Re: 장내 유해균이 만드는 장내 가스(방귀).. 황화수소. 파킨슨병

[문형철]

장내세균이 만드는 가스(방귀)

수소, 이산화탄소, 메탄가스 99%

황산염 환원 박테리아

다이설포비브리오

엔테로박테리아

장내 가스인 황화수소(H2S)를 생성

장내가스의 1%밖에 안되는 황화수소는 독성을 가지고 있고.. 아래와 같이 활성산소를 증가시키고, 파킨슨병을 일으킴

Cells. 2022 Mar; 11(6): 978.

Published online 2022 Mar 12. doi: 10.3390/cells11060978

PMCID: PMC8946538

PMID: 35326429

Hydrogen Sulfide Produced by Gut Bacteria May Induce Parkinson’s Disease

Kari Erik Murros

Andrea Bugarcic, Academic Editor

Author information Article notes Copyright and License information PMC Disclaimer

Associated DataData Availability Statement

Abstract

Several bacterial species can generate hydrogen sulfide (H2S). Study evidence favors the view that the microbiome of the colon harbors increased amounts of H2S producing bacteria in Parkinson’s disease. Additionally, H2S can easily penetrate cell membranes and enter the cell interior. In the cells, excessive amounts of H2S can potentially release cytochrome c protein from the mitochondria, increase the iron content of the cytosolic iron pool, and increase the amount of reactive oxygen species. These events can lead to the formation of alpha-synuclein oligomers and fibrils in cells containing the alpha-synuclein protein. In addition, bacterially produced H2S can interfere with the body urate metabolism and affect the blood erythrocytes and lymphocytes. Gut bacteria responsible for increased H2S production, especially the mucus-associated species of the bacterial genera belonging to the Desulfovibrionaceae and Enterobacteriaceae families, are likely play a role in the pathogenesis of Parkinson’s disease. Special attention should be devoted to changes not only in the colonic but also in the duodenal microbiome composition with regard to the pathogenesis of Parkinson’s disease. Influenza infections may increase the risk of Parkinson’s disease by causing the overgrowth of H2S-producing bacteria both in the colon and duodenum.

여러 박테리아 종은 

황화수소(H2S)를 생성할 수 있습니다. 

데설포비브리오 박테리아...

https://www.mdpi.com/2076-2607/11/7/1772

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544126/

카바페넴 항생제 내성 엔테로박테리아..

http://www.snuh.org/health/nMedInfo/nView.do?category=DIS&medid=AA001120

연구 결과에 따르면 

파킨슨병 환자의 대장 미생물군집에는 

H2S를 생성하는 박테리아의 양이 증가한다는 견해를 지지하는 

증거가 있습니다. 

또한 

H2S는 

세포막을 쉽게 투과하여 

세포 내부로 들어갈 수 있습니다. 

세포에서 과도한 양의 H2S는 

잠재적으로 미토콘드리아에서 시토크롬 c 단백질을 방출하고 

세포질 철 풀의 철 함량을 증가시키며 

활성 산소 종의 양을 증가시킬 수 있습니다. 

이러한 사건은 

알파-시누클레인 단백질을 함유한 세포에서 

알파-시누클레인 올리고머와 

피브릴의 형성으로 이어질 수 있습니다. 

또한 

박테리아에 의해 생성된 H2S는 

체내 요산 대사를 방해하고 

혈액 적혈구 및 림프구에 영향을 미칠 수 있습니다. 

장내 세균, 특히 

데설포비브리오과 및 

장내 세균과에 속하는 세균 속의 점액 관련 종은 

파킨슨병의 발병에 중요한 역할을 할 가능성이 높습니다. 

파킨슨병의 발병과 관련하여 

대장뿐만 아니라 

십이지장 미생물군집 구성의 변화에도 

특별한 주의를 기울여야 합니다. 

인플루엔자 감염은 

결장과 십이지장에서 

H2S 생성 박테리아의 과증식을 유발하여

 파킨슨병의 위험을 증가시킬 수 있습니다.

Keywords: hydrogen sulfide, Parkinson’s disease, gut microbiome, Desulfovibrio, enteroendocrine cells, cytochrome c, alpha-synuclein, iron, reactive oxygen species, influenza

1. Introduction

In humans, hydrogen sulfide (H2S) plays various roles in a myriad of physiologic processes relating to inflammatory, immune, endocrine, respiratory, vascular and neuromodulatory actions [1]. Furthermore, H2S is endogenously produced in the human cells by enzymes including cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), which both use L-cysteine as a substrate, and via 3-mercapto-sulfurtransferase (3-MST) pathway that uses 3-mercaptopyruvate as a substrate. Both the brain and colonic tissue generate and modulate H2S production via the activity of CSE and CBS [2]. In healthy humans, the plasma baseline levels of H2S have been reported to lie in the range of 34 μM–274 μM [3,4]. In the gut lumen, the sulfate-reducing bacteria (SRB) and the bacteria of the desulfhydrase enzyme are notable H2S producers. In addition, various bacteria which are homologs of the mammalian CBS, CSE, and 3-MST enzymes are capable of producing H2S. At low concentrations, bacterially produced H2S displays cytoprotective properties by maintaining gut mucus integrity but is toxic to the host at high concentrations [5]. When administered to the human body, H2S diffuses rapidly to blood and, after administration, only a small part of H2S remains in a soluble form [6]. In the blood, H2S combines easily with hemoglobin (Hb) and methemoglobin (metHb) [7,8]. MetHb and H2S form relatively stable metHb-H2S complexes which have a slow reduction rate. Thus, metHb keeps Hb in an oxygen-binding form and acts as a scavenger and regulator of sulfide in the blood [8,9]. In the cells, the main route of H2S elimination is mitochondria, by a chain of several oxidative enzymes [10]. Overall, the toxicity-dose relationship in H2S exposition has been documented to be extremely steep and toxic symptoms such as hypotension and apnea occur when the concentration of free H2S reaches only a few moles per litre in the blood [6]. High H2S concentrations are toxic to cells, causing the inhibition of the cytochrome oxidase, a hemeprotein which is the last enzyme of the electron transport chain in the mitochondria [11]. In addition, H2S induces a release of cytochrome c protein from the mitochondrial membrane, an event though to be associated with the etiopathogenesis of Parkinson’s disease (PD) [12,13].

사람의 경우 

황화수소(H2S)는 

염증, 면역, 내분비, 호흡기, 혈관 및 신경 조절 작용과 관련된 

수많은 생리학적 과정에서 다양한 역할을 합니다[1]. 

또한, H2S는 

L-시스테인을 기질로 사용하는 

시스타티오닌 β-신타제(CBS)와 

시스타티오닌 γ-리아제(CSE) 등의 효소와 

3-메르캅토피루베이트를 기질로 사용하는 

3-MST 경로를 통해 인간 세포에서 내인성적으로 생성됩니다.

 뇌와 대장 조직 모두

 CSE와 CBS의 활동을 통해 

H2S 생성을 생성하고 조절합니다[2].

 건강한 사람의 혈장 기준치 H2S는 

34μM~274μM 범위인 것으로 

보고되었습니다[3,4]. 

장 내강에서 

황산염 환원 박테리아(SRB)와 

탈황수소 효소 박테리아는 

주목할 만한 H2S 생산자입니다. 

또한 

포유류의 CBS, CSE 및 

3-MST 효소의 상동체인 

다양한 박테리아가 H2S를 생성할 수 있습니다. 

저농도에서 박테리아에 의해 생성된 H2S는 

장 점액의 무결성을 유지하여 

세포 보호 특성을 나타내지만 고

농도에서는 숙주에게 독성을 나타냅니다[5]. 

인체에 투여하면

 H2S는 혈액으로 빠르게 확산되며, 

투여 후 H2S의 일부만 용해성 형태로 남게 됩니다[6]. 

혈액에서 H2S는 

헤모글로빈(Hb) 및 메트헤모글로빈(metHb)과 쉽게 결합합니다[7,8]. 

메트헤모글로빈과 H2S는 

비교적 안정적인 메트헤모글로빈-H2S 복합체를 형성하며 

감소 속도가 느립니다. 

따라서 

metHb는 

Hb를 산소 결합 형태로 유지하며 

혈액 내 황화물의 제거제 및 조절제 역할을 합니다[8,9]. 

