장신경계 enteric nervous system 탐구

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• Review Article
• Published: 09 March 2020

Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility

• Nick J. Spencer & 
• Hongzhen Hu 

Nature Reviews Gastroenterology & Hepatology volume 17, pages338–351 (2020)Cite this article

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Abstract

The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut–brain axis.

요약

위장관은 

장신경계(ENS)로 알려진 독립적인 신경계를 가지고 

진화한 유일한 내부 기관입니다. 

이 리뷰에서는 

ENS 내의 뉴런이 감각과 운동 기능을 조정하는 방식에 대한 

이해의 진전에 대한 최신 정보를 제공합니다. 

이 기능을 이해하는 것은 

신경인성 운동 패턴의 결함이 어떻게 발생하는지 파악하는 데 매우 중요합니다. 

장의 팽창 또는 화학적 자극이 

어떻게 ENS와 중추 신경계에서 감각 반응을 유발하는지에 대한 지식은 

팽창 유발 대장 연동 운동의 기계 전달의 기초가 되는 

중요한 요소를 포함하여 발전해 왔습니다. 

기존의 생각과는 달리, 

점막 세로토닌이 

연동 운동이나 대장 이동 운동 복합체의 특성을 조절할 수는 있지만 

연동 운동에 반드시 필요한 것은 아니라는 증거가 제시되었습니다. 

내강에 적용된 화학감각 자극은 

장내분비 세포에서 물질을 방출할 수 있으며, 

이는 이후 ENS 활동을 조절할 수 있습니다.

 광유전학 기술이 발전하여 

특정 신경화학 계열의 장 신경세포를 자극할 수 있게 되었습니다. 

이 리뷰의 주요 초점은

 ENS의 내재적 감각 뉴런이 감각 자극을 감지하고 반응하는 방법과 

이러한 메커니즘이 장-뇌 축의 기초가 되는 장의 외재적 감각 신경 종말과 어떻게 다른지에 대한 최신 이해의 진전입니다.

Key points

• In vertebrates, the enteric nervous system (ENS) is critical for gastrointestinal function.

• There has been much progress in understanding the mechanisms by which mechanical or chemical stimulation of the gut is converted into neural activity within the ENS and propulsive motility.

• Mechanosensory elements critical for distension-evoked colonic peristalsis have been identified to lie in the myenteric plexus and/or circular muscle of the gastrointestinal tract and do not require the mucosa or submucosal plexus.

• Evidence suggests that substances released from cells in the mucosa (such as enteroendocrine cells) can modulate ENS activity, but the release of mediators like serotonin is not required for distension-evoked peristalsis or for colonic migrating motor complexes.

• Fundamental differences have been revealed in the mechanisms of activation of extrinsic spinal afferent nerves compared with those of intrinsic sensory nerves in the same region of the bowel.

• Recent refinements in optogenetic technologies now permit the stimulation of specific neurochemical classes of neurons in the ENS to elucidate function.

• 척추동물에서 장 신경계(ENS)는 위장 기능에 매우 중요한 역할을 합니다.
• 장의 기계적 또는 화학적 자극이 ENS 내의 신경 활동과 추진성 운동으로 전환되는 메커니즘을 이해하는 데 많은 진전이 있었습니다.
• 팽창 유발 대장 연동 운동에 중요한 기계 감각 요소는 위장관의 장신경총 및/또는 원형 근육에 존재하며 점막이나 점막하 신경총이 필요하지 않은 것으로 확인되었습니다.
• 점막의 세포(예: 장내분비 세포)에서 방출되는 물질이 ENS 활동을 조절할 수 있다는 증거가 있지만, 세로토닌과 같은 매개 물질의 방출은 팽창 유발 연동 운동이나 대장 이동 운동 복합체에는 필요하지 않은 것으로 나타났습니다.
• 장의 같은 부위에서 내재성 감각 신경과 비교하여 외재성 척추 구심 신경의 활성화 메커니즘에 근본적인 차이가 있음이 밝혀졌습니다.
• 최근 광유전학 기술의 발전으로 이제 ENS에서 특정 신경화학 계열의 뉴런을 자극하여 기능을 규명할 수 있게 되었습니다.

