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The neurobiology of irritable bowel syndrome

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• Published: 02 February 2023

The neurobiology of irritable bowel syndrome

• Emeran A. Mayer, 
• Hyo Jin Ryu & 
• Ravi R. Bhatt 

Molecular Psychiatry volume 28, pages1451–1465 (2023)Cite this article

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Abstract

Irritable bowel syndrome (IBS) is the most preval‎ent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future.

요약

과민성 대장 증후군(IBS)은 

전 세계 일반 인구의 5~10%가 겪는 가장 흔한 

뇌-장 상호작용 장애입니다. 

현재의 증상 기준은 

변형된 배변 습관과 관련된 재발성 복통으로 진단을 제한하고 있지만, 

대부분의 환자들은 

통증이 없는 복부 불편감, 

관련 정신 질환(불안과 우울증), 

기타 내장 및 신체 통증 관련 증상도 보고하고 있습니다. 

수십 년 동안 IBS는 

장 운동성 장애로 간주되어 왔으며, 

최근에는 장 질환으로 간주되고 있습니다. 

그러나 

IBS 증상의 병태 생리학에 관여하는 

중추, 말초 기전 및 유전적 요인에 대한 광범위한 보고된 정보를 바탕으로, 

장-뇌-미생물 군집 상호 작용의 포괄적인 질병 모델이 등장하여, 

장 습관의 변화, 

만성 복통 및 정신적 동반 질환을 설명할 수 있게 되었습니다. 

이 리뷰에서는 먼저 

장 연결망과 장 신경계의 변화에 대한 보고를 시작으로, 

뇌-장 미생물 군집 상호작용의 여러 핵심 구성요소에 대한 새로운 통찰력을 설명하고, 

뚜렷한 기능적, 구조적 뇌 특징 목록을 제시하며, 

이를 불안 장애에서 제안된 뇌 변화와 비교합니다. 

그런 다음, 

뇌 네트워크와 게놈, 

위장, 

면역, 그리고 

장내 미생물군 관련 변수 사이의 새로운 상관관계를 지적할 것입니다. 

이 새로운 정보를 IBS의 시스템 기반 질병 모델에 통합할 것입니다. 

마지막으로, 

이러한 모델이 장애에 대한 이해를 높이고 

향후 보다 효과적인 치료 접근법을 개발하는 데 

어떤 영향을 미치는지 논의할 것입니다.

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Introduction

IBS is one of the most common disorders of brain-gut interaction globally, with preval‎ence rates between 1.1 and 45% worldwide, and between 5 and 10% for most Western countries and China [1]. In contrast to many chronic non-communicable diseases, such as metabolic, neurological, cardiovascular and some forms of cancer, there has been no progressive increase in preval‎ence during the past 75 years, even though preval‎ence numbers have been fluctuating due to the periodic changes in official symptom criteria. Based on questionnaire data, women are 1.5–3.0 times more likely to have IBS, reflecting a preval‎ence in women of 14% and in men of 8.9% [2, 3]. However, based on healthcare system utilization, women are up to 2–2.5 times more likely to see a healthcare provider for their symptoms [4]. Based on the current symptom criteria [5], IBS is defined by chronically recurring abdominal pain associated with altered bowel habits in the absence of detectable organic disease. IBS symptoms can be debilitating in a small number of patients, but are mild to moderate in the majority of affected individuals [6]. Based on this definition, other frequently associated somatic or visceral pain and discomfort, as well as anxiety and depression are considered so called comorbid conditions.

The gut-restricted definition of the Rome criteria overlooks the fact that a large number of individuals who meet diagnostic criteria for an anxiety or depressive disorder have IBS and vice versa [7,8,9,10], and a majority of IBS patients show elevated levels of trait anxiety and neuroticism [10,11,12,13], or meet diagnostic criteria for an anxiety disorder [14]. Currently, the commonly associated psychiatric and somatic symptoms are generally referred to as comorbidities, separate from the primary GI diagnosis [15] and not present in all patients. However, detailed patient histories, frequently reveal symptoms of abdominal discomfort, anxiety and behavioral disturbances starting in early childhood in a majority of patients, and a large recent genetic epidemiological study has provided an intriguing explanation for the co-occurrence of abdominal and psychiatric symptoms in IBS patients on the basis of several shared single nucleotide polymorphisms (see paragraph IBS related genes shared with anxiety disorders below) [8]. These new findings are consistent with genetic vulnerabilities affecting both the central and the enteric nervous system (ENS), and argue against the long held linear pathophysiological concepts that emotional factors may cause IBS symptoms, or that chronic IBS gut symptoms lead to anxiety and depression Box 1.

Much of research and drug development in IBS patients has been based on descriptive and symptomatic features, rather than on biology-based disease definitions. These definitions suggest a core abnormality shared by all IBS patients (chronic, recurrent abdominal pain) as well as heterogeneity based on self reports of predominant bowel habit. However, a comprehensive identification of distinct biology-based subgroups of patients including those based on sex, with different underlying pathophysiological components and differential responsiveness to specific therapies, has not been achieved. Subtypes based on bowel habits are generally based on subjective reports of altered bowel habits, without consistent correlates in intestinal transit times, altered regional motility patterns or altered fluid and electrolyte handling by the gut [16]. Even though some of the most commonly used pharmacological and behavioral therapies are targeted at the level of the brain (low dose tricyclic antidepressants [17], serotonin reuptake inhibitors [18], cognitive behavioral therapies [19, 20], gut directed hypnosis, stress management [21]), research and drug development efforts are still predominantly focused on single, usually peripheral targets identified in preclinical models [16].

Based on such studies and on clinical reports from small samples, an astonishing list of biological abnormalities at various levels of the brain gut axis have been reported in the last 30 years and proposed as potential biomarkers or pathophysiological factors [2]: smooth muscle cells [22, 23], the gut epithelium [24]; bile acids [25,26,27,28]; immune system activation [29, 30]; neuroendocrine mechanisms [31]; brain structure and function [32, 33]; stress responsiveness [34]; affective [35, 36], cognitive [37,38,39,40], pain modulation [41, 42], gene polymorphisms [8]; and most recently the gut microbiome [43,44,45,46,47]. In addition, there has been a wealth of comprehensive data and clinical reports demonstrating a strong relationship between psychosocial factors and IBS symptoms [48]. However, despite the emergent discoveries about possible peripheral [29, 30] and central [32, 33, 35, 49, 50] components in IBS pathophysiology, the development of animal models with high face and construct validity [51], the reproduction of visceral hypersensitivity and IBS-relevant features after transplantation of human biospecimen into rodent models, and the recent acceptance of a brain-gut model of IBS [52], the controversy on the primary role of the nervous system versus peripheral factors still persists in the field [33, 53].

In this review, we will discuss the evidence supporting an integrative brain gut microbiome (BGM) model (Fig. 1) which incorporates a large body of evidence from studies on peripheral and central neurobiological disease mechanisms, brain and gut targeted influences of the exposome, and results from recently reported large scale genetic analyses with relevance for neuronal dysfunction of the CNS (central nervous system) and ENS (enteric nervous system). This systems biological model is consistent with the frequent comorbidity of IBS with other so-called functional GI disorders, and with other chronic pain and psychiatric disorders, in particular with anxiety. We will use this model to discuss the implications for the pathophysiology of IBS, its association with psychiatric symptoms, and the development of more effective treatment approaches in the future.