세포에서 H2S 제거의 주요 경로는 

여러 산화 효소 사슬에 의한 

미토콘드리아입니다 [10]. 

전반적으로 

H2S 노출의 독성-선량 관계는 

매우 가파른 것으로 기록되어 있으며, 

유리 H2S의 농도가 혈중 리터당 몇 몰에 불과할 때 

저혈압 및 무호흡과 같은 독성 증상이 발생합니다[6]. 

높은 H2S 농도는 

세포에 독성이 있어 

미토콘드리아에서 전자 수송 사슬의 마지막 효소인 

혈액 단백질인 시토크롬 산화 효소를 억제합니다 [11]. 

또한, 

H2S는 

미토콘드리아 막에서 시토크롬 c 단백질의 방출을 유도하는데, 

이는 파킨슨병(PD)의 발병 기전과 관련이 있는 것으로 알려져 있습니다[12,13].

2. H2S Releases Cytochrome c from the Mitochondria—Start for Alpha-Synuclein Aggregation

Cytochrome c is (Cyt c) is a small heme protein responsible for the electron shuttle between Complex III and Complex IV of the respiratory chain in the mitochondria. It binds to the mitochondrial inner membrane partly by weak readily mobilized electrostatic interactions [14]. In an experiment where cultured human lung fibroblasts were treated with increased H2S concentrations, a release of Cyt c from the mitochondria was observed [15]. In a study where human gingival epithelial cells were incubated for up to three days with air containing a low concentration (50 ng/mL) of H2S, a remarkable release of Cyt c from the mitochondria was noted [16]. Accordingly, when human dental pulp stem cells were exposed to air somposed of a similar low concentration of H2S, significant increases in the apoptotic enzyme levels (caspase-9 and -3), accompanied by increases in the Cyt c release from the mitochondria were observed [17]. Special information on the dynamics of Cyt c release from the mitochondria provides information on the effects of rotenone, a poisonous isoflavone which has been used in animal studies to induce experimental PD. In a proportional rotenone titration, a proportional increase in the release of Cyt c from the mitochondria was documented in this study [18]. Of importance, neurons can tolerate Cyt c release into the cytosol without inducing apoptosis. Although Cyt c concentrations were already modestly increased in the cytosol, the activity of the apoptosis indicator caspase 9 was not increased [18]. In its compact state, Cyt c possesses peroxidase activity [19]. In the preapoptotic phase when Cyt c relase has already started, Cyt c can interact with anionic lipids and due to these interactions, Cyt c can develop remarkable peroxidase activity [20,21]. The anionic lipids containing Cyt c-peroxidase can utilize cytoplasmic alpha-synuclein (aSyn) as a peroxidase substrate which leads to an aggregation of aSyn and Cyt c, a reaction reflecting mostly a protective role of aSyn against apoptosis [21]. The native Cyt c, which leads to peroxidase activity, can potentially take part in the aSyn oligomerization and aggregation in the cytosol. It has been shown that aSyn aggregation and aSyn radical formation occurs in the interaction between Cyt c, aSyn and hydrogen peroxide, a member of the reactive oxygen species (ROS) [22,23].

사이토크롬 c는 

미토콘드리아에서 

호흡 사슬의 복합체 III과 

복합체 IV 사이의 전자 셔틀을 담당하는 

작은 헴 단백질입니다(Cyt c). 

이 단백질은 

부분적으로 쉽게 동원되는 

약한 정전기적 상호작용을 통해 

미토콘드리아 내막에 결합합니다[14]. 

배양된 인간 폐 섬유아세포를 증가된 H2S 농도로 처리한 실험에서 

미토콘드리아에서 Cyt c가 방출되는 것이 

관찰되었습니다 [15]. 

인간 치은 상피 세포를 저농도(50ng/mL)의 H2S가 포함된 공기와 함께 

최대 3일 동안 배양한 연구에서 미토콘드리아에서 

Cyt c의 현저한 방출이 관찰되었습니다 [16]. 

따라서, 

인간 치수 줄기세포를 유사한 

저농도의 H2S로 구성된 공기에 노출했을 때 

미토콘드리아에서 Cyt c 방출의 증가와 함께 

세포 사멸 효소 수준(caspase-9 및 -3)의 현저한 증가가 관찰되었습니다 [17]. 

미토콘드리아에서 

Cyt c 방출의 역학에 대한 특별한 정보는 

실험적 PD를 유도하기 위해 동물 연구에서 사용된 

독성 이소플라본인 로테논의 효과에 대한 정보를 제공합니다. 

이 연구에서는 로테논 적정에서 미토콘드리아에서 

Cyt c의 방출이 비례적으로 증가하는 것이 

기록되었습니다[18]. 

중요한 것은 

뉴런이 세포 사멸을 유도하지 않고도 

세포질로의 Cyt c 방출을 견딜 수 있다는 것입니다. 

세포질에서 Cyt c 농도는 

이미 완만하게 증가했지만 

세포 사멸 지표인 카스파제 9의 활성은 증가하지 않았습니다 [18]. 

압축된 상태에서 Cyt c는 

퍼옥시다아제 활성을 가지고 있습니다 [19]. 

Cyt c 릴라제가 이미 시작된 세포 사멸 전 단계에서 

Cyt c는 음이온성 지질과 상호 작용할 수 있으며 

이러한 상호 작용으로 인해 Cyt c는 

놀라운 퍼옥시다아제 활성을 나타낼 수 있습니다 [20,21]. 

Cyt c-퍼옥시다제를 포함하는 

음이온성 지질은 세

포질 알파-시누클레인(aSyn)을 퍼옥시다제 기질로 활용할 수 있으며, 

이 반응은 대부분 세포 사멸에 대한 

aSyn의 보호 역할을 반영하는 

aSyn과 Cyt c의 응집으로 이어집니다 [21]. 

퍼옥시다제 활성을 유도하는 네이티브 Cyt c는 잠재적으로 세포질에서 aSyn 올리고머화 및 응집에 참여할 수 있습니다. 활성 산소 종(ROS)의 일원인 Cyt c, aSyn 및 과산화수소 간의 상호 작용에서 aSyn 응집 및 aSyn 라디칼 형성이 발생하는 것으로 나타났습니다[22,23].

Alterations in the iron metabolism induced by H2S probably take part in the aSyn aggregation. It has been reported that sulfide releases iron from the mammalian ferritin and rises the ferrous iron levels of the cytosolic labile iron pool (LIP) and some evidence favors the view that H2S can reduce intracellular bound ferric iron to form unbound ferrous iron [24,25,26]. Furthermore, it has been demonstrated that ferrous iron promotes both aSyn aggregation and transmission by inhibiting the autophagosome-lysosome fusion [27]. In case the iron content of the LIP reaches abnormally high levels, ROS formation in the cell eventually increases [26,28]. The possible presence of magnetite nanoparticles produced by some Desulfovibrio gut bacteria may be an additional factor in the increase in cytosolic ROS levels in the gut cells [13,29,30]. The increased ROS formation likely favors the emergence of aSyn oligomers and fibrils in the presence of Cyt c and aSyn (Figure 1)

H2S에 의해 유도된 철 대사의 변화는 

아마도 aSyn 응집에 관여할 것입니다. 

황화물은 

포유류의 페리틴에서 철을 방출하고 

세포질 불안정 철 풀(LIP)의 철 수치를 상승시키는 것으로 보고되었으며, 

일부 증거는 H2S가 세포 내 결합 철을 감소시켜 

결합되지 않은 철을 형성할 수 있다는 견해를 지지합니다 [24,25,26]. 

또한, 

철분은 

오토파지좀-리소좀 융합을 억제하여 

aSyn 응집과 전달을 모두 촉진한다는 사실이 입증되었습니다 [27]. 

LIP의 철분 함량이 

비정상적으로 높은 수준에 도달하면 

결국 세포 내 ROS 형성이 증가합니다 [26,28]. 

일부 데설포비브리오 장내 세균에 의해 생성되는 

자철광 나노 입자의 존재 가능성은 

장 세포의 세포질 ROS 수준을 증가시키는 

추가적인 요인이 될 수 있습니다 [13,29,30]. 