Over the past decade, there has been extraordinary interest in how the gut and brain communicate with one another, in particular with regard to the microbiome and how substances within the wall of the gut could be responsible for changes in health and wellbeing. Understanding how the gut responds to different substances in the lumen requires an understanding of how the different sensory nerves are activated. Discerning how the gut detects sensory stimuli is of supreme importance to understanding the control of the gut–brain axis. There have been important advances in our knowledge of the different types of intrinsic and extrinsic sensory neurons that communicate local reflexes within and outside the gut to the spinal cord and brain. It has been known since the mid-1700s that segments of intestine isolated from vertebrates can respond to particular stimuli, despite the intestine being disconnected from the brain and spinal cord1 . Surprisingly, it was not until the mid-1990s that unequivocal evidence was presented of the enteric nervous system (ENS) containing its own population of sensory neurons2 and that these neurons are capable of initiating reflex responses mediated solely via the ENS3 . Over the past 5–10 years, there have been important advances in our understanding of how chemical and mechanical stimuli applied to the gut wall can elicit neural reflex responses within the ENS. There have also been major advances in our understanding of how extrinsic afferents, with sensory nerve endings in the gut wall (but their cell bodies outside the gut) respond to certain stimuli. Interestingly, studies have shown that even within the same region of the bowel from the same species, the mechanisms that transduce mechanical or chemical stimuli of the bowel into neural reflexes can differ substantially between intrinsic sensory neurons (in the ENS) and extrinsic sensory nerve endings in the gut that have their cell bodies outside the gut wall. Understanding how the gut detects sensory stimuli is of supreme importance to understanding the control of the gut–brain axis. In this Review, we discuss the major advances that have been made regarding the mechanisms underlying the transduction of sensory stimuli in the gut wall into neural activity within intrinsic and extrinsic sensory nerves.

지난 10년 동안 장과 뇌가 서로 소통하는 방식, 특히 마이크로바이옴과 장 벽에 있는 물질이 건강과 웰빙의 변화를 일으키는 방식에 대한 관심이 매우 높아졌습니다. 장이 내강의 여러 물질에 어떻게 반응하는지 이해하려면 다양한 감각 신경이 어떻게 활성화되는지 이해해야 합니다. 

장이 감각 자극을 감지하는 방법을 파악하는 것은 

장-뇌 축의 제어를 이해하는 데 가장 중요합니다. 

장 안팎의 국소 반사를 척수와 뇌에 전달하는 

다양한 유형의 내재성 및 외재성 감각 뉴런에 대한 지식에 중요한 발전이 있었습니다. 

장이 뇌와 척수에서 분리되어 있음에도 불구하고 

척추동물에서 분리된 장의 일부가 특정 자극에 반응할 수 있다는 사실은 

1700년대 중반부터 알려져 왔습니다1 . 

놀랍게도 

1990년대 중반이 되어서야 

장 신경계(ENS)가 자체 감각 뉴런을 포함하고 있으며2 

이러한 뉴런이 ENS를 통해서만 매개되는 반사 반응을 일으킬 수 있다는 

명백한 증거가 제시되었습니다3 . 

지난 5~10년 동안 장벽에 가해지는 화학적 및 기계적 자극이 

어떻게 ENS 내에서 신경 반사 반응을 이끌어낼 수 있는지에 대한 

이해에 중요한 진전이 있었습니다. 

또한 장 벽에 감각 신경 종말이 있지만 

세포체는 장 밖에 있는 외인성 구심체가 

특정 자극에 어떻게 반응하는지에 대한 이해에도 큰 진전이 있었습니다. 

흥미롭게도 연구에 따르면 

같은 종의 같은 부위 내에서도 장의 기계적 또는 화학적 자극을 신경 반사로 전환하는 메커니즘은 

내재성 감각 신경세포(ENS)와 세포체가 

장 벽 밖에 있는 장 외재성 감각 신경 종말 사이에 크게 다를 수 있는 것으로 나타났습니다. 

장이 감각 자극을 감지하는 방법을 이해하는 것은 

장-뇌 축의 제어를 이해하는 데 가장 중요합니다. 

이 리뷰에서는 

장 벽의 감각 자극이 내재성 및 외재성 감각 신경의 신경 활동으로 전달되는 

기본 메커니즘과 관련하여 이루어진 주요 진전에 대해 논의합니다.