소개

IBS는 전 세계적으로

가장 흔한 뇌-장 상호작용 장애 중 하나이며,

전 세계적으로 유병률은 1.1~45%,

대부분의 서방 국가와 중국에서는 5~10%입니다 [1].

대사, 신경, 심혈관, 일부 형태의 암과 같은 많은 만성 비전염성 질병과는 달리,

공식적인 증상 기준의 주기적인 변화로 인해 유병률 수치가 변동하고 있음에도 불구하고

지난 75년 동안 유병률이 점진적으로 증가하지 않았습니다.

설문조사 데이터에 따르면,

여성은 IBS에 걸릴 확률이 1.5~3.0배 더 높으며,

이는 여성 14%, 남성 8.9%의 유병률을 반영합니다 [2, 3].

그러나

의료 시스템 이용을 기준으로 볼 때,

여성은 의료 서비스 제공자를 찾아가 증상을 확인하는 경우가

남성보다 2~2.5배 더 많습니다 [4].

현재의 증상 기준에 따르면[5],

IBS는 발견 가능한 유기적 질병이 없는 상태에서

변형된 배변 습관과 관련된 만성적으로 재발하는 복통으로 정의됩니다.

IBS 증상은 소수의 환자들에게서 쇠약하게 만들 수 있지만,

대부분의 환자에게는 경증 내지 중등도입니다[6].

이 정의에 따르면,

다른 자주 동반되는 신체적 또는 내장적 통증과 불편함,

불안과 우울증은 소위 동반 질환으로 간주됩니다.

로마 기준의 장 제한적 정의는

불안 또는 우울 장애의 진단 기준을 충족하는 많은 사람들이 IBS를 가지고 있다는 사실과

그 반대의 경우도 간과하고 있습니다 [7,8,9,10],

그리고

대부분의 IBS 환자는

높은 수준의 특성 불안과 신경성향을 보입니다 [10,11,12,13],

또는

불안 장애의 진단 기준을 충족합니다 [14].

현재,

일반적으로 연관되는 정신적, 신체적 증상은

일차적인 위장병 진단과는 별개로, 동반질환으로 언급되며[15]

모든 환자에게 나타나는 것은 아닙니다.

그러나,

상세한 환자 병력 조사를 통해

대부분의 환자들에게서

어린 시절부터 시작된 복부 불편감, 불안, 행동 장애의 증상이 자주 발견되고 있으며,

최근에 실시된 대규모 유전적 역학 연구에서

복부 불편감과 정신과적 증상이 동시에 발생하는 IBS 환자들의 경우,

여러 가지 단일 염기 다형성(아래의 단락 IBS 관련 유전자와 불안 장애의 공통점 참조)을 근거로

흥미로운 설명을 제시하고 있습니다[8].

이러한 새로운 발견은

중추신경계와 장신경계(ENS)에 영향을 미치는 유전적 취약성과 일치하며,

감정적 요인이 IBS 증상을 유발할 수 있다는 기존의 선형 병리생리학적 개념이나

만성 IBS 장 증상으로 인해

불안과 우울증이 유발된다는 주장에 반박합니다. 박스 1.

과민성 대장 증후군 환자의 연구와 약물 개발의 대부분은

생물학 기반의 질병 정의보다는

술적, 증상적 특징에 기반을 두고 있습니다.

이러한 정의는

모든 과민성 대장 증후군 환자(만성, 재발성 복통)가 공유하는 핵심적인 이상과 더불어,

우세한 배변 습관에 대한 자가 보고에 기반한 이질성을 시사합니다.

그러나

성별에 따라 근본적인 병리 생리학적 구성 요소가 다르고

특정 치료법에 대한 반응이 다른 환자들을 포함하여

생물학적으로 구별되는 하위 그룹을 포괄적으로 식별하는 것은 아직 이루어지지 않았습니다.

배변 습관에 기반한 하위 유형은 일반적으로

장 통과 시간,

변화된 국소 운동성 패턴 또는

장에 의한 체액 및 전해질 처리의 일관된 상관 관계 없이 변화된 배변 습관에 대한 주관적인 보고를

기반으로 합니다 [16].

가장 일반적으로 사용되는 약리학적 치료법과 행동 치료법 중 일부는

뇌 수준을 대상으로 하고 있지만

(저용량 삼환계 항우울제[17],

세로토닌 재흡수 억제제[18],

인지 행동 치료법[19, 20],

장을 대상으로 하는 최면,

스트레스 관리[21]),

연구와 신약 개발 노력은

여전히 전임상 모델에서 확인된 단일, 일반적으로 말초 표적에 주로 집중되어 있습니다[16].

이러한 연구와 소규모 표본의 임상 보고서를 바탕으로 지난 30년 동안 뇌-장 축의 다양한 수준에서 생물학적 이상 현상이 보고되었으며, 잠재적 바이오마커 또는 병태생리학적 요인으로 제안되었습니다[2]:

평활근 세포[22, 23],

장 상피[24];

담즙산[25,26,27,28];

면역계 활성화[29, 3 0];

신경 내분비 메커니즘 [31];

뇌 구조와 기능 [32, 33];

스트레스 반응성 [34];

정서적 [35, 36], 인지적 [37,38,39,40], 통증 조절 [41, 42],

유전자 다형성 [8];

그리고 가장 최근에는 장내 미생물군 [43,44,45,46,47]. 또한,

심리사회적 요인과 과민성 대장 증후군 증상 사이의 강력한 관계를 입증하는

방대한 양의 종합적인 데이터와 임상 보고서가 있습니다 [48].

Based on such studies and on clinical reports from small samples, an astonishing list of biological abnormalities at various levels of the brain gut axis have been reported in the last 30 years and proposed as potential biomarkers or pathophysiological factors [2]:

smooth muscle cells [22, 23],

the gut epithelium [24];

bile acids [25,26,27,28];

immune system activation [29, 30];

neuroendocrine mechanisms [31];

brain structure and function [32, 33];

stress responsiveness [34];

affective [35, 36],

cognitive [37,38,39,40],

pain modulation [41, 42],

gene polymorphisms [8]; and most recently the

gut microbiome [43,44,45,46,47]

In addition, there has been a wealth of comprehensive data and clinical reports demonstrating a strong relationship between psychosocial factors and IBS symptoms

그러나,

과민성 대장 증후군 병태 생리학에서 가능한 말초 [29, 30] 및 중추 [32, 33, 35, 49, 50] 구성 요소에 대한 새로운 발견, 높은 얼굴 및 구성 타당성을 가진 동물 모델의 개발 [51], 시각적 자극의 재현 내장 과민증과 IBS 관련 특징을 설치류 모델에 인간 생체 표본을 이식한 후 재현하고, 최근 IBS의 뇌-장 모델을 받아들인 [52] 상황에서도, 신경계와 말초 요인의 주요 역할에 대한 논란은 여전히 이 분야에서 지속되고 있습니다 [33, 53].

이 리뷰에서는

말초 및 중추 신경생물학적 질병 메커니즘,

뇌와 장을 대상으로 한 엑스포좀의 영향,

그리고 최근 보고된 중추신경계(CNS)와 장신경계(ENS)의 신경 기능 장애와 관련된

대규모 유전자 분석 결과에 대한 연구에서 나온 방대한 양의 증거를 통합한

통합적인 뇌-장 미생물군(BGM) 모델(그림 1)을 뒷받침하는 증거에 대해 논의할 것입니다.