증가된 ROS 형성은 

Cyt c와 aSyn이 존재하는 경우 

aSyn 올리고머와 피브릴의 출현을 선호할 가능성이 높습니다(그림 1).

Figure 1

Plausible pathophysiological mechanism of Parkinson’s disease. Overgrowth of H2S producing gut bacteria raises H2S concentrations in the gut cells and blood. In the gut cells, excessively increased H2S releases Cyt c from the mitochondria and increases cytosolic iron (Fe2+) levels. Consequently, the amount of reactive oxygen species (ROS) increases. The presence of magnetite nanoparticles originating from the Desulfovibrio species can further increase the emergence of ROS. The co-occurence of aSyn, Cyt c, and ROS (especially hydrogen peroxide) leads to aSyn aggregation. Emerged aSyn aggregates (oligomers and fibrils) may spread in a prion-like manner to the lower brain stem via the vagal nerve. In the blood H2S combines with hemoglobin. Part of H2S may remain in a free form and possibly induce aSyn aggregation even in the brain neurons.

파킨슨병의 그럴듯한 병리 생리학적 메커니즘. 

H2S를 생성하는 장내 박테리아가 과도하게 증식하면 

장 세포와 혈액의 H2S 농도가 높아집니다. 

장 세포에서 과도하게 증가된 H2S는 

미토콘드리아에서 Cyt c를 방출하고 

세포질 철(Fe2+) 수치를 증가시킵니다. 

결과적으로 

활성 산소 종(ROS)의 양이 증가합니다. 

데설포비브리오 종에서 유래한 

마그네타이트 나노 입자의 존재는 

ROS의 출현을 더욱 증가시킬 수 있습니다. 

aSyn, Cyt c, ROS(특히 과산화수소)의 동시 발생은 

aSyn 응집으로 이어집니다. 

생성된 aSyn 응집체(올리고머 및 피브릴)는 

미주 신경을 통해 프리온과 유사한 방식으로 

뇌간 하부로 퍼질 수 있습니다. 

혈액에서 H2S는 

헤모글로빈과 결합합니다. 

H2S의 일부는 유리 형태로 남아 

뇌 신경세포에서도 aSyn 응집을 유도할 수 있습니다.

3. Overgrowth of H2S Producing Gut Bacteria—Putative Consequences

Several bacterial species generate H2S in the human gastrointestinal canal. A prominent overgrowth of these species may lead to a spectrum of undesired consequences. Notably, H2S is capable of penetrating cell membranes easily without any help of a facilitator for this transport [31]. To counteract the toxic effects of H2S the colonic mucosal cells are subject to an efficient mechanism to dispose H2S by oxidizing it to thiosulfates [32]. In mitochondria, a chain of enzymatic reactions starting with the actions of sulfide quinone oxidoreductase (SQR) catalyze the oxidation of sulfide to thiosulfate, which is further oxidized to sulfate and excreted by the kidney [10]. In case H2S is produced in abnormally high amounts by the gut bacteria, the concentration of H2S may exceed the capacity of the gut cells to detoxify all H2S and part of it may end up in the blood. Experimentally, it has been shown that free H2S levels are reduced in the plasma and gastrointestinal tissue of germ-free mice, indicating that the gut microbiota activity can increase plasma H2S concentrations [33]. A large study where plasma metabolome data were integrated with the gut microbiome data of PD patients and healthy controls revealed changes in sulfur metabolism driven by Akkermansia muciniphila and Bilophila wadsworthia bacteria [34]. Notably, the secretion potential of H2S was detected to increase in the PD microbiome in that study. Further support for the view that increased H2S production occurs in PD is a study where blood metHb content was reported to be increased in PD patients [35]. In addition, it has been shown that PD patients have significantly higher concentrations of H2S in the cerebrospinal fluid when compared to control subjects [36]. Studies providing information on the correlations between blood concentrations of H2S and quantities of gut bacteria producing H2S are not availabe. If the production of H2S by gut bacteria leads to unphysiologically high blood concentrations, the brain tissue may be especially sensitive to the toxic actions of H2S as the activity of SQR enzyme activity is apparently very low in the mammalian brain cells [37]. As to changes in the blood constituents, CD8+ cytotoxic T-lymphocytes have been especially reported to be decreased in the blood of PD patients and this decrease seems to be associated with the severity of PD [38]. Furthermore, H2S effects may provide an explanation for the finding as it has been found that exogenous H2S induces the cell death of peripheral blood lymphocytes with relevant subset specifity for the CD8+ T lymphocytes and natural killer cells [39]. As an additional observation, increased H2S levels likely modify plasma uric acid (UA) concentrations which reflect the intestinal metabolism of dietary purines such as xanthine [40]. Additionally, H2S has been reported to decrease UA formation from xanthine, giving one explanation for the finding that plasma UA levels are lowered in patients with PD [41,42].

몇몇 박테리아 종은 

사람의 위장관 내에서 

H2S를 생성합니다. 

이러한 박테리아가 눈에 띄게 과도하게 증식하면 

여러 가지 원치 않는 결과를 초래할 수 있습니다. 

특히, 

H2S는 이 수송을 위한 촉진제의 도움 없이도 

세포막을 쉽게 투과할 수 있습니다[31]. 

H2S의 독성 영향에 대응하기 위해 

대장 점막 세포는 

H2S를 티오황산염으로 산화시켜 폐기하는 

효율적인 메커니즘을 사용합니다 [32]. 

미토콘드리아에서는 

황화물 퀴논 산화 환원 효소(SQR)의 작용으로 시작하는 

일련의 효소 반응이 황화물이 

티오황산염으로 산화되는 것을 촉매하여 

황산염으로 더 산화되어 

신장을 통해 배설됩니다 [10]. 

장내 세균에 의해 

H2S가 비정상적으로 많은 양이 생성되는 경우 

H2S의 농도가 장 세포가 

모든 H2S를 해독하는 능력을 초과하여 

일부가 혈액에 남아있을 수 있습니다. 

실험적으로 

무균 마우스의 혈장 및 위장 조직에서 

유리 H2S 수준이 감소하는 것으로 나타났는데, 

이는 장내 미생물 활동이 혈장 H2S 농도를 증가시킬 수 있음을 나타냅니다[33]. 

혈장 대사체 데이터를 PD 환자 및 건강한 대조군의 장내 미생물 데이터와 통합한 대규모 연구에서는 

아커만시아 뮤시니필라(Akkermansia muciniphila) 및 

빌로필라 와드워시아(Bilophila wadsworthia) 박테리아에 의한 

황 대사의 변화가 밝혀졌습니다 [34]. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856723/

특히, 해당 연구에서 

PD 마이크로바이옴에서 

H2S의 분비 잠재력이 증가하는 것으로 나타났습니다. 

PD에서 H2S 생산이 증가한다는 견해를 뒷받침하는 또 다른 연구는

 PD 환자에서 혈중 metHb 함량이 증가한다고 보고된 연구입니다 [35]. 

또한 PD 환자는 대조군과 비교했을 때 

뇌척수액 내 H2S 농도가 상당히 높은 것으로 나타났습니다 [36]. 

혈중 H2S 농도와 H2S를 생성하는 

장내 박테리아의 양 사이의 상관관계에 대한 정보를 제공하는 연구는 아직 없습니다. 

장내 세균에 의한 H2S 생성으로 인해 

혈중 농도가 비생리적으로 높아지면 

포유류 뇌세포에서 SQR 효소 활성이 매우 낮기 때문에 

뇌 조직이 특히 H2S의 독성 작용에 민감할 수 있습니다 [37]. 

혈액 성분의 변화와 관련하여, 

특히 PD 환자의 혈액에서 CD8+ 세포독성 T 림프구가 감소하는 것으로 보고되었으며 

이러한 감소는 PD의 중증도와 관련이 있는 것으로 보입니다 [38]. 

또한, 외인성 H2S가 CD8+ T 림프구 및 

자연 살해 세포에 대한 관련 하위 집합 특이성을 가진 

말초 혈액 림프구의 세포 사멸을 유도하는 것으로 밝혀졌기 때문에 

H2S 효과는 이러한 결과에 대한 설명을 제공할 수 있습니다 [39]. 