Enteric nervous system Of all the hollow organs in the body, the gastrointestinal tract is the only organ to have evolved with its own complete nervous system, known as the ENS, which can function fully independently of any neural inputs from the central nervous system (CNS), that is, the brain and spinal cord1 . Perhaps the best evidence to support the autonomous nature of the ENS is exemplified when bowel segments are removed from vertebrates and studied in isolation ex vivo. Under these conditions, the intestine continues to generate complex propulsive neurogenic motor patterns despite all extrinsic nerves being severed4–6 . The notion that the gut was capable of generating reflex responses independent of the CNS was actually first identified in 1755 by Von Haller, who stated that, after removing the intestine from the body “the intestines in this state after being deprived from all communication with the brain, preserve their peristaltic motion”1 (Fig. 1). His discovery was further supported 135 years later by Lüderitz, who provided the first clear description that local stimulation of the bowel could evoke polarized responses in isolated segments of the intestine7,8 . About 10 years later, Bayliss and Starling then confirmed the presence of polarized neural responses in exteriorized segments of dog intestine following local stimulation, leading them to formulate the ‘law of the intestine’, which stated: “Local stimulation of the gut produces excitation above and inhibition below the excited spot”9 (Fig. 1). However, it was through work by Trendelenburg during the first World War that the now common term ‘peristaltic reflex’ was coined, which he used to describe the actual propulsion of content along isolated bowel segments4 . Since these early seminal studies, there has been much progress identifying the fundamental control mechanisms underlying neurogenic propulsion in the small and large intestine of small vertebrates5,6,10–17, including the small intestine18 and colon19 of humans, confirm‎ing that the ENS alone is capable of generating complex neurogenic motor patterns without inputs from the CNS (Fig. 2). The ENS consists of many thousands of discrete small ganglia that retain neural continuity with each other, forming two distinct ganglionated neuronal plexuses called the myenteric and submucosal plexuses14. Unlike skeletal muscle, which is only innervated by excitatory neurons20, smooth muscle cells of the gastrointestinal tract are densely innervated by both excitatory and inhibitory motor neurons21–24. Within each plexus lies a heterogeneous population of individual neurons with distinct neurochemical coding, projections and functional roles14,25,26. Ganglia within the submucosal and myenteric plexuses are connected to neighbouring ganglia via internodal strands that carry axons over substantial distances (even up to 13cm) to facilitate the rapid conduction of neuronal signals along the bowel27,28. There is considerable redundancy in the ENS — loss of large numbers of enteric neurons does not necessarily lead to loss of motility or function. Mice that lose at least half of their ENS can still generate rhythmic propagating neurogenic colonic motor complexes and live a normal lifespan29. The evolutionary process that has led to the development of the ENS has not been restricted to vertebrates. Simple invertebrates in the cnidarian phylum with radial symmetry, such as Hydra, evolved an intrinsic nervous system without any central ganglia (that is, a CNS)30 that is clearly capable of generating propulsive peristaltic-like movements31 and expelling waste. In general, the role of the myenteric plexus is to coordinate muscle movements underlying the propulsion of content, while the submucosal plexus is broadly involved in secretion and absorption14. It is presumed that the myenteric plexus fulfils a similar role in invertebrates. The importance of the ENS for life is best exemplified in vertebrates that are born with genetic mutations that lead to complete loss of enteric ganglia in the terminal colorectum32,33. Several animal species with a complete loss of enteric neurons over a substantial length of colorectum lack neurogenic motility patterns and have improper expulsion of colonic contents; this defect usually leads to the development of megacolon and animals commonly die shortly after birth5,32.

장 신경계 신체의 모든 속이 빈 장기 중에서 위장관은 중추 신경계(CNS), 즉 뇌와 척수의 신경 입력과 완전히 독립적으로 기능할 수 있는 자체적인 완전한 신경계로 진화한 유일한 기관입니다1 . 아마도 ENS의 자율적 특성을 뒷받침하는 가장 좋은 증거는 척추동물에서 장 분절을 제거하여 생체 외에서 분리하여 연구할 때 예시될 수 있습니다. 이러한 조건에서 장은 모든 외인성 신경이 절단되었음에도 불구하고 복잡한 추진성 신경성 운동 패턴을 계속 생성합니다4-6 . 장이 중추신경계와 독립적으로 반사 반응을 일으킬 수 있다는 개념은 1755년 폰 할러에 의해 처음 확인되었는데, 그는 신체에서 장을 제거한 후 “뇌와의 모든 통신이 차단된 상태의 장은 연동 운동을 보존한다”1 고 말했습니다(그림 1). 그의 발견은 135년 후, 장의 국소 자극이 장의 고립된 부분에서 양극화된 반응을 유발할 수 있다는 최초의 명확한 설명을 제공한 뤼데리츠에 의해 더욱 뒷받침되었습니다7,8 . 