이 시스템 생물학적 모델은 IBS가 다른 소위 기능성 위장 장애, 그리고 다른 만성 통증 및 정신 장애, 특히 불안과 함께 자주 동반되는 병태와 일치합니다. 우리는 이 모델을 사용하여 IBS의 병태 생리학, 정신적 증상과 IBS의 연관성, 그리고 향후 더 효과적인 치료 접근법의 개발에 대한 의미를 논의할 것입니다.

Fig. 1: The brain-gut-microbiome system.

The brain connectome, gut connectome and gut microbiome communicate in a bidirectional way. The response characteristics of the system are determined by vulnerability genes interacting with different influences from the exposome. The different loops use neural, endocrine, paracrine and immune signaling mechanisms. Perturbations (stressors) of the different nodes of the system (brain, gut, immune, microbiota) result in non-linear effects and alterations in response characteristics manifesting as psychiatric and/or gut symptoms. ANS autonomic nervous system, SNS sympathetic nervous system, PBMCs peripheral blood mononuclear cells, SCFAs short chain fatty acids, AhR aryl hydrocarbon receptor.

뇌 커넥토메, 장 커넥토메, 장 미생물 군집은 양방향으로 소통합니다. 이 시스템의 반응 특성은 노출 환경의 다양한 영향과 상호 작용하는 취약성 유전자에 의해 결정됩니다. 다양한 루프는 신경, 내분비, 파라크린, 면역 신호 전달 메커니즘을 사용합니다. 시스템의 다양한 노드(뇌, 장, 면역, 미생물 군집)의 교란(스트레스 요인)은 비선형 효과를 초래하고, 반응 특성의 변화는 정신 및/또는 장 증상으로 나타납니다. ANS 자율신경계, SNS 교감신경계, PBMCs 말초혈액 단핵세포, SCFA 단쇄지방산, AhR 아릴화합물수용체.

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Box 1 Brain-gut-system abnormalities reported in IBS

Gastrointestinal

 Altered intestinal motility and transit time

 Altered fluid secretion/absorption

 Hypersensitivity of visceral afferents

 Altered mucus layer

Gut microenvironment

 Altered microbiome composition

 Altered fecal bile acid profile

 Increased intestinal barrier permeability

Neurological

 Structural and functional brain alterations

 Alterations in brain receptors for cortical corticotropin release factor (CRF), neurokinin-1 (NRK-1), and cannabinoid-1 receptor systems

Genetic

 Female sex

 Gene polymorphisms

 CADM2

 BAG6

 PHF2, FAM120AOS

 NCAM1

 CKAP2, TPTE2P3

 DOCK9

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The brain-gut-microbiome system

The enteric nervous system and gut connectome

The ENS is a vast network of different types of intrinsic enteric neurons and glia which are “sandwiched” between the mucosa, and the circular and longitudinal muscle layers of the gut, containing motor neurons, intrinsic primary afferent neurons, and interneurons. Nearly every neurotransmitter class found in the CNS is present in the ENS [54]. These neurons are organized into two interconnected networks, the myenteric and submucosal plexus, which regulate motility and secretion respectively in a coordinated fashion [55]. Different classes of neurons are chemically coded by different combinations of neurotransmitters and modulators, many of which are also found in the CNS [56].

Within the gut, the ENS is closely connected with the gut-based immune system, endocrine system, glial and epithelial cells, making up the gut connectome [57] (Fig. 2). The term connectome reflects close proximity, connectivity, and functional interactions between many cell types and functions in the gut that interact with ENS and CNS.

뇌-장-미생물 군집 시스템

장 신경계와 장 연결망

ENS는

점막과 장의 원형 및 세로 근육층 사이에 “끼어 있는”

다양한 유형의 고유 장 신경세포와 신경교로 구성된 광대한 네트워크로, 운동 신경세포,

고유 1차 구심성 신경세포, 간성 신경세포를 포함합니다.

CNS에서 발견되는 거의 모든 신경전달물질 종류가

ENS에 존재합니다 [54].

이 신경세포들은 두 개의 상호 연결된 네트워크,

즉 운동 신경총과 점막하 신경총으로 구성되어 있으며,

각각 운동성과 분비를 조정하는 방식으로 조절합니다 [55].

다양한 종류의 신경세포는

신경전달물질과 조절제의 다양한 조합에 의해 화학적으로 코딩되며,

그 중 다수는 중추신경계에서도 발견됩니다 [56].

장 내에서,

장내 신경계는 장 기반 면역 체계,

내분비계,

신경교 및 상피 세포와 밀접하게 연결되어 장 연결망을 구성합니다 [57] (그림 2).

연결망이라는 용어는 장에서 ENS 및 CNS와 상호 작용하는 많은 세포 유형과 기능 간의 근접성, 연결성, 기능적 상호 작용을 반영합니다.

Fig. 2: Bidirectional interactions of the gut microbiome with the Enteric Nervous System, the enteroendocrine system, the gut-associated immune system, and the brain.

Alterations in these interactions can present as psychiatric and/or IBS symptoms. Modified with permission from [79].

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Beyond the gut, the ENS is connected with the spinal cord, brainstem, and brain via primary spinal and vagal afferents, and postganglionic sympathetic and vagal efferent fibers [58, 59]. Although the ENS is capable of regulating all GI functions without input from the CNS, the CNS (brain and spinal cord) has strong modulatory functions in regulating intestinal behaviors [60] in accordance with the overall state of the organisms and homeostatic perturbations [53].

Even though the ENS is often being referred to as the “second brain” [61], evolutionarily speaking, the ENS can be traced back to the cnidaria phylum and epitomized by the hydra genus 650 million years ago [62]. Historically, it has been classified as a nerve net, but evidence has shown specialized neurons with neurotransmitters such as serotonin, catecholamines, and neuropeptides are also involved [63, 64]. In the hydra, the main function of the ENS is peristalsis, mixing movements and expulsion in addition to avoidance behaviors, [62]. The process of cephalization and the development of bilateria (i.e., organisms through evolution with a head/tail [anterior/posterior axis] and belly/back [dorsal/ventral axis]) led to the development of more complex neuronal systems, most notably the CNS around a central region and highly developed brains. Thus from an evolutionary standpoint, the ENS can be considered “the first brain” [56, 62].

gut을 넘어,

ENS는 1차 척추 및 미주신경 구심성 신경,

그리고 신경절 후부 교감신경 및 미주신경 원심성 신경섬유를 통해

척수, 뇌간, 뇌와 연결되어 있습니다 [58, 59].

ENS는

중추신경계의 입력 없이도 모든 위장 기능을 조절할 수 있지만,

중추신경계(뇌와 척수)는

유기체의 전반적인 상태와 항상성 교란에 따라 장의 행동을 조절하는 강력한 조절 기능을 가지고 있습니다 [60].

비록 ENS가 종종 “제2의 뇌”로 언급되기는 하지만[61],

진화론적으로 보면, ENS는 cnidaria 문으로 거슬러 올라가

6억 5천만 년 전 hydra 속에 의해 대표되는 것으로 볼 수 있습니다[62].

역사적으로, 그것은 신경망으로 분류되어 왔지만,

증거에 따르면 세로토닌, 카테콜아민, 신경펩티드와 같은 신경전달물질을 가진

특수화된 뉴런도 관여하고 있는 것으로 나타났습니다 [63, 64].

히드라에서, ENS의 주요 기능은 회피 행동 외에도 연동 운동, 혼합 운동, 배출입니다 [62]. 두족화 과정과 양쪽성(즉, 머리와 꼬리[전방/후방 축], 배와 등[등쪽/배축]을 가진 유기체가 진화를 통해 생겨남)의 발달은 더 복잡한 신경계 시스템의 발달로 이어졌고, 그 중에서도 특히 중앙부 주변의 중추신경계와 고도로 발달된 뇌가 두드러지게 발달했습니다.

