 소통을 더 잘 이해해야 합니다. 여러 연구에서 보고된 상반된 결과는 이러한 복잡성을 반영하는 것일 수 있습니다. 장내 미생물의 구성 요소는 기질 가용성, 항균 화합물에 대한 노출 및 다른 박테리아 균주와의 경쟁에 따라 역동적인 평형 상태에 있습니다. 시험관 내에서 프로바이오틱스에 의한 신경 활성 대사산물의 생산은 영양소 가용성에 의해 영향을 받을 수 있습니다[61]. 

마찬가지로, 

인간과 박테리아의 신진대사 사이에는 복잡한 상호 작용이 존재하며, 

검토된 신진대사 경로 사이에도 복잡한 상호 작용이 존재합니다. 

예를 들어,

 장내 신경전달물질 생산은 

본질적으로 장내 SCFA 및 담즙산의 풍부함과 관련이 있으며 

질산염과 같은 염증 분자는 

콜린 활용 박테리아의 콜린 대사를 촉진하므로[242] 

특정 대사물질의 향정신성 효과는 다른 대사물질의 존재에 밀접하게 의존할 수 있음을 시사합니다. 

장-뇌 축 연구에서 직면한 또 다른 과제는 

장내 미생물에 의한 말초 신경 활성 대사산물의 생산과 

뇌에서 동일한 대사산물의 숙주 생산을 구별하는 능력입니다. 

따라서 

우울한 행동에 대한 관찰된 효과가 

장내 미생물 대사 그 자체에 기인하는 정도를 숙주 중심 대사에 비해 

어느 정도까지 이해할 수 있는지 파악하기가 어렵습니다.

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CONCLUSION

MDD is a multifaceted mental disorder characterized by a dysfunction of neurochemical, neuroendocrine, immune and metabolic systems. The microbiota-gut-brain axis is a bidirectional network linking the central and enteric nervous systems through the same neural, immune and metabolic routes that are dysregulated in depression [243, 244]. Therefore, gut-brain axis abnormalities in depressed patients may, at least partly, account for the symptomatic presentations of depression. This review highlights how metabolites modulated by the intestinal microbiota can influence mood through their direct action on central receptors, through activation of peripheral receptors on neural, immune or neuroendocrine pathways, and through epigenetic regulation of histone deacetylation or DNA methylation (Table 9).

MDD는 

신경화학, 

신경내분비, 

면역 및 대사 시스템의 기능 장애를 특징으로 하는 다면적인 정신 장애입니다. 

미생물-장-뇌 축은 우울증에서 조절 장애가 발생하는 동일한 신경, 면역 및 대사 경로를 통해 중추 신경계와 장 신경계를 연결하는 양방향 네트워크입니다 [243, 244]. 따라서 우울증 환자의 장-뇌 축 이상은 적어도 부분적으로는 우울증의 증상 발현을 설명할 수 있습니다. 이 리뷰에서는 장내 미생물에 의해 조절되는 대사산물이 중추 수용체에 직접 작용하거나 신경, 면역 또는 신경 내분비 경로의 말초 수용체를 활성화하고 히스톤 탈아세틸화 또는 DNA 메틸화의 후성 유전적 조절을 통해 기분에 영향을 미칠 수 있는 방법을 강조합니다(표 9).

TABLE 9.

Effects of microbial metabolites on depressive behavior in rodent and human studies.

Microbial metaboliteFamilyMetabolic pathwayMetabolising bacteriaEffects on helplessness (rodent studies)Effects on mood (human studies)Potential mechanisms