약 10년 후, Bayliss와 Starling은 국소 자극 후 개 장의 외부화된 부분에서 양극화된 신경 반응이 나타나는 것을 확인하여 다음과 같은 '장의 법칙'을 공식화했습니다: “장의 국소 자극은 흥분 지점 위에서는 흥분을, 흥분 지점 아래에서는 억제를 일으킨다"9 (그림 1). 그러나 지금은 흔히 사용되는 '연동 반사'라는 용어가 만들어진 것은 1차 세계대전 중 트렌델렌부르크의 연구를 통해 고립된 장 분절을 따라 내용물이 실제로 추진되는 것을 설명하는 데 사용되었습니다4 . 이러한 초기 연구 이후, 인간의 소장18 및 결장19을 포함한 소형 척추동물의 소장 및 대장에서 신경성 추진의 근본적인 제어 메커니즘을 규명하는 데 많은 진전이 있었으며, ENS만으로도 CNS의 입력 없이 복잡한 신경성 운동 패턴을 생성할 수 있다는 것이 확인되었습니다(그림 2). ENS는 서로 신경 연속성을 유지하는 수천 개의 개별적인 작은 신경절로 구성되어 있으며, 내장 신경총과 점막하 신경총이라는 두 개의 별개의 신경절 신경총을 형성합니다14. 흥분성 뉴런에 의해서만 신경이 전달되는 골격근과 달리20, 위장관의 평활근 세포는 흥분성 및 억제성 운동 뉴런에 의해 조밀하게 신경이 전달됩니다21-24. 각 신경총 내에는 뚜렷한 신경 화학적 코딩, 투영 및 기능적 역할을 가진 개별 뉴런의 이질적인 집단이 존재합니다14,25,26. 점막하 및 장신경총 내의 신경절은 장내 신경 신호의 빠른 전도를 촉진하기 위해 상당한 거리(최대 13cm까지)에 걸쳐 축삭돌기를 운반하는 절간 가닥을 통해 이웃 신경절과 연결되어 있습니다27,28. 많은 수의 장 신경세포가 손실된다고 해서 반드시 운동성이나 기능의 상실로 이어지지는 않으며, ENS에는 상당한 중복성이 있습니다. ENS의 절반 이상을 잃은 생쥐는 여전히 리드미컬하게 전파되는 신경성 대장 운동 복합체를 생성하고 정상적인 수명을 살 수 있습니다29. ENS의 발달로 이어진 진화 과정은 척추동물에만 국한되지 않았습니다. 히드라처럼 방사형 대칭을 이루는 섬모목의 단순 무척추동물은 중심 신경절이 없는 내재 신경계(즉, CNS)30를 진화시켜 연동 운동과 같은 추진성 운동31을 생성하고 노폐물을 배출할 수 있는 능력을 분명히 갖추게 되었습니다. 일반적으로 장 신경총의 역할은 내용물 추진의 기초가 되는 근육 운동을 조정하는 것이며, 점막하 신경총은 분비 및 흡수에 광범위하게 관여합니다14. 장신경총은 무척추동물에서도 비슷한 역할을 하는 것으로 추정됩니다. 생명에 대한 ENS의 중요성은 말단 결장에서 장 신경절이 완전히 소실되는 유전적 돌연변이를 가지고 태어난 척추동물에서 가장 잘 드러납니다32,33. 상당한 길이의 결장에 걸쳐 장 신경세포가 완전히 소실된 몇몇 동물 종은 신경성 운동 패턴이 부족하고 결장 내용물의 배출이 부적절하며, 이러한 결함은 일반적으로 거대 결장의 발달로 이어지고 동물은 일반적으로 출생 직후에 사망합니다5,32.