따라서

진화론적 관점에서 볼 때,

ENS는 “최초의 뇌”로 간주될 수 있습니다[56, 62].

ENS related genes

A recent profiling of the human ENS at single-cell resolution highlighted important genes related to neuropathic, inflammatory, and extraintestinal diseases [65]. Overlapping with the largest GWAS of IBS to date [8], CADM2, encoding the cell-adhesion molecule, was highly expressed in myenteric but not mucosal glia [65]. The known functions of myenteric glia include modulating myenteric neuron activity, regulating oxidative stress and neuroinflammation, providing trophic support, gliogenesis, and neurogenesis [66]. CADM2 encodes a member of synaptic cell adhesion molecules (SynCAMs) involved in synaptic organization and signaling [67], and cell adhesion-mediated mechanisms underlying the communication between glia and neurons in the ENS are important in understanding of ENS function in health and disease. For example, perturbed communication between enteric glia and neurons may play a role in dysfunctional ENS circuits in IBS [66]. The mechanisms underlying neuronal-glia signaling of the ENS in the context of gastrointestinal disorders, IBS, and visceral pain has recently been extensively reviewed [66, 68]. It is worth noting that CADM2 has been implicated in a wide range of psychological and neurological traits often observed in IBS patient including, but not limited to psycho-behavioral traits, risk-taking behavior, nervousness-like traits, and neurodevelopmental disorders (e.g., intellectual disability and autism spectrum disorder) [69]. Moreover, SynCAMs have a large role in synaptogenesis, axon guidance, and synaptic plasticity at a basic neurodevelopmental level which has the potential to affect a variety of disorders [70].

Similarly, NCAM1 is another gene found in the largest GWAS to date and has been implicated in the development of the ENS. In a similar manner to CADM2, NCAM1 has been shown to play a role in the ENS regarding cell migration, axon growth, neuronal plasticity and fasciculation [71], but has not been as thoroughly investigated as CADM2. A recent cross-tissue atlas applied single-nucleus RNA sequencing from eight healthy human organs showed that a cluster of genes including NCAM1 and CADM2 were involved particularly with cognitive/psychiatric symptoms including general cognitive ability, risk-taking behavior, intelligence, and neuroticism [72]. Even though the study did not contain tissue samples from the intestinal regions of the ENS, these genes involved in cognitive/psychiatric functions were highly expressed in Schwann cells in the esophagus mucosa, and interstitial cells of Cajal (ICCs) and neurons in the esophagus muscularis [72].

ENS 관련 유전자

최근 인간 ENS의 단일 세포 분해능 프로파일링은 신경병증, 염증성, 장외 질환과 관련된 중요한 유전자를 강조했습니다 [65]. 지금까지 가장 큰 IBS GWAS와 중복되는 [8], 세포 부착 분자를 암호화하는 CADM2는 점막 신경교가 아닌 장간막 신경교에서 높게 발현되었습니다 [65]. 미주신경교세포의 알려진 기능에는 미주신경교세포의 신경세포 활동 조절, 산화 스트레스와 신경염 조절, 영양 지원, 신경세포 생성, 신경세포 생성이 포함됩니다 [66]. CADM2는 시냅스 조직과 신호 전달에 관여하는 시냅스 세포 부착 분자(SynCAMs)의 일종입니다 [67], 그리고 미주신경교세포와 신경세포 사이의 의사소통을 가능하게 하는 세포 부착 매개 메커니즘은 건강과 질병에서 미주신경교세포의 기능을 이해하는 데 중요합니다. 예를 들어, 장내 신경교세포와 신경세포 사이의 교란된 소통은 IBS에서 기능 장애가 있는 ENS 회로에 중요한 역할을 할 수 있습니다 [66]. 최근에 위장 장애, IBS, 내장 통증의 맥락에서 ENS의 신경-신경교세포 신호 전달의 기저 메커니즘에 대한 광범위한 검토가 이루어졌습니다 [66, 68]. CADM2가 IBS 환자에서 흔히 관찰되는 광범위한 심리적, 신경학적 특성(정신 행동적 특성, 위험 감수 행동, 신경과민과 유사한 특성, 신경 발달 장애(예: 지적 장애 및 자폐 스펙트럼 장애)를 포함하되 이에 국한되지 않음)과 관련이 있다는 점은 주목할 만합니다 [69]. 또한, SynCAMs는 다양한 장애에 영향을 미칠 수 있는 잠재력을 지닌 기초적인 신경 발달 수준에서 시냅스 형성, 축삭 유도, 시냅스 가소성에 큰 역할을 합니다 [70].

마찬가지로, NCAM1은 현재까지 가장 큰 GWAS에서 발견된 또 다른 유전자이며, ENS의 발달과 관련이 있는 것으로 밝혀졌습니다. CADM2와 유사한 방식으로, NCAM1은 세포 이동, 축삭 성장, 신경 가소성 및 근섬유화[71]와 관련하여 ENS에서 역할을 하는 것으로 밝혀졌지만, CADM2만큼 철저하게 연구되지는 않았습니다. 최근에 적용된 조직 간 아틀라스는 8개의 건강한 인간 장기의 단일핵 RNA 염기서열 분석을 통해 NCAM1과 CADM2를 포함한 일련의 유전자가 일반적인 인지 능력, 위험 감수 행동, 지능, 신경성 등을 포함한 인지/정신과적 증상과 관련되어 있음을 보여주었습니다 [72]. 이 연구에 장의 신경총 조직 샘플이 포함되지 않았음에도 불구하고, 인지/정신 기능에 관여하는 이 유전자들은 식도 점막의 슈반 세포, 식도 근막의 간질 세포(ICC), 그리고 식도 근육의 뉴런에서 높게 발현되었습니다[72].

The gut microbiome

The term gut microbiome refers to the 40 trillion microbial organisms (bacteria, fungi, and archae) and their millions of genes that live throughout the gastrointestinal tract, from the oral cavity to the rectum, with the highest concentration and diversity in the large bowel [73]. The symbiotic interactions of the 3 groups of microorganisms within the microbiome, and with the extensive gut virome are incompletely understood [74, 75]. The characterization of these microorganisms in IBS to date is primarily based on identification of relative abundances and diversity using 16S rRNA sequencing techniques with limited resolution beyond the species level. We refer to several recent review articles on this topic [76, 77]. The extensive literature reveals inconsistent findings and a causative relationship of specific microorganisms with IBS symptoms has not been demonstrated. However, both preclinical and some clinical studies have demonstrated a significant effect of psychosocial stress on the relative abundance of gut microbes which is mediated both by stress-induced alterations in regional transit and secretion, and by direct effects of norepinephrine and possibly other signaling molecules released from gut cells on gut microbial gene expression‎ and virulence [78], suggesting the possibility that the microbiome in subgroups of IBS patients with greater stress reactivity may contribute to certain symptoms [79].

장내 미생물군

장내 미생물군이라는 용어는

구강에서 직장까지 위장관에 서식하는 40조 개의 미생물(박테리아, 곰팡이, 고세균)과

수백만 개의 유전자를 가리키며,

그중에서도 대장에 가장 많이 집중되어 있고 다양하게 분포되어 있습니다 [73].

미생물군 내의 세 가지 미생물 그룹과

광범위한 장 바이러스군과의 공생적 상호작용은

아직 완전히 이해되지 않았습니다 [74, 75].