Propionate	SCFA	Fermentation of fibres / carbohydrate metabolism	Roseburia, Ruminococcus, Salmonella, Blautia, Phascolarctobacterium, Dialister, Coprococcus, Megasphaera	Improves depressed mood	Depleted in MDD patients	Epigenetics (HDACi and DNA methylation modulator); receptors (GPR43, GPR41)
Acetate			Blautia, Marvinbryantia	-
Butyrate			Eubacterium, Roseburia, Anaerostipes, Coprococcus, Feacalibacterium	Improves depressed mood; augments the effect of antidepressant drugs
GABA	NT		Lactobacillus, Bifidobacterium	Antidepressant effect	Depleted in MDD patients
Serotonin			Escherichia coli, Streptococcus, Enterococcus, Akkermansia, Alistipes, Roseburia	Antidepressant effect	Depleted in MDD patients
Dopamine			Escherichia coli, Bacillus cereus, Bacillus mycoides, Bacillus subtilis, Proteus vulgaris, Serratia marcescens and Staphylococcus aureus	Antidepressant effect	Depleted in MDD patients
Acetylcholine			Lactobacillus	-	Increased in MDD patients
Oxindole	Indoles	Tryptophan metabolism	Escherichia coli, Vibrio cholerae and many others	Neurodepressant;	-	Epigenetics (HDACi); modulation of tryptophan availability; receptor AhR
Isatin				Anxiogenic and pro-depressive;	-
Deoxycholic acid	Bile acids	Primary bile acid conjugation	Lactobacillus, Enterococcus, Bacteroides, Clostridium	permealization of the BBB	permealization of intestinal barrier (Caco-2 monolayer)	receptors (FXR and TGR5, PXR and VDR)
Glycocholic acid				increased in serum of depression model	-	receptors (FXR and TGR5, PXR and VDR)
TUDCA				neuroprotective against microglia	-	receptors (FXR and TGR5, PXR and VDR)
Taurocholic acid				FXR overexpression‎ in the rat hippocampus is sufficient to induce depressive-like behavior, while FXR knockdown is both protective and reversing again depressive-like behavior; increased abundance of bile acids in urine, plasma and faecesof depression models	-	receptors (FXR and TGR5, PXR and VDR)
Betaine	Choline derivatives	Choline metabolism	Bacteroidetes	Reverses depressive-like behavior	Reduced in urine of MDD patients; ameliorates symptoms of depression	Affects abundance of choline available for DNA methylation and acetylcholine synthesis
TMA				-	Reduced in urine of MDD patients
TMAO				-	Reduced in urine but elevated in plasma of MDD patients
Lactate	-	Carbohydrate metabolism	L. lactis, L. gasseri, and L. reuteri, Bifidobacteria and Proteobacteria, Eubacterium, Anaerostipes, Veillonella	protective and reversing effects against depression	Increased in urine of MDD patients	Epigenetics (HDACi and DNA methylation modulator); receptor GPR81
Folate (B9)	Vitamin	GTP metabolism	Lactobacillus (L. acidophilus, L. casei, L. paracasei, L. plantarum, L. reuteri, and L. salivarius) and Bifidobacterium	antidepressant effect	enhances action of antidepressant drugs (but lack of conclusive evidence)	Epigenetics (DNA methylation modulator); serotonergic, noradrenergic, opioid and NMDA receptors; BH4 and SAM synthesis

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AhR: Aryl Hydrocarbon Receptor; BBB: Blood Brain Barrier; BH4: Tetrahydrobiopterin; FXR: Farnesoid X Receptor; GPR41: G-protein coupled receptor 41; GPR43: G-protein coupled receptor 43; GPR81: G-protein coupled receptor 81; GTP: Guanosine triphosphate; HDACi: Histone deacetylase inhibitor; MDD: Major Depressive Disorder; NT: Neurotransmitter; PXR: Pregnane X receptor; SAM: S-adenosylmethionine; SCFA: Short-Chain Fatty Acids; TGR5: Takeda G-protein receptor 5; TMA: Trimethylamine; TMAO: Trimethylamine N-oxide; TUDCA: Tauroursodeoxycholic acids; VDR: Vitamin D Receptor

Addressing knowledge gaps on the multifactorial interplay between products of microbial metabolism in relation to their antidepressant effects will advance our understanding of the pathological mechanisms of depression (via the gut-brain axis) and may facilitate the development of more refined pharmacological strategies.

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Abbreviations:

3-HK	– 3-hydroxykynurenine,
5-HIAA	– 5-hydroxyindole acetic acid,
5-HT	– 5-hydroxytryptamine,
AhR	– aryl hydrocarbon receptor,
BBB	– blood-brain barrier,
BDNF	– brain-derived neurotrophic factor,
CNS	– central nervous system,
CUMS	– chronic unpredictable mild stress,
FXR	– farnesoid X receptor,
GABA	– γ-aminobutyric acid,
GI	– gastrointestinal,
HDAC	– histone deacetylase,
HPA	– hypothalamic pituitary adrenal,
IAld	– Indole-3-aldehyde,
IDO	– Indoleamine-2,3-dioxygenase,
IFN	– interferon,
IL	– interleukin,
IPA	– indole-3-propionic acid,
KYNA	– kynurenic acid,
LPS	– lipopolysaccharide,
MDD	– major depressive disorder,
NMDA	– N-methyl-D-aspartate,
PXR	– pregnane X receptor,
SAM	– S-adenosylmethionine,
SCFA	– short-chain fatty acid,
TDO	– tryptophan-2,3-dioxygenase,
TET	– ten-eleven translocation,
TGR5	– Takeda G protein-coupled receptor 5,
TMA	– trimethylamine,
TMAO	– trimethylamine-N-oxide,
TNF-α	– tumor necrosis factor-α,
TPH	– tryptophan hydroxylase,
TUDCA	– tauroursodeoxycholic acid,
VDR	– vitamin D receptor.

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Funding Statement

Giorgia Caspani is supported by the MRC (grant number MR/N014103/1). This research was conducted as part of CAN-BIND, an Integrated Discovery Program supported by the Ontario Brain Institute, which is an independent non-profit corporation, funded partially by the Ontario Government.

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