There has been long-term interest in generating enteric neurons in aganglionic regions of the bowel of a variety of mammals born with Hirschsprung disease32,34 or in mammals that develop enteropathies associated with a deficiency in a number of enteric neurons (for example, Chagas disease). In the past few years, studies have demonstrated that transplanted neural progenitor-containing neurospheres from mouse and human can integrate into the aganglionic mouse colon both in vivo35–37 and ex vivo38,39. However, because of the extreme phenotype of the aganglionic mouse model used, the vast majority of the offspring died within the first 1–2 months of birth (independent of the neurosphere treatment), making it difficult to determine the potential benefits of treatment. It has now been demonstrated that ENS progenitors from human pluripotent stem cells can be efficiently derived and isolated, leading to their differentiation into functional enteric neurons40. This research showed that ENS precursors derived in vitro display targeted migration in the developing embryo of chicks and colonization of the large intestine of adult rodents40. Exciting in vivo studies have demonstrated that enteric neural stem cells can be successfully transplanted and integrated in vivo to restore nitrergic neurons in nitric oxide-deficient mouse colon41. This study demonstrated that transplantation of enteric neural stem cells in vivo leads to a recovery of neuronal nitric oxide synthase-positive enteric neurons and restoration of motility. These effects were associated with the development of elaborate networks of transplanted cells41. This finding was a major advance because it demonstrated, for the first time, that enteric neural stem cell transplantation can lead to an improvement in colonic function. There has been some controversy regarding the lifespan and turnover rates of enteric neurons. The controversy arises because original studies in mice showed that neurogenesis continues postnatally through to about postnatal day 21, at which point neurogenesis declines42. However, a very different concept was proposed in 2017 by Kulkarni et al., namely that the rate of enteric neuronal turnover and neurogenesis in adult mice occurs at a rapid rate, whereby >85% of myenteric neurons in the adult mouse small intestine are less than 2 weeks of age43. If this is true, this rate of neuronal turnover would require substantial cell death, yet apoptosis has been shown to occur infrequently44, if at all, in the developing ENS of mice44,45. The study by Kulkarni et al. proposed that, despite ongoing neuronal cell loss (due to apoptosis), the substantial turnover and neurogenesis of adult enteric neurons means that the total number of myenteric neurons remains constant in adult mouse small intestine43. This was suggested to occur owing to the formation of neurons from dividing precursor cells located within myenteric ganglia that express nestin and p75NTR43. Furthermore, this study suggested that there was a loss of approximately 4–5% of myenteric neurons daily, equivalent to about 30% of myenteric neurons every 7 days43. If the majority of neurons are turning over at such a high rate, it is unclear how retrograde neuronal tracing studies can visualize labelled enteric neurons many days after the application of tracers to autonomic ganglia46. It is also unclear how synaptic connections between neurons and neurotransmission can persist if nerve cell bodies are turning over so rapidly47. Future studies will be required to provide a better understanding of the rates of neuronal turnover and whether similar turnover rates occur throughout the full length of the gastrointestinal tract.