현재까지 IBS와 관련된 미생물의 특성화는

주로 종 수준을 넘어서는 제한된 분해능을 가진 16S rRNA 시퀀싱 기술을 사용하여

상대적 풍부도와 다양성을 확인하는 데 기반을 두고 있습니다.

이 주제에 대한 최근의 여러 리뷰 기사를 참조합니다 [76, 77].

방대한 문헌을 통해 일관되지 않은 결과가 드러났으며, 특정 미생물이 IBS 증상과 인과 관계가 있다는 사실이 입증되지 않았습니다. 그러나 전임상 연구와 일부 임상 연구에서 스트레스가 장내 미생물의 상대적 풍부도에 미치는 상당한 영향이 입증되었습니다. 이는 스트레스에 의해 유발된 지역 내 이동 및 분비 변화와 장내 미생물 유전자 발현 및 독성에 대한 장내 세포에서 분비되는 노르에피네프린 및 기타 신호 분자의 직접적인 영향에 의해 매개됩니다 [78]. 따라서 스트레스 반응성이 더 큰 IBS 환자의 하위 그룹에서 미생물 군집이 특정 증상에 기여할 수 있다는 가능성을 시사합니다 [79].

Brain Connectome alterations in IBS

A growing body of research paired with clinical observations supports a critical role of the brain in the generation and maintenance of IBS symptoms. Regardless of primary symptom triggers, the brain is ultimately responsible for constructing and generating the conscious perception of abdominal pain, discomfort, and anxiety based on sensory input from the gut. Stressful and traumatic events during early life increase chances of developing IBS, and psychosocial stressors in adulthood play a crucial role during the first onset, symptom flare, and perceived severity of the symptoms [80]; centrally targeted pharmacological treatments and cognitive behavioral strategies have been some of the most effective IBS treatment strategies [3, 16, 81].

Specific brain functions such as sensory processing and modulation, emotion regulation, or cognition are the result of dynamic interactions of distributed brain areas operating in large-scale networks. As summarized in Fig. 3C and Table 1, these central networks and their properties have been assessed by neuroanatomical and neurophysiological studies in animals [51], as well as by a wealth of studies using different structural and functional brain imaging techniques and analyses in humans [82,83,84,85,86].

과민성 대장 증후군에서 뇌 연결망의 변화

임상 관찰과 함께 진행되고 있는 연구의 결과들은 과민성 대장 증후군의 발생과 유지에 있어 뇌가 중요한 역할을 한다는 것을 뒷받침하고 있습니다. 일차적 증상 유발 요인과 관계없이, 뇌는 궁극적으로 장의 감각적 자극에 기초하여 복통, 불편감, 불안감에 대한 의식적 인식을 구성하고 생성하는 역할을 담당합니다.

어린 시절의 스트레스와 트라우마는

과민성 대장 증후군 발병 가능성을 높이며,

성인기의 심리사회적 스트레스 요인은

첫 발병, 증상 악화, 증상의 심각성 인식에 중요한 역할을 합니다 [80];

중추를 대상으로 하는 약리학적 치료와

인지 행동 전략은

가장 효과적인 과민성 대장 증후군 치료 전략 중 하나입니다 [3, 16, 81].

감각 처리 및 조절, 감정 조절, 인지 등 특정 뇌 기능은

대규모 네트워크에서 작동하는 분산된 뇌 영역의 역동적인 상호 작용의 결과입니다.

그림 3C와 표 1에 요약된 바와 같이,

이러한 중심 네트워크와 그 속성은 동물에 대한 신경해부학적, 신경생리학적 연구[51]와 인간에 대한 다양한 구조적, 기능적 뇌 영상 기법과 분석을 이용한 수많은 연구[82,83,84,85,86]를 통해 평가되었습니다.

Fig. 3: Programming of the brain and gut connectome based on shared vulnerability genes and environmental influences.

a Vulnerability genes and prenatal influences (including maternal health, nutrition, and stress level) on BGM system development. 

b the brain and gut transcriptome is influenced by mode of delivery, early adversity, and early nutrition, leading to the development of distinct intermediate brain gut phenotypes 

c which shape the adult response to influences from the exposome (diet, psychosocial stress).

a BGM 시스템 개발에 대한 취약성 유전자와 태아기 영향(모성 건강, 영양, 스트레스 수준 포함).

b 뇌와 장의 전사체는 분만 방식, 초기 역경, 초기 영양에 의해 영향을 받아 뚜렷한 중간 뇌 장 표현형을 형성합니다.

c 노출체(식이, 심리사회적 스트레스)의 영향에 대한 성인의 반응을 형성합니다.

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Table 1 Brain network alterations in IBS.

In humans, several types of networks have been reported [33] (summarized in Table 1): functional brain networks based on evoked responses [87] or intrinsic connectivity of the brain during rest [82, 83]; structural networks based on gray matter parameters [88] and white matter properties; and anatomical networks based on white matter connectivities [89]. Both evoked and resting state studies performed in patients with IBS have demonstrated abnormalities in regions and task-related networks linked to salience detection [90, 91], emotional arousal [92,93,94,95], central autonomic control [38, 96,97,98], central executive control [90, 94, 99], and sensorimotor processing [38, 100, 101]. IBS-related alterations in these networks have provided plausible neurobiological substrates for several information-processing abnormalities reported in patients with IBS, such as stress hyperresponsiveness, biased threat appraisal, expectancy of outcomes, cognitive inflexibility, autonomic hyperarousal (emotional arousal and central autonomic networks), symptom-focused attention (central executive network) [33, 53] and cognitive inflexibility (central executive network). Supporting the concept of shared pathophysiological factors (so called p-factors), several reported brain network alterations have also been described in other chronic pain conditions [102] and in anxiety disorders (see Table 1).

인간에서는 여러 유형의 네트워크가 보고되었습니다 [33] (표 1에 요약):

유발된 반응에 기반한 기능적 뇌 네트워크 [87] 또는 휴식 중 뇌의 본질적 연결성 [82, 83]; 회백질 매개 변수 [88]와 백질 특성에 기반한 구조적 네트워크; 백질 연결성에 기반한 해부학적 네트워크 [89]. 과민성 대장 증후군 환자들을 대상으로 수행된 유발 및 휴식 상태 연구에서, 두드러짐 탐지[90, 91], 정서적 각성[92,93,94,95]과 관련된 영역과 작업 관련 네트워크의 이상이 입증되었습니다.

중추 자율 조절 [38, 96,97,98], 중추 집행 조절 [90, 94, 99], 그리고 감각운동 처리 [38, 100, 101]와 관련된 영역과 작업 관련 네트워크에서 이상을 보였습니다.

이러한 네트워크의 IBS 관련 변화는 스트레스 과민반응, 편향된 위협 평가, 결과 기대, 인지적 경직성, 자율신경과잉각성(감정적 각성 및 중추 자율신경 네트워크), 증상 중심 주의(중추 집행 네트워크) [33, 53] 및 인지적 경직성(중추 집행 네트워크)과 같은 IBS 환자에서 보고된 여러 정보 처리 이상에 대한 그럴듯한 신경생물학적 근거를 제공했습니다. 공통 병리 생리학적 요인(소위 p-요인)의 개념을 뒷받침하는 여러 가지 뇌 네트워크 변화는 다른 만성 통증 상태[102]와 불안 장애(표 1 참조)에서도 설명되었습니다.