추가 관찰 결과, 

H2S 수치가 증가하면 

크산틴과 같은 식이 퓨린의 장내 대사를 반영하는 

혈장 요산(UA) 농도가 

변경될 가능성이 있습니다[40]. 

또한 

H2S는 

크산틴으로부터의 UA 형성을 감소시키는 것으로 보고되어, 

PD 환자에서 혈장 UA 수치가 낮아진다는 결과에 대한 

한 가지 설명을 제공합니다 [41,42].

Go to:

4. H2S and aSyn Containing Gut Cells

Of special concern is the part of the gut epithelial cells which faces the gut lumen without vascular covering. Consequently, those epithelial cells such as the enteroendocrine cells (EECs) which lack the protective role of blood Hb and metHb to scavenge H2S are at an increased risk of H2S toxicity. An excess production of H2S by bacterial species belonging to the genus Desulfovibrio (gDSV) has been suggested to induce Cyt c release from the mitochondria and aSyn oligomerization in the EECs [12,13]. It has been reported that aSyn is expressed in EECs both of the small and large intestine and that EECs are connected to enteric nerves [43,44]. In addition, EECs express both pre- and postsynaptic proteins, implying that EECs both send and receive neural signals [44]. Similarly to EECs, enteric neurons carry a potential risk to produce aSyn oligomers when exposed to high levels of H2S as enteric neurons contain aSyn [45]. Hypothetically, if aSyn oligomers are produced in EECs and enteric neurons, part of them are possibly secreted in the blood. Significantly elevated levels of oligomeric forms of aSyn have been observed in the blood plasma of PD patients [46]. However, the origin of these oligomeric aggregates has remained an open issue. As a potential mechanism, aSyn oligomers and fibrils propagate, in the same way as prions, from the EECs and enteric neurons by a cell-to-cell mechanism to the lower brain stem via the vagal nerve (Figure 1). Experimentally, it has been shown that different forms of aSyn, after being injected into the intestinal wall, are transported to the brainstem via the vagal nerve [47]. In another study on transgenic rats expressing an excess of human aSyn, injections of aSyn fibrils into the duodenum wall induced aSyn pathology both in the parasympathetic and sympathetic pathways [48].

특히 우려되는 부분은 

혈관으로 덮여 있지 않고 

장 내강과 마주하고 있는 

장 상피 세포 부분입니다. 

따라서 

혈중 헤모글로빈과 메트헤모글로빈의 보호 역할이 부족한 

장내분비세포(EEC)와 같은 상피 세포는

 H2S를 제거하기 위해 H2S 독성 위험이 높습니다. 

데설포비브리오 속(gDSV)에 속하는 

박테리아 종에 의한 H2S의 과잉 생산은 

미토콘드리아에서 Cyt c 방출과 EEC에서 aSyn 올리고머화를 유도하는 것으로 제안되었습니다[12,13]. 

소장 및 대장 모두에서 aSyn이 발현되고 

EEC가 장 신경과 연결되어 있는 것으로 보고되었습니다 [43,44]. 

또한 EEC는 시냅스 전 단백질과 시냅스 후 단백질을 모두 발현하는데, 이

는 EEC가 신경 신호를 주고 받는다는 것을 의미합니다[44]. 

EEC와 유사하게, 장 뉴런은 aSyn을 포함하고 있기 때문에 

높은 수준의 H2S에 노출되면 

aSyn 올리고머를 생성할 수 있는 잠재적 위험이 있습니다 [45]. 

가설적으로, 

EEC와 장 뉴런에서 aSyn 올리고머가 생성되면

 그 중 일부가 혈액으로 분비될 수 있습니다. 

PD 환자의 혈장에서 

유의미하게 높은 수준의 올리고머 형태의 aSyn이 관찰되었습니다 [46]. 

그러나 

이러한 올리고머 형태의 응집체의 기원은 

아직 미해결 과제로 남아 있습니다. 

잠재적인 메커니즘으로, aSyn 올리고머와 피브릴은 프리온과 같은 방식으로 세포 간 메커니즘에 의해 EEC와 장 신경세포에서 미주 신경을 통해 하부 뇌간으로 전파됩니다(그림 1). 실험적으로, 장 벽에 주입된 후 다양한 형태의 aSyn이 미주 신경을 통해 뇌간으로 운반되는 것으로 나타났습니다 [47]. 인간 aSyn을 과도하게 발현하는 형질전환 쥐를 대상으로 한 또 다른 연구에서는 십이지장 벽에 aSyn 원섬유를 주입하면 부교감 및 교감 경로 모두에서 aSyn 병리가 유발되었습니다 [48].

5. H2S Producing Colonic Bacteria and PD

With regard to humans, the excess production of H2S by gut bacteria may induce the emergence of PD. Sulfate-reducing bacteria (SRB) form the main group of H2S-producing bacteria in the feces of healthy people [49]. In this group, the most preval‎ent genera are the hydrogen- and lactate utilizing gDSV, acetate utilizing genus Desulfobacter, and hydrogen and propionate utilizing genus Desulfobulbus [50,51]. Notably, SRB are the only gut microbes that rely on inorganic sulfate for energy conservation [51]. Numerous other bacteria that do not belong to the SRB group produce H2S as well. Among others, bacterial genera such as Alistipes, Bacteroides, Escherichia, Enterobacter, Clostridium, Collinsella, Fusobacterium, Klebsiella, Oscillibacter, Prevotella, Proteus, Porphyromonas, Streptococcus, Veillonella, and Yearsinia include species that have the capacity for primary H2S production via cysteine degradation [51,52]. Of special interest, Bilophila wadsworthia bacteria produces H2S via the taurine degradation pathway [51]. As to specific bacterial species known to produce H2S, Helicobacter pylori, Clostridium difficile, and Desulfovibrio desufuricans have been reported to be associated with the occurrence of PD [13,53,54].

인간의 경우, 

장내 세균에 의한 H2S의 과도한 생산은 

PD의 출현을 유도할 수 있습니다. 

황산염 환원 박테리아(SRB)는 

건강한 사람의 대변에서 

H2S를 생성하는 주요 박테리아 그룹을 형성합니다[49]. 

이 그룹에서 가장 널리 퍼진 속은 

수소 및 젖산염을 활용하는 gDSV 속, 

아세테이트를 활용하는 Desulfobacter 속, 

수소 및 프로피오네이트를 활용하는 Desulfobulbus 속입니다 [50,51]. 

특히 SRB는 

에너지 보존을 위해 무기 황산염에 의존하는 

유일한 장내 미생물입니다[51]. 

SRB 그룹에 속하지 않는 

수많은 다른 박테리아도 H2S를 생성합니다. 

그중에서도 

알리스티페스, 

박테로이데스, 

에스테리치아, 

엔테로박터, 

클로스트리디움, 

콜린셀라, 

푸소박테리움, 

클렙시엘라, 

오실리박터, 

프리보텔라, 

프로테우스, 

포르피로모나스,

 스트렙토코커스, 

베일로넬라, 

예시니아 같은 세균 속에는 시스테인 분해를 통한 

1차 H2S 생산 능력을 가진 종들이 포함됩니다 [51,52]. 

특히 흥미로운 것은 

빌로필라 워즈워디아(Bilophila wadsworthia) 박테리아가 

타우린 분해 경로를 통해 

H2S를 생성한다는 것입니다[51]. 

헬리코박터 파일로리, 

클로스트리디움 디피실리, 

데설포비브리오 

데수푸리칸스 등 H2S를 생성하는 것으로 알려진 특정 박테리아 종은 

PD 발생과 관련이 있는 것으로 보고되었습니다 [13,53,54].