허쉬스프룽병32,34을 가지고 태어난 다양한 포유류의 장의 신경교세포 영역에서 장 신경세포를 생성하거나, 여러 장 신경세포의 결핍과 관련된 장 병증(예: 샤가스병)이 발생하는 포유류에 대해 오랫동안 관심이 있어 왔습니다. 지난 몇 년 동안, 생체 내35-37 및 생체 외38,39에서 마우스와 인간으로부터 이식된 신경 전구체 함유 신경구가 아교세포성 마우스 결장에 통합될 수 있다는 사실이 입증된 연구가 있었습니다. 그러나 사용된 아교세포 생쥐 모델의 극단적인 표현형으로 인해 대다수의 자손이 생후 1~2개월 이내에 (신경구 치료와 무관하게) 사망하여 치료의 잠재적 이점을 판단하기 어려웠습니다. 이제 인간 만능 줄기세포에서 ENS 전구세포를 효율적으로 추출하고 분리하여 기능성 장 신경세포로 분화시킬 수 있음이 입증되었습니다40. 이 연구는 시험관 내에서 유래된 ENS 전구체가 병아리의 발달 중인 배아에서 표적 이동과 성체 설치류의 대장에서 식민지화를 보인다는 것을 보여주었습니다40. 흥미로운 생체 내 연구에서는 장 신경 줄기세포를 생체 내에서 성공적으로 이식하고 통합하여 산화질소가 결핍된 마우스 결장에서 질소 신경세포를 복원할 수 있다는 사실이 입증되었습니다41. 이 연구는 장 신경 줄기세포를 생체 내에 이식하면 산화질소 합성효소 양성 장 신경세포가 회복되고 운동성이 회복된다는 것을 입증했습니다. 이러한 효과는 이식된 세포의 정교한 네트워크의 발달과 관련이 있습니다41. 이 발견은 장 신경 줄기세포 이식이 대장 기능 개선으로 이어질 수 있다는 사실을 처음으로 입증했다는 점에서 중요한 진전입니다. 장 신경세포의 수명과 회전율에 대해서는 논란이 있어 왔습니다. 이러한 논란은 생쥐를 대상으로 한 기존 연구에서 신경 생성이 출생 후 약 21일까지 지속되며, 이 시점이 되면 신경 생성이 감소하는 것으로 나타났기 때문에 발생했습니다42. 그러나 2017년 쿨카니(Kulkarni) 등은 성체 생쥐의 장 신경세포 회전율과 신경 발생이 빠른 속도로 진행되어 성체 생쥐 소장의 장 신경세포의 85% 이상이 생후 2주 미만이라는 매우 다른 개념을 제안했습니다43. 이것이 사실이라면, 이러한 신경세포 회전율은 상당한 세포 사멸을 필요로 하지만, 발달 중인 생쥐의 ENS에서 세포 사멸은 드물게44,45 발생하는 것으로 나타났습니다. 쿨카르니 등의 연구에 따르면 (세포 사멸로 인한) 지속적인 신경 세포 손실에도 불구하고 성체 장 신경세포의 상당한 회전율과 신경 발생은 성체 마우스 소장에서 장 신경세포의 총 수가 일정하게 유지된다는 것을 의미합니다43. 이는 네스틴과 p75NTR43을 발현하는 장 신경절 내에 위치한 분열 전구세포에서 신경세포가 형성되기 때문에 발생하는 것으로 추정됩니다. 또한 이 연구에 따르면 매일 약 4~5%의 장 신경세포가 손실되며, 이는 7일마다 장 신경세포의 약 30%에 해당하는 양입니다43. 대부분의 뉴런이 이렇게 빠른 속도로 뒤집어지는 경우, 역행성 뉴런 추적 연구에서 자율신경절에 추적자를 적용한 지 며칠이 지난 후에도 라벨이 부착된 장 신경세포를 어떻게 시각화할 수 있는지는 불분명합니다46. 또한 신경 세포체가 그렇게 빠르게 뒤집히는 경우 신경세포와 신경전달 사이의 시냅스 연결이 어떻게 지속될 수 있는지도 불분명합니다47. 향후 연구에서는 신경세포의 회전율과 위장관의 전체 길이에 걸쳐 유사한 회전율이 발생하는지에 대한 더 나은 이해를 제공해야 할 것입니다.

Just like the heart, the gut contains non-neuronal pacemaker cells that generate electrical rhythmicity in the smooth muscle cells. These electrical oscillations in the smooth muscle are called slow waves. The pacemaker cells of the gastrointestinal tract that generate slow waves have been identified as interstitial cells of Cajal (ICC)48. Slow waves cause phasic contractions of the gut without any requirement of activity from enteric neurons49. It is accepted that the ENS is required for propulsion along the gut. However, according to evidence in experimental models, pacemaker-type ICC (at the level of the myenteric plexus) and the electrical rhythmicity these cells generate are not required for normal gastrointestinal function, at least in the small intestine, where they can be selectively ablated50,51. By contrast, mice that fail to develop an ENS but still develop ICC in the aganglionic smooth muscle region52, and are therefore unable to generate sufficient propulsion or polarized contractions that could propel content, die soon after birth53. This research showed that, while ICC at the level of the myenteric plexus (referred to as ICC–Myenteric, termed ‘ICCMY’) were important for slow wave-mediated peristalsis49, these pacemaker cells and the rhythmic electrical depolarizations they generate were unable to take over the critical role of the ENS. Interestingly, mutant mice that lack pacemaker-type ICC at the level of the myenteric plexus and consequently lack electrical slow waves in the small intestine live a full lifespan with minor or no obvious gastrointestinal deficits50,51 and still generate propagating neurogenic contractions54. Evidence exists that another population of ICC lying adjacent to smooth muscle cells are important for neurotransmission55,56, although this is still controversial and some remain unconvinced57–59 as excitatory60 and inhibitory61 neurotransmission persists in animals without this ICC population. With the rapid increase in interest in sensory communication within the gut and along the gut–brain axis, our understanding of sensory innervation of the gastrointestinal tract has been the focus of much attention. Since the gastrointestinal tract is the only internal organ that has evolved its own sensory neurons, there is intense interest in understanding how the mechanisms of activation of intrinsic sensory neurons differ from extrinsic sensory nerve endings in the gastrointestinal tract (Fig. 3). Additionally, understanding the relative contribution of intrinsic versus extrinsic sensory nerves to the generation of chemosensory and mechanosensory reflex responses is of supreme relevance to the development of future therapeutic interventions to modify gastrointestinal function.