The Salience Network

The salience network (SN) is integral in mediating the switching of activation between the default mode network (DMN) and central executive network, coordinating and adjusting physiologic/behavioral responses to internal and environmental perturbations of homeostasis [103]. Visceral inputs to the affective-motivational component of the SN converge onto the anterior insula coordinating response selection and conflict monitoring with the dACC [103]. Controlled rectal distention in IBS subjects has been shown consistently to result in increased engagement of the core hubs of the SN which are associated with increased affective, emotional, and arousal processes [104,105,106]. Reduced neurokinin-1 receptor (NK-1R) availability in the dACC, reflecting NK-1R endocytosis in response to substance P release, was found to be associated with duration of IBS symptoms [107]. Increased substance P release is thought to result from noxious visceral stimuli and increased engagement of endogenous pain or stress inhibition systems [107]. In adolescent girls with IBS, lower gray matter volume of the dACC has been observed [108], and greater salience-sensorimotor connectivity quantified by multiple neuroimaging techniques predicts a lack of symptom alleviation over 3–12 months in patients with IBS [109].

살리언스 네트워크(Salience Network)

살리언스 네트워크(SN)는 기본 모드 네트워크(DMN)와 중심 집행 네트워크 사이의 활성화 전환을 중재하고, 항상성의 내부 및 환경적 교란에 대한 생리적/행동적 반응을 조정 및 조절하는 데 필수적입니다 [103]. SN의 정서-동기적 구성요소에 대한 내장적 입력은 전방 내측섬모(anterior insula)로 수렴되어 dACC와의 반응 선택 및 갈등 모니터링을 조정합니다 [103]. 과민성 대장 증후군 환자의 직장 팽창 조절은 정서, 감정, 각성 과정의 증가와 관련된 SN의 핵심 허브의 참여를 증가시키는 것으로 일관되게 나타났습니다 [104,105,106]. 물질 P 방출에 대한 반응으로 NK-1R 내인성 세포내수용체를 반영하는 dACC에서의 감소된 신경키닌-1 수용체(NK-1R) 가용성은 IBS 증상의 지속 기간과 관련이 있는 것으로 밝혀졌습니다 [107]. 물질 P의 방출 증가는 유해한 내장 자극과 내인성 통증 또는 스트레스 억제 시스템의 증가된 관여로 인한 것으로 생각됩니다 [107]. IBS를 가진 사춘기 소녀의 경우, dACC의 회백질 부피가 더 적게 관찰되었습니다 [108], 그리고 여러 신경 영상 기법으로 정량화된 더 큰 두드러짐-감각운동 연결성은 IBS 환자의 3-12개월 동안의 증상 완화 부족을 예측합니다 [109].

The default mode network (DMN)

The DMN’s role in pain perception is known to act as an opposite manner to the SN, such that the DMN is suppressed when attention is placed on present sensory stimuli, and is activated when attention is engaged with thoughts away from present sensory stimuli and engaged in mind wandering (i.e., thoughts unrelated to the present sensory environment) [110]. Studies in chronic pain subjects have shown altered functional connectivity and topological reorganization in various regions, consistent with DMN dysregulation [111]. Overall neuroimaging research suggests decreased activity of the DMN in patients with IBS [112]. Lower integrity of anatomical connectivity and resting-state functional connectivity, and lower morphological integrity within the DMN (between the aMPFC and PCC) were found to be predictive of sustained IBS symptom severity over 3–12 months [109]. Rectal lidocaine administration in IBS subjects was associated with decreased pain perception and with increased coherence in the DMN [113], supporting an involvement of the DMN in visceral hypersensitivity in patients with IBS.

The Sensorimotor Network

Similar to other chronic pain disorders, imaging studies in IBS subjects have shown alterations of the sensorimotor network (SMN), consistent with alterations in central processing and modulation of viscerosensory and somatosensory information [32, 100, 109, 114,115,116,117]. This network consists of the primary motor cortex, area 24 of the cingulate cortex, premotor cortex, supplementary motor area (SMA), posterior operculum/insula, as well as primary and sensory cortices in the parietal lobe. In addition, lower gray matter volume in the basal ganglia and thalamus as well as greater functional connectivity within the SMN have been observed in young children with chronic pain [108]. Greater intrinsic functional connectivity in adults, greater cortical thickness of the posterior insula positively associated with symptom duration, and increasing functional coupling of area 24 and the thalamus, and greater SMN connectivity to the SN predicting sustained symptoms over 3–12 months [109]. When viewed together, current evidence suggests patients with IBS have functional, morphological, and microstructural SMN alteration, which are likely to play a role in the increased perception of both visceral and somatic stimuli.

감각운동 네트워크

다른 만성 통증 장애와 마찬가지로, 과민성 대장 증후군 환자의 영상 검사 결과, 감각운동 네트워크(SMN)의 변화가 관찰되었으며, 이는 내장 감각 및 체성 감각 정보의 중심 처리 및 조절의 변화와 일치합니다 [32, 100, 109, 114,115,116,117]. 이 네트워크는 1차 운동피질, 대상피질의 24번 영역, 전운동피질, 보조운동영역(SMA), 후방개/섬, 그리고 정수리엽의 1차 및 감각피질로 구성되어 있습니다. 또한, 만성 통증을 앓고 있는 어린 아이들의 경우, 기저핵과 시상 하부의 회백질 부피가 적고, SMN 내의 기능적 연결성이 더 큰 것으로 관찰되었습니다 [108]. 성인의 경우 내재적 기능적 연결성이 더 크고, 후두부 피질의 두께가 두꺼울수록 증상 지속 기간과 양의 상관관계가 있으며, 24번 영역과 시상과의 기능적 결합이 증가하고, SN에 대한 SMN 연결성이 더 커서 3~12개월 동안 지속되는 증상을 예측할 수 있습니다 [109]. 이 모든 증거를 종합해 볼 때, IBS 환자는 기능적, 형태적, 미세구조적 SMN의 변화가 있으며, 이는 내장 및 신체 자극에 대한 지각 증가에 영향을 미칠 가능성이 높습니다.

The central autonomic network

The central autonomic network (CAN) regulates visceromotor, neuroendocrine, pain, and behavioral responses essential for survival [118]. Afferents project through the spinal cord and eventually arrive at the main homeostatic processing sites in the brainstem/central autonomic network (including hypothalamus, amygdala, and PAG), and higher cortical processing and modulatory regions [119]. Historically it has been difficult to non-invasively study the brain stem nuclei in humans due to the limited spatial resolution of neuroimaging methods, but new imaging protocols with a resolution of 1mm3 and below are allowing new insights [120].

The CAN is closely connected by vagal and sympathetic efferent projections with the ENS, and afferents from the ENS send viscerosensory signals back to the brain. The hubs of the SN also participate in autonomic control via descending projections to the amygdala (tagging emotional valence and engaging autonomic survival responses to behaviorally relevant stimuli), hypothalamus (regulating homeostasis and a pattern generator for the stress response) and brainstem structures including the periaqueductal gray (PAG) and locus coeruleus (LC). The PAG is a key structure for integrating autonomic, pain modulatory/analgesic, and motor responses to stress [121], and the LC-norepinephrine system plays a central role in behavioral arousal and stress responses [122,123,124].

When viewed together, based on a large number of structural, and functional (resting state and evoked) studies, IBS patients show alterations in several brain networks related to salience assessment, attention, stress perception and responsiveness, and sensory processing. The responsiveness and connectivity of these networks are modulated by several vulnerability genes, which are shared both with ENS genes, and with genes identified in anxiety disorders. Based on these findings, we hypothesize that perturbations of homeostasis arising from the exposome, in the form of psychosocial and gut-targeted stressors interact with genetic factors to a spectrum of clinical phenotypes, ranging from gut symptoms to anxiety.