Numerous studies have been conducted on the microbiome changes in PD with variable results. A large meta-analysis of ten case–control studies on the gut microbiome in PD showed that the fecal samples of PD patients were most consistently enriched by the genera Lactobacillus, Bifidobacterium and Akkermansia [55]. In contrast, the butyrate-producing genera Roseburia, Blautia, Faecalibacterium, Moryella and Anaerostipes were found to be less enriched. In a large microbiome-wide association study (MWAS) the genera Prevotella, Corynebacterium_1, and Porphyromonas, as a cluster of co-occurring opportunistic pathogens, were reported to be enriched in PD [56]. As noted, the genera Prevotella and Porphyromonas are H2S producers. In addition, sulfite reductase, an iron flavoprotein enzyme which produces H2S, has been suggested to be present in the species of the genus Corynebacterium [57]. However, concerning the enrichment of the genus Prevotella in the fecal samples of PD patients in the MWAS study, contrasting results have been reported in some other studies [58,59,60]. In the MWAS study, the relative abundances of the genera Butyricoccus, Lachnospira, Fusikatenibacter, Roseburia, Blautia, Agathobacter and Faecalibacterium, all of which are butyrate producers, were found to be significantly decreased in the PD gut microbiome. An overgrowth of H2S-producing bacteria provides a reasonable explanation for the reduced population of butyrate-reducing bacteria. Furthermore, H2S inhibits acetyl-CoA synthesis and produces CoA-persulfide when reacting with CoA, an essential molecule in the butyrate synthesis pathways [61,62]. In an innovative study on a synthetic microbiome community, composed of several butyrate-producing bacteria, it was observed that H2S, in concentrations similar to those produced by Desulfovibrio piger, inhibited butyrate production across the designed bacterial community, including the members Faecalibacterium prausnitzii and and Roseburia intestinalis [63]. Decreased butyrate production most probably reflects the amount of butyrate-producing gut bacteria. Advocating this view, it has been reported that the amount of butyrate correlate with the abundancies of bacteria of the genus Blautia and bacterial species such as Faecalibacterium prausnitzii and Roseburia faecis [64]. An enrichment of the genera Lactobacillus and Bifidobacterium in the fecal samples of PD patients has been reported in several studies [55,65]. The finding can be explained, at least partly, by the availability of these probiotics as commercial products.

PD의 마이크로바이옴 변화에 대한 수많은 연구가 수행되었으며 

그 결과는 다양합니다. 

PD의 장내 미생물군에 대한 1

0건의 사례 대조 연구에 대한 대규모 메타 분석에 따르면

 PD 환자의 분변 샘플에서 

락토바실러스, 

비피도박테리움, 

아커만시아 속이 가장 일관되게 풍부하게 검출되었습니다 [55]. 

반면 

부티레이트 생성 속인 

로즈부리아, 

블라우티아, 

페칼리박테리움, 

모리엘라, 

아네로스티페스는 그 농도가 낮은 것으로 밝혀졌습니다. 

대규모 마이크로바이옴 전체 연관성 연구(MWAS)에서 공존하는 기회주의 병원균의 군집인 Prevotella, Corynebacterium_1, Porphyromonas 속은 PD에서 더 풍부하게 발견되는 것으로 보고되었습니다[56]. 

앞서 언급했듯이 

Prevotella와 Porphyromonas 속은 

H2S를 생성합니다. 

또한, H2S를 생성하는 

철 플라보단백질 효소인 

아황산염 환원효소는 

코리네박테리움 속의 종에 존재하는 것으로 제안되었습니다 [57]. 

그러나 

MWAS 연구에서 PD 환자의 분변 샘플에서 

프레보텔라 속의 농축과 관련하여 

일부 다른 연구에서 대조적인 결과가 보고되었습니다 [58,59,60]. 

MWAS 연구에서 부티레이트 생산자인 부티리코커스, 라크노스피라, 푸시카테니박터, 로즈부리아, 블라우티아, 아가토박터, 페칼리박테리움 속의 상대적 풍부도가 PD 장내 미생물군에서 현저히 감소한 것으로 나타났습니다. H2S 생성 박테리아의 과다 증식은 부티레이트 감소 박테리아의 개체수 감소에 대한 합리적인 설명을 제공합니다. 

또한, H2S는 부티레이트 합성 경로의 필수 분자인 CoA와 반응할 때 아세틸-CoA 합성을 억제하고 CoA-퍼설파이드를 생성합니다[61,62]. 여러 부티레이트 생산 박테리아로 구성된 합성 마이크로바이옴 커뮤니티에 대한 혁신적인 연구에서, H2S는 데설포비브리오 피거에서 생성되는 것과 유사한 농도로, 페칼리박테리움 프라우스니치(Faecalibacterium prausnitzii)와 로즈부리아 인테스티날리스(Roseburia intestinalis)를 포함하여 설계된 세균 커뮤니티에서 부티레이트 생산을 억제하는 것으로 관찰되었습니다 [63]. 부티레이트 생산 감소는 부티레이트 생성 장내 세균의 양을 반영할 가능성이 높습니다. 이러한 견해를 지지하면서 부티레이트의 양은 Blautia 속 박테리아의 풍부함과 Faecalibacterium prausnitzii 및 Roseburia faecis와 같은 박테리아 종의 풍부함과 상관관계가 있다고 보고되었습니다 [64]. 

여러 연구에서

 PD 환자의 분변 샘플에서 

락토바실러스 속과 비피도박테리움 속이 

농축된 것으로 보고되었습니다 [55,65]. 

이러한 발견은 적

어도 부분적으로는 

이러한 프로바이오틱스가 

상용 제품으로 출시되었기 때문으로 설명할 수 있습니다.

Concerning SRB such as gDSV, their role in the gut microbiota of PD patients requires particular attention. In an Italian study, many bacterial genera, including gDSV, were observed to be enriched in the fecal samples of PD patients. However, after adjusting for several covariates, only the genus Veillonella remained as the enriched genus [66]. The finding is of interest as Veillonella species produce H2S from L-cysteine and an enrichment of this genus has been found to be enriched in the fecal microbiome of the PD patients in an earlier study [52,58,67]. In two Chinese studies, the relative abundance of the family Desulfovibrionaceae was observed to be significantly increased in the fecal samples of PD patients [58,68]. In addition, in a study from southern China, the relative abundance of gDSV was increased in PD patients [68]. Further confirmation for the overgrowth of the family Desulfovibrionaceae in the gut microbiota of PD patients is provided in a Canadian study where the Desulfovibrionaceae and Christensenellaceae families showed overgrowth in the fecal samples of PD patients [69]. The family Christensenellaceae has been reported to be significantly increased in the PD microbiota [55]. One explanation for its increased abundance is linked to body mass index (BMI). Patients with PD have significantly lower BMIs when compared to healthy controls and on the other hand, an inverse correlation exists between BMI and the relative abundance of the Christensenellaceae family [70,71].

gDSV와 같은 SRB의 경우, 

PD 환자의 장내 미생물총에서 

이들의 역할에 특별한 주의가 필요합니다. 

이탈리아의 한 연구에서는 

PD 환자의 분변 샘플에서 g

DSV를 포함한 많은 박테리아 속이 풍부하게 관찰되었습니다. 

그러나 여러 공변량을 조정한 결과, 바일로넬라 속만 농축된 속으로 남아있었습니다 [66]. 바일로넬라 속은 L-시스테인에서 H2S를 생산하며, 이 속은 이전 연구에서 PD 환자의 분변 마이크로바이옴에서 농축된 것으로 밝혀졌기 때문에 이 발견은 흥미롭습니다 [52,58,67]. 두 개의 중국 연구에서, PD 환자의 분변 샘플에서 Desulfovibrionaceae 계통의 상대적 풍부도가 크게 증가하는 것으로 관찰되었습니다 [58,68]. 또한 중국 남부의 한 연구에서는 PD 환자에서 gDSV의 상대적 풍부도가 증가했습니다 [68]. PD 환자의 장내 미생물총에서 Desulfovibrionaceae 계통의 과증식에 대한 추가 확인은 캐나다의 한 연구에서 PD 환자의 분변 샘플에서 Desulfovibrionaceae 및 Christensenellaceae 계통이 과증식한 것으로 나타났습니다 [69]. 크리스텐세넬라과는 PD 미생물총에서 유의미하게 증가한 것으로 보고되었습니다 [55]. 이 미생물의 증가에 대한 한 가지 설명은 체질량 지수(BMI)와 관련이 있습니다. PD 환자는 건강한 대조군에 비해 BMI가 현저히 낮으며, 반면에 BMI와 크리스텐세넬라과의 상대적 풍부도 사이에는 역의 상관관계가 존재합니다 [70,71].