중추 자율 신경망

중추 자율 신경망(CAN)은 생존에 필수적인 내장 운동, 신경 내분비, 통증, 행동 반응을 조절합니다 [118]. 구심성 신경은 척수를 통해 투영되어 결국 뇌간/중추 자율 신경망(시상 하부, 편도체, PAG 포함)의 주요 항상성 처리 부위와 더 높은 피질 처리 및 조절 영역에 도달합니다 [119]. 역사적으로, 신경 영상 기법의 공간 해상도가 제한되어 있기 때문에 인간의 뇌간 핵을 비침습적으로 연구하는 것이 어려웠지만, 1mm3 이하의 해상도를 가진 새로운 영상 프로토콜을 통해 새로운 통찰력을 얻을 수 있게 되었습니다 [120].

CAN은 미주신경과 교감신경의 원심성 신경 돌기(afferents)에 의해 ENS와 밀접하게 연결되어 있으며, ENS의 원심성 신경 돌기(afferents)는 내장 감각 신호를 뇌로 다시 보냅니다. SN의 허브는 또한 편도체(감정적 가치를 표시하고 행동과 관련된 자극에 대한 자율적 생존 반응을 유도함), 시상하부(항상성 조절 및 스트레스 반응에 대한 패턴 생성기), 그리고 뇌간 구조물(뇌간수질회색질(PAG)과 청반(LC) 포함)에 대한 하강성 투영을 통해 자율적 제어에 참여합니다. PAG는 자율 신경계, 통증 조절/진통, 스트레스에 대한 운동 반응을 통합하는 핵심 구조입니다 [121], 그리고 LC-노르에피네프린 시스템은 행동 각성과 스트레스 반응에서 중심적인 역할을 합니다 [122,123,124].

많은 수의 구조적, 기능적(휴식 상태 및 유발) 연구를 바탕으로 종합해 볼 때, IBS 환자는 두드러짐 평가, 주의력, 스트레스 지각 및 반응성, 감각 처리와 관련된 여러 뇌 네트워크의 변화를 보입니다. 이러한 네트워크의 반응성과 연결성은 여러 취약성 유전자에 의해 조절되는데, 이 유전자는 ENS 유전자와 불안 장애에서 확인된 유전자와 공유됩니다. 이러한 연구 결과를 바탕으로, 우리는 노출로 인해 발생하는 항상성 교란이 심리사회적 스트레스 요인과 장을 표적으로 하는 스트레스 요인의 형태로 작용하여, 장 증상에서 불안에 이르는 다양한 임상 표현형에 영향을 미친다는 가설을 세웠습니다.

IBS-related genes shared with anxiety disorders

Prior to the availability of biobank scale data, many candidate gene studies uncovered potential pathways underlying IBS symptoms. These pathways have been extensively reviewed and include the serotonin pathway, SCN5A, and intestinal channelopathy, and sucrase-isomaltase malabsorption [125]. As serotonin is secreted from enteroendocrine cells and activates enteric sensory and motor neurons, expression‎ level alterations in serotonin receptors and transporters are likely to play a potential role in visceral hypersensitivity, pain, intestinal motility, and secretion. SCN5A encodes the voltage-gated sodium Nav1.5 channel present on interstitial cells of Cajal (ICCs) in the ENS [31, 126]. Genetic mutations on this gene have shown to impair peristalsis and cause constipation, even though slow transit constipation is an uncommon finding in IBS-C [127]. Lastly, two faulty copies of the SI gene result in reduced disaccharide activity responsible for degradation of sucrose and starch, resulting in diarrhea and gas production in the large intestine from bacterial fermentation and is termed congenital sucrase-isomaltase deficiency (CSID), and should not be considered as IBS [125]. Even though these findings have established causal relationships between specific genetic abnormalities and non-specific IBS-like GI symptoms in a small number of affected individuals, it is highly unlikely that they play an important role in the great majority of patients.

Recently, the largest genome wide association study with 53,000 cases of IBS across multiple cohorts was completed [8]. In this study, the strongest risk factors for IBS included long-term or recurring antibiotic exposure in childhood, somatic pain conditions (back pain, limb pain, headaches), psychiatric conditions (anxiety, depression, excessive worrying) and fatigue. The genes included CADM2, BAG6, PHF2/FAM120AOS, NCAM1, CKAP2/TPTE2P3, and DOCK9. Four of the six loci are highly implicated in anxiety/mood disorders and there was a strong genome-wide genetic correlation of IBS with anxiety, neuroticism, depression, insomnia, and schizophrenia. Moreover, the high genetic correlations persisted after taking into account individuals with phenotypic overlap, suggesting common etiological pathways between IBS and anxiety/mood disorders. Implication of the central nervous system was further suggested by the finding that the six identified loci regulate gene expression‎ in many genes primarily expressed in the brain. As already mentioned under ENS above, the genes NCAM1 and CADM2 were two genes which regulate neural circuit formation and influence changes in white matter microstructure in IBS and mood disorders [128,129,130]. Specifically, they regulate synaptic cell adhesion molecules, which are present in dorsal root ganglia sensory neurons throughout development, mediate adhesion of sensory axons, and induce neurite outgrowth [130]. Mechanisms relating to brain development were further implicated by the genes PHF2 (i.e., proper expansion of neural progenitors) and DOCK9 (i.e., dendritic development of the hippocampus), but have not yet been studied in patients with IBS [131,132,133].

Importantly, the heritability of IBS was estimated to be a modest 5.8%, suggesting that perturbation of the brain-gut axis by environmental factors arising from the exposome such as early adversity, psychosocial stress, learned behaviors, diet, and possibly dysbiosis play a prominent role.

Considering these new genetic findings and the reported frequent comorbidities of IBS with other chronic pain and psychiatric conditions it is becoming increasingly recognized that IBS is part of a constellation of symptoms that occur on a larger spectrum of altered brain-body interactions [134, 135]. This concept is consistent with the “somatic symptom disorder” concept, previously proposed [2]. The main co-occurring symptoms include hypersensitivity to multiple internal and external sensory stimuli, which could explain the observed association with a variety of seemingly unrelated external and internal factors, previously reported. Other co-occurring symptoms include mood problems, fatigue, and problems with sleep onset and maintenance, as well as memory disturbance [134]. The neurogenetic basis integrating mood/anxiety and central amplification of sensory inputs (“central sensitization”) based on many of these genetic hits have been well established, which will be discussed below.

Known functions of NCAM1, DOCK9, and PHF2 and possible roles in IBS pathophysiology are summarized in Table 2.

Table 2 Genetic Factors in the Neurobiology of IBS.

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Central sensitization and comorbid chronic pain conditions

The primary mechanism for the core symptom of persistent, chronically recurring abdominal pain that patients with IBS report is thought to result from alterations in the central processing of sensory input from the gut, also referred to as central sensitization [134, 136]. The term was originally coined to represent the specific spinal mechanisms responsible for the amplification of nociceptive signaling involving spinal activation of the NMDA receptor [137, 138], and is present in various chronic pain disorders such as chronic neuropathic pain, fibromyalgia, headaches, and IBS [6, 134, 139,140,141]. Today, it is understood that spinal and supraspinal mechanisms both play key roles in the development and maintenance of central sensitization. Based on rodent models of pain, plausible spinal mechanisms include alterations in converging sensory input from different sites on the GI tract and body, temporal and spatial summation, reduced endogenous dorsal horn inhibition, and glial cell activation. Based on human brain imaging studies, supraspinal mechanisms include an altered balance between facilitatory and inhibitory endogenous pain modulation influences, hyperconnectivity between brain networks, alterations of gray matter architecture, elevated CSF glutamate and substance P levels, reduced GABAergic transmission, altered noradrenergic signaling/receptors, and glial cell activation [122, 134].

The large overlap - up to a 4.27 odds ratio - between psychiatric phenotypes (primarily anxiety and depression [136, 142]) and IBS and other chronic pain disorders, as well as genetic overlap [8, 143,144,145] mentioned earlier, suggests central sensitization as a possible shared pathophysiological factor (p factor) [134, 146,147,148]. The concept of central sensitization was introduced in psychological research in the 1990s based on the observation that highly sensitive persons (HSPs) often share a history of early adversity, psychological profile of introversion (“neuroticism”), and greater emotionality [149]. Patients with IBS are significantly more likely to exhibit qualities of HSPs, and show central sensitization which is expressed as general sensory hypersensitivity [150]. The association between chronic pain disorders, psychiatric symptoms, and mechanisms of central sensitization is likely due to the above-mentioned supraspinal alterations, including monoamine neurotransmitter systems (i.e., serotonin, dopamine, noradrenaline), the amino acid GABA, and brain regions underlying both pain transmission/modulation and mood disorders [151, 152]. Striato-thalamic-frontal cortical pathways including the prefrontal cortex, amygdala, nucleus accumbens, and thalamic nuclei are key hubs, and alterations in neuronal firing and communication underlie sensory sensitivity and psychiatric symptoms including altered perception, arousal, cognition, and mood [152,153,154]. Behaviorally, chronification of central sensitization and negative mood states have been proposed to be in the same continuum of aversion, such that pain motivates the avoidance of further injury, and anxiety promotes behaviors that diminish anticipated danger [154].

An extensive literature supports the importance of early programming by early adverse life (EAL) events for the development not only of IBS [76], but also of other chronic pain conditions and psychiatric syndromes [155, 156]. Perturbations to the developing brain play a large sole in sensitizing cortical nociceptive circuitry [157], with the most mechanistic study in humans showing larger event-related potentials (ERPs) to nociceptive stimuli, but not tactical stimuli in infants exposed to many invasive, skin-breaking, painful procedures and morphine [158]. Moreover, up to 68.4% of children who are exposed to early life traumatic events such as the NICU can develop chronic pain by age 10. Greater amounts of pain-related stressors, painful procedures, and morphine are associated with lower global gray matter volumes throughout childhood [159, 160]. In addition to the well documented changes in stress response systems [161,162,163], the effect of early-life dietary influences on the gut microbiome and the BGM axis have received increasing attention, even though a direct link with chronic abdominal pain has not been established [164, 165].

Clinical and therapeutic implications

Despite a decades-long effort by the pharmaceutical industry, a large number of IBS candidate drugs identified and validated in preclinical models and targeted at both central and gut mechanisms have failed, either due to lack of efficacy or serious side effects [16]. Of the small number of new drugs obtaining FDA approval, efficacy above placebo has generally not exceeded 10% in phase 3 trials. The great majority of available, FDA approved IBS medications are targeted at intestinal secretion and motility, and the gut microbiome with the goal to improve altered bowel habits and bloating-type symptoms in subgroups of patients [16].

Pharmacological treatments have been clinically divided into first and second-line approaches [16], and are aimed at specific symptoms. Moderate quality data has shown low-dose tricyclic antidepressants and SSRIs to be effective for pain (primarily the former) and comorbid anxiety and depression (primarily the latter) [16, 18]. As 5-HT receptor-mediated signaling plays important roles both in the brain, as well as in the gut, there is a good rationale for IBS treatments targeted at these receptors. 5-HT released from enterochromaffin cells mediates many GI functions including peristalsis, secretion, pain, and nausea via receptors on ENS and vagal nerve endings [31]. For example, 5HT-3 receptor antagonists (acting on both gut and brain-located 5HT-3 receptors (such as alosteron, and ramosteron) have shown effectiveness in slowing colonic transit, improving diarrhea, and reducing visceral pain in well-designed randomized controlled trials [16]. High-quality preclinical data has shown the antagonism of 5HT-3 receptors on the area postrema and vagus nerve have shown a reduction of visceral pain and diarrhea [16, 18, 166], and older data have demonstrated anxiolytic effects [167,168,169].

Despite evidence obtained in rodent models of IBS, efforts to develop peripheral visceral analgesics or central stress modulators (antagonists for CRF-1 and NK-1 receptors) have failed to show therapeutic benefits in IBS. This is surprising, as multiple preclinical studies as well as a human brain imaging study had demonstrated effectiveness of the CRF-R1 antagonist Emicerfont (GW876008) on evoked visceral pain and on central stress circuits [170, 171]. Because of these disappointing results, increased attention has been shifted to behavioral treatments, including gut-directed hypnosis [21, 81, 172,173,174,175], mindfulness-based stress reduction [176], and cognitive behavioral approaches [19, 20, 177,178,179]. Several of these therapeutic approaches have shown promise in improving IBS symptoms, and a few studies have demonstrated associated neurobiological effects on brain mechanisms in salience, emotional arousal, and executive networks [172, 177].

As access to therapists specialized in these behavioral IBS treatments is limited, and traditional delivery is time-consuming, web-based versions of these therapies have been eval‎uated, some of which have been FDA approved and are becoming available to patients [180]. In addition, several randomized controlled studies have shown some benefits of certain dietary interventions (low FODMAP diet [16]), and microbiome-targeted treatments (probiotics, antibiotics) [181].

Summary and conclusions

Even though in subsets of patients, SSRIs and bowel movement targeted therapies are helpful, the model of IBS presented in this review provides precedence for a multidisciplinary therapeutic approach including pharmacological, behavioral, and dietary approaches. Current evidence suggests that there are significant interindividual variations in the response to such therapies, including the predominant bowel habit subtype, severity of gut and psychiatric symptoms, and possibly the presence of gut microbial alterations.

There is growing evidence from clinical, preclinical, and genetic studies supporting the existence of shared p factors in IBS and often comorbid gastrointestinal and non-gastrointestinal pain conditions, as well as psychiatric conditions. Despite shared vulnerability genes, different influences from the environment (exposome) in particular during childhood ultimately shape the specific clinical phenotype. The emerging disease model can explain the failure of reductionistic single mechanism targeted treatment approaches, and is consistent with the evidence for the effectiveness of personalized multidisciplinary approaches involving behavioral, dietary, and pharmacological interventions.

Glossary

irritable bowel syndrome (IBS); brain-gut-microbiome (BGM); gastrointestinal (GI); enteric nervous system (ENS); central nervous system (CNS); synaptic cell adhesion molecules (SynCAMs); default mode network (DMN); salience network (SAL); sensorimotornNetwork (SMN); central autonomic network (CAN); central executive network (CEN); locus coeruleus (LC); periaqueductal grey (PAG); dorsal anterior cingulate cortex (dACC); posterior cingulate cortex (PCC); N-methyl-D-aspartate (NMDA); gamma-aminobutyric acid (GABA); cerebrospinal fluid (CSF); early adverse life events (EAL); serotonin (5-HT); selective serotonin reuptake inhibitor (SSRI); long-term potentiation (LTP); event-related potentials (ERPs).

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