In contrast to a focus on the relative abundances of a multitude of gut bacteria representing various taxonomic levels, one study provided data on the absolute concentrations of the gDSV species Desulfovibrio desulfuricans, D. fairfieldensis, D. piger and D. vulgaris in the fecal samples of PD patients and healthy controls [13]. Excluding D. vulgaris, not found in the PD samples, the gDSV species were present at significantly higher concentrations in the PD samples than in the control samples. In addition, the presence of the periplasmic [FeFe]-hydrogenase, which was used as a common denominator of different gDSV species, correlated with the presence of PD [13]. Apparent cross-feeding takes place between gDSV and genus Akkermansia. In studies on fecal samples, the relative overgrowth of the genus Akkermansia is a common finding in PD patients [55,56,65]. Akkermansia muciniphila, a bacterium residing abundantly in the mucus layer of the large intestine releases sulfate in mucin fermentation, thus offering sulfate to the mucosa-associated SRB [72,73]. A study on sequence analyses of functional gene clones of colonic biopsy samples revealed that SRB populations associate with the mucosa throughout the colon and are phylogenetically related to hydrogenotrophic Desulfovibrio piger, Desulfovibrio desulfuricans and Bilophila wadsworthia bacteria [74]. In colonic mucus samples of healthy people, Bilophila wadsworthia was reported to have a high colonisation rate [75]. Of apparent importance, the relative abundance of the genus Bilophila has been reported to be significantly increased in the fecal samples of PD patients when compared to controls, and to correlate with the clinical stage of PD by the Hoehn and Yahr clinical criteria [76]. As an apparent weakness, the gut microbiome studies on PD have focused mainly on the relative abundancies of various bacterial taxa occurring in the fecal samples. The composition of the mucosal-associated microbiome evidently differs significantly from that of the fecal microbiome, as demonstrated in an analysis comprising both sigmoidoscopy and fecal samples [77]. Genus Escherichia resides especially in the mucosal area [77,78]. Notably, a significantly more intense staining for Eschericia coli has been reported in the sigmoid mucosal samples of PD patients than in the samples of the control subjects [79]. In agreement with this study, the relative abundance of the genus Escherichia-Shigella has been reported to be significantly increased in the fecal samples of PD patient and to correlate with the severity and duration of PD [80].

다양한 분류학적 수준을 대표하는 

여러 장내 세균의 상대적 풍부도에 초점을 맞춘 것과는 대조적으로, 

한 연구에서는 PD 환자와 건강한 대조군의 분변 샘플에서 

gDSV 종인 

데설포비브리오 데설퓨리칸스, 

D. 페어필드엔시스, 

D. 피거 및 D. 불가리스[13]의 절대 농도에 대한 데이터를 제공했습니다 [13]. 

PD 샘플에서 발견되지 않은 D. vulgaris를 제외하고, 

gDSV 종은 대조 샘플보다 P

D 샘플에서 훨씬 더 높은 농도로 존재했습니다. 

또한, 서로 다른 gDSV 종의 공통 분모로 사용된 원형질질 [FeFe]-수소화효소의 존재는 PD의 존재와 상관관계가 있었습니다 [13]. 

gDSV와 아커만시아 속 사이에는

 명백한 교차 먹이가 발생합니다.

 분변 샘플에 대한 연구에서 

아커만시아 속의 상대적 증식은 

PD 환자에서 흔히 발견됩니다 [55,56,65]. 

대장의 점액층에 풍부하게 존재하는 박테리아인 

아커만시아 뮤시니필라는 뮤

신 발효 시 황산염을 방출하여 

점막과 관련된 SRB에 황산염을 제공합니다 [72,73]. 

대장 생검 샘플의 기능 유전자 클론 서열 분석에 대한 연구에 따르면 

SRB 집단은 대장 전체의 점막과 연관되어 있으며 

수소영양성 데설포비브리오 피거, 

데설포비브리오 데설퓨리칸스 및 

빌로필라 와드워디아 박테리아와 

계통 발생학적으로 관련이 있는 것으로 밝혀졌습니다 [74]. 

건강한 사람의 대장 점액 샘플에서 빌로필라 와드워시아는 높은 식민지화율을 보이는 것으로 보고되었습니다 [75]. 명백한 중요성은 대조군과 비교했을 때 PD 환자의 분변 샘플에서 빌로필라 속의 상대적 풍부도가 유의하게 증가했으며, Hoehn 및 Yahr 임상 기준에 따른 PD의 임상 단계와 상관관계가 있는 것으로 보고되었습니다 [76]. PD에 대한 장내 미생물군집 연구는 주로 분변 샘플에서 발생하는 다양한 박테리아 분류군의 상대적 풍부도에 초점을 맞추었습니다. 점막 관련 마이크로바이옴의 구성은 시그모이도스코프와 분변 샘플을 모두 포함한 분석에서 입증된 바와 같이 분변 마이크로바이옴과 크게 다른 것으로 나타났습니다 [77]. 대장균 속은 특히 점막 부위에 많이 서식합니다 [77,78]. 특히, PD 환자의 시그모이드 점막 샘플에서 대조군의 샘플보다 훨씬 더 강렬한 대장균 염색이 보고되었습니다 [79]. 이 연구와 일치하여, PD 환자의 분변 샘플에서 대장균 속의 상대적 풍부도가 유의하게 증가하며 PD의 중증도 및 기간과 상관관계가 있는 것으로 보고되었습니다 [80].

6. H2S Producing Small Intestinal Bacteria and PD

Apart from the changes in the colonic microbiota composition, changes in the quantities of small intestinal bacteria likely relate to the pathogenesis of PD as it suggests the high preval‎ence of small intestinal bacterial overgrowth (SIBO) in the PD population. According to a large meta-analysis, based on lactulose-hydrogen breath test results, a strong association was reported to exist between SIBO and PD [81]. Although increased hydrogen production from the small intestinal microbiome seems to take place in several PD subjects, it is not yet known which bacterial genera or species in the small intestine explain this increase. Hydrogen-utilizing bacteria such as Desulfovibrio species and Bilophila wadsworthia likely benefit from these circumstances. At a general level, the small intestinal microbiome composition has been found to differ markedly from the fecal microbiome composition in humans [82]. A study performed on SIBO and non-SIBO subjects provides interesting information about the duodenal microbiome changes in the SIBO subjects at a general level [82]. In that study, over four-fold higher relative abundance of the class Gammaproteobacteria and three-fold higher relative abundance of the class Deltaproteobacteria was reported to be present in the duodenal aspirates of SIBO subjects when compared to non-SIBO subjects. Of further interest, the family Enterobacteriaceae represented 89 % of the total relative abundance of the Gammaproteobacteria in the duodenum of the SIBO subjects [83]. Notably, hydrogen sulfide-producing genera such as Escherichia, Klebsiella, and Proteus belong to the family Enterobacteriaceae. As to the family members of the class Deltaproteobacteria, especially concerning the family Desulfovibrionaceae, they are best known for their ability to produce H2S. Swallowed bacteria from the oral cavity, emerging, e.g., from the areas of periodontal infections, may possibly play a role in modulating the small intestinal microbiome composition. In a large-scale cohort study, periodontitis was shown to increase the risk of PD [84]. Subgingival deposits occurring with periodontal disease, including cases with aggressive periodontitis, have been reported to contain SRB (which mainly represent the class Deltaproteobacteria) and, among others, bacterial genera such as Porphyromonas and Prevotella [85,86]. Of interest, in a Finnish study on oral mucosal biofilm, significantly increased abundances of the Prevotella and Veillonella genera were observed in PD patients [87].

대장 미생물 구성의 변화와는 별개로, 

소장 박테리아의 양 변화는 

PD 집단에서 소장 박테리아 과증식(SIBO)의 높은 유병률을 시사하기 때문에 

PD의 발병과 관련이 있을 가능성이 높습니다. 

락툴로스-수소 호흡 검사 결과를 기반으로 한 대규모 메타 분석에 따르면, 

SIBO와 PD 사이에는 강력한 연관성이 있는 것으로 보고되었습니다 [81]. 

소장 마이크로바이옴의 수소 생산 증가는 

여러 PD 대상자에서 발생하는 것으로 보이지만, 

소장의 어떤 박테리아 속 또는 종이 이러한 증가를 설명하는지는 아직 알려지지 않았습니다. 

데설포비브리오 종과 

빌로필라 와드워디아 같은 수소 활용 박테리아가 

이러한 상황에서 이득을 볼 가능성이 높습니다. 

일반적인 수준에서 소장의 마이크로바이옴 구성은 

사람의 분변 마이크로바이옴 구성과 현저하게 다른 것으로 밝혀졌습니다 [82]. 

SIBO 및 비 SIBO 피험자를 대상으로 수행된 한 연구는 

일반적인 수준에서 SIBO 피험자의 십이지장 마이크로바이옴 변화에 대한 흥미로운 정보를 제공합니다 [82]. 

이 연구에서 

SIBO 피험자의 십이지장 흡인물에서 

감마프로테오박테리아 계열의 상대적 풍부도가 4배 이상, 

델타프로테오박테리아 계열의 상대적 풍부도가 3배 이상 높은 것으로 보고되었으며, 

이는 비 SIBO 피험자에 비해 더 높은 것으로 나타났습니다. 

더욱 흥미롭게도, 

장내 세균과(Enterobacteriaceae)는 

SIBO 피험자의 십이지장에서 

감마프로테오박테리아의 전체 상대적 풍부함의 89%를 차지했습니다 [83]. 

특히 황화수소를 생성하는 

대장균, 

클렙시엘라, 

프로테우스와 같은 속은 장내 세균과에 속합니다. 

델타프로테오박테리아과, 특히 

데설포비브리오과에 속하는 박테리아는 

황화수소를 생산하는 능력으로 가장 잘 알려져 있습니다. 

구강에서 삼킨 박테리아, 

예를 들어 

치주 감염 부위에서 발생하는 박테리아는 

소장 마이크로바이옴 구성을 조절하는 데 

중요한 역할을 할 수 있습니다. 

대규모 코호트 연구에서 

치주염은 PD의 위험을 증가시키는 것으로 나타났습니다[84]. 

공격적인 치주염을 포함하여 

치주 질환과 함께 발생하는 치은 침착물에는 

SRB(주로 델타프로테오박테리아 계열을 대표함)와 

포르피로모나스 및 프레보텔라와 같은 세균 속이 포함되어 있는 것으로 보고되었습니다 [85,86]. 

흥미로운 점은 

구강 점막 바이오필름에 대한 핀란드의 한 연구에서

 PD 환자에서 Prevotella 및 Veillonella 속이 

현저히 증가하는 것이 관찰되었다는 점입니다[87].

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7. Viral Infections, PD, and H2S Producing Gut Bacteria

Influenza infection evidently increases the risk of PD. In a population-based case–control study in Canada, a significant association was reported to exist between a history of severe influenza and PD [88]. Recently, a case–control study based on the data of over 60 000 individuals from the Danish National Patient Registry showed that a history of influenza was significantly associated with a later occurrence of PD [89]. In addition, the Spanish flu (influenza A subtype H1N1) has been considered to be a risk factor for a later PD occurrence. As to animal studies, it has been shown that influenza A virus (H5N1) can induce a disruption of the mucus layer integrity of the small intestine and cause enteric dysbiosis by increasing the relative amounts of Gammaproteobacteria and Bacilli [90]. In a mice study, the influenza A (PR8) virus infection was demonstrated to induce a significant increase in the intestinal Escherichia coli species [91]. As to another study, influenza A (PR8) infection caused a significant increase in the Enterobacteriaceae population in the stool samples of the wild-type mice [92]. In addition, influenza A virus H3N2 infection has been reported to increase the fecal content of the genus Escherichia in mice [93]. As to human studies, an interesting cross-sectional study on alterations in the gut microbiota of 30 patients with COVID-19 infection, 24 patients with influenza (H1N1), and 30 matched healthy controls showed that the relative abundance of the genus Escherichia-Shigella was significantly higher in the fecal samples of H1N1 patients than in controls [94].

인플루엔자 감염은 

PD의 위험을 분명히 증가시킵니다. 

캐나다의 인구 기반 사례 대조군 연구에서 

중증 인플루엔자 병력과 PD 사이에 유의미한 연관성이 있는 것으로 보고되었습니다[88]. 

최근 덴마크 국가 환자 레지스트리의 60,000명 이상의 데이터를 기반으로 한 사례 관리 연구에 따르면 

인플루엔자 병력이 나중에 PD 발생과 유의미한 관련이 있는 것으로 나타났습니다 [89]. 

또한 스페인 독감(인플루엔자 A 아형 H1N1)은 

추후 PD 발생의 위험 요인으로 간주되었습니다. 

동물 연구에 따르면 인플루엔자 A 바이러스(H5N1)는 

소장의 점액층 완전성을 파괴하고 

감마프로테오박테리아와 바실리의 상대적 양을 증가시켜 

장내 미생물 이상증을 유발할 수 있는 것으로 나타났습니다 [90]. 

생쥐를 대상으로 한 연구에서 인플루엔자 A(PR8) 바이러스 감염은 장내 대장균 종의 상당한 증가를 유도하는 것으로 입증되었습니다 [91]. 또 다른 연구에 따르면 인플루엔자 A (PR8) 감염은 야생형 생쥐의 대변 샘플에서 장내 세균군 개체수를 크게 증가시켰습니다 [92]. 또한 인플루엔자 A 바이러스 H3N2 감염은 생쥐에서 대장균 속의 분변 함량을 증가시키는 것으로 보고되었습니다 [93]. 인간 연구와 관련하여, COVID-19 감염 환자 30명, 인플루엔자(H1N1) 환자 24명, 건강한 대조군 30명의 장내 미생물총 변화에 대한 흥미로운 단면 연구에 따르면 H1N1 환자의 분변 샘플에서 대조군보다 대장균-시겔라 속의 상대적 풍부도가 유의하게 높았습니다 [94].

Hepatitis C virus (HCV) infection has been reported to be a significant risk factor for Parkinson’s disease [95]. HCV infection can be classified into three types, which consist of the persistently normal serum alanine transferase type, chronic hepatitis, and liver cirrhosis. In all these stages, an enrichment of the family Enterobacteriaceae present in the gut microbiome has been a consistent finding [96]. Evidently, influenza and hepatitis C virus infections may be inductors for the development of PD by inducing gut dysbacteriosis, whereby an overgrowth of the H2S-producing members of the family Enterobacteriaceae, especially the genus Escherichia, play a crucial role. Clinical studies on fecal microbiome content in PD provide support for the view that the Enterobacteriaceae family is an important player in the pathogenesis of PD. Notably, this family has been reported to be significantly more abundant in the fecal samples of PD patients when compared to healthy controls [80,97,98]. Postural instability and gait difficulty have been reported to correlate with the relative abundance of the Enterobacteriaceae in the fecal samples of PD patients [97]. In addition, an increase in Enterobacteriaceae in the fecal samples has been reported to be associated with the non-tremor dominant subtype of PD [99].

C형 간염 바이러스(HCV) 감염은 

파킨슨병의 중요한 위험 요인으로 보고되었습니다 [95]. 

HCV 감염은 

지속적으로 정상인 혈청 알라닌 전이효소 유형, 

만성 간염, 

간경변증의 세 가지 유형으로 분류할 수 있습니다. 

이 모든 단계에서 

장내 미생물 군집에 존재하는 장내 세균과가 

풍부해지는 것은 일관된 발견이었습니다 [96]. 

인플루엔자와 

C형 간염 바이러스 감염은 

장내 이상 세균 증을 유도하여 

PD 발병을 유발할 수 있으며, 

이 과정에서 

장내 세균과, 특히 

대장균 속의 H2S 생성 물질을 생성하는 세균의 과잉 증식이 중요한 역할을 합니다. 

PD의 분변 마이크로바이옴 함량에 대한 임상 연구는 

장내 세균과가 PD의 발병에 중요한 역할을 한다는 견해를 뒷받침합니다. 

특히, 이 과는 건강한 대조군과 비교했을 때 PD 환자의 분변 샘플에서 훨씬 더 풍부한 것으로 보고되었습니다 [80,97,98]. 자세 불안정성과 보행 장애는 PD 환자의 분변 샘플에서 장내 세균총의 상대적 풍부도와 상관관계가 있는 것으로 보고되었습니다 [97]. 또한, 분변 샘플에서 장내 세균군의 증가는 PD의 비진전 우성 아형과 관련이 있는 것으로 보고되었습니다 [99].

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8. Bacterially Produced H2S and Risk Factors for PD

Advancing age has been established as the largest risk factor for developing PD. Globally, the preval‎ence of PD begins rise steeply in the age range of 60–70 years and peaks in the age range of 80–90 years [100]. As to the colonic microbiome in advancing age, a community study on changes in the microbiome composition during the aging process showed that in older people, a sharp and continuous increase takes place in the relative abundance of the H2S-producing Desulfovibrio, Bilophila and Corynebacterium gut bacteria [101]. In case additional and substantial overgrowth of the H2S producing bacterial genera such as Escherichia or gDSV takes place, the risk for PD development will likely increase as a function of age.

고령은 

다발성 경화증 발병의 가장 큰 위험 요인으로 밝혀졌습니다. 

전 세계적으로 PD의 유병률은

 60-70세 연령대에서 가파르게 증가하기 시작하여 

80-90세 연령대에서 최고조에 달합니다[100]. 

노화 과정에서의 대장 마이크로바이옴 구성 변화에 대한 커뮤니티 연구에 따르면

 노년층에서는 H2S를 생성하는 

데설포비브리오, 

빌로필라, 

코리네박테리움 장내 세균의 상대적으로 풍부한 양이 

급격하고 지속적으로 증가하는 것으로 나타났습니다 [101]. 

대장균이나 gDSV와 같은 

H2S 생성 박테리아 속이 추가로 상당히 많이 증식하는 경우, 

연령에 따라 PD 발병 위험이 증가할 가능성이 높습니다.

In addition to aging, male gender is an established risk factor for PD. Furthemore, with regard to the incidence rates, male to female ratios have been reported to vary from 1.37 to 3.7 [102]. Estrogen, especially 17beta-estradiol which has been reported to display neuroprotective properties may provide an explanation for this difference [103,104]. It has been stated that long-term exposure to estrogen may be important in the PD risk reduction [104]. Experimental studies on ischemia models have shown that 17beta-estradiol prevents the release of Cyt c from mitochondria and by this action, estradiol displays cytoprotective properties [105,106]. Ultimately, given that H2S levels increase in the gut cells and perhaps even at the brain level, estadiol can probably counteract H2S actions by preventing the release of Cyt c from the mitochondrial membrane.

노화 외에도 남성의 성별도 PD의 위험 요인으로 알려져 있습니다. 

또한 발병률과 관련하여 남성과 여성의 비율은 1.37에서 3.7까지 다양한 것으로 보고되었습니다[102]. 

에스트로겐, 특히 신경 보호 특성을 나타내는 것으로 보고된 17베타-에스트라디올이 이러한 차이를 설명할 수 있습니다 [103,104]. 

에스트로겐에 장기간 노출되는 것이 

PD 위험 감소에 중요할 수 있다고 언급되었습니다 [104]. 

허혈 모델에 대한 실험 연구에 따르면 17베타-에스트라디올은 미토콘드리아에서 Cyt c의 방출을 방지하고 이러한 작용으로 에스트라디올은 세포 보호 특성을 나타냅니다 [105,106]. 궁극적으로 장 세포와 심지어 뇌 수준에서도 H2S 수치가 증가한다는 점을 고려할 때, 에스트라디올은 미토콘드리아 막에서 Cyt c의 방출을 방지하여 H2S 작용에 대응할 수 있을 것으로 보입니다.

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9. Conclusions

Considerable amounts of evidence support the view that an overgrowth of H2S-producing bacteria takes place in the gut microbiome of PD patients. It is plausible that by inhibiting acetyl-CoA synthesis, H2S decreases the amount of butyrate-producing gut bacteria. Furthemore, H2S can diffuse easily to gut cells and the vascular compartment. In blood circulation, some part of the bacterially produced H2S may end up at the brain level. When the gut cells are exposed to unphysiologically high concentrations of H2S, the release of Cyt c from the mitochondria will likely begin. In addition, H2S increases the iron content in the labile iron pool of the cell cytosol and the ROS content. In case the cell expresses aSyn, in the way that EECs and enteric neurons do, a development of aSyn oligomers and fibrils may start in the presence of Cyt c and increased ROS. The toxic oligomers and fibrils may spread to the lower brainstem via the vagal nerve and some oligomers will likely end up in the blood circulation. As to H2S producers, species of the genera Desulfovibrio, Escherichia, Bilophila, Porhyromonas, Prevotella, Corynebacterium, Veillonella, Helicobacter, and Clostridium invite particular attention when identifying the role of different bacterial genera in the etiology of PD. The bacterial composition of the microbiome in duodenum require special attention in PD as it is likely that the quantities and characteristics of the small intestinal bacteria, including the H2S-producing bacteria, differ significantly from those of the colon. Notably, studies on the bacterial composition of duodenal microbiome in PD are lacking. In future, microbiological and metabolomics-based studies on duodenal aspirates combined with the corresponding analyses of fecal samples may offer key information on the pathogenesis of PD. In case H2S plays a substantial role in the pathogenesis of PD, several strategies are already available to counteract its actions. In 2003, Braak and his colleagues proposed that PD is caused by an intestinal pathogen [107]. H2S could be that ”pathogen”.

PD 환자의 장내 미생물군집에서 

H2S를 생성하는 박테리아가 과도하게 증식한다는 견해를 뒷받침하는 증거가 상당수 존재합니다. 

아세틸-CoA 합성을 억제함으로써 

H2S가 부티레이트 생성 장내 박테리아의 양을 감소시킨다는 것은 그럴듯한 설명입니다. 

또한, H2S는 

장 세포와 혈관으로 쉽게 확산될 수 있습니다. 

혈액 순환 과정에서 박테리아에 의해 생성된 H2S의 일부가 

뇌까지 도달할 수 있습니다. 

장 세포가 비생리적으로 높은 농도의 H2S에 노출되면 미토콘드리아에서 Cyt c의 방출이 시작될 가능성이 높습니다. 또한, H2S는 세포 세포질의 불안정한 철분 풀의 철분 함량과 ROS 함량을 증가시킵니다. 세포가 aSyn을 발현하는 경우, EEC 및 장 뉴런과 마찬가지로 Cyt c와 증가된 ROS의 존재 하에서 aSyn 올리고머와 피브릴의 발달이 시작될 수 있습니다. 독성 올리고머와 피브릴은 미주 신경을 통해 하부 뇌간으로 퍼질 수 있으며 일부 올리고머는 혈액 순환에 도달할 수 있습니다. H2S 생산자의 경우, 데설포비브리오, 대장균, 빌로필라, 포르피로모나스, 프레보텔라, 코리네박테리움, 베일로넬라, 헬리코박터, 클로스트리디움 속 종은 PD의 원인에서 다양한 세균의 역할을 파악할 때 특히 주의가 요구되는 세균입니다. 십이지장 마이크로바이옴의 박테리아 구성은 H2S 생성 박테리아를 포함한 소장 박테리아의 양과 특성이 결장과 크게 다를 가능성이 높기 때문에 PD에서 특별한 주의가 필요합니다. 특히, PD에서 십이지장 마이크로바이옴의 박테리아 구성에 대한 연구는 부족합니다. 향후 십이지장 흡인에 대한 미생물학 및 대사체학 기반 연구와 대변 샘플의 해당 분석을 결합하면 PD의 발병 기전에 대한 핵심 정보를 제공할 수 있습니다. H2S가 PD 발병에 중요한 역할을 하는 경우, 그 작용에 대응할 수 있는 몇 가지 전략이 이미 존재합니다. 2003년에 Braak과 그의 동료들은 PD가 장내 병원체에 의해 발생한다고 제안했습니다[107]. 

H2S가 바로 그 

'병원체'일 수 있습니다.

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Acknowledgments

Ulla Sederlöf, Senior Lecturer, Information Technology, Metropolia UAS, is acknowledged as the designer of Figure 1.

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Funding

This research received no external funding.

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Institutional Review Board Statement

Not applicable.

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Data Availability Statement

Not applicable.

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Conflicts of Interest

The author (K.M.) declares no conflict of interest.

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Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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