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Hirschsprung disease is defined by the absence of enteric neurons at the end of the bowel. The enteric nervous system (ENS) is the intrinsic nervous system of the bowel and regulates most aspects of bowel function. When the ENS is missing, there are no neurally mediated propulsive motility patterns, and the bowel remains contracted, causing functional obstruction. Symptoms of Hirschsprung disease include constipation, vomiting, abdominal distension and growth failure. Untreated disease usually causes death in childhood because bloodstream bacterial infections occur in the context of bowel inflammation (enterocolitis) or bowel perforation. Current treatment is surgical resection of the bowel to remove or bypass regions where the ENS is missing, but many children have problems after surgery. Although the anatomy of Hirschsprung disease is simple, many clinical features remain enigmatic, and diagnosis and management remain challenging. For example, the age of presentation and the type of symptoms that occur vary dramatically among patients, even though every affected child has missing neurons in the distal bowel at birth. In this Review, basic science discoveries are linked to clinical manifestations of Hirschsprung disease, including partial penetrance, enterocolitis and genetics. Insights into disease mechanisms that might lead to new prevention, diagnostic and treatment strategies are described.

Key Points The lining of the digestive tract is exposed to an extraordinarily broad range of chemicals and organisms The gut continuously monitors the composition of its contents to optimize digestion and absorption, and to ward off threats to its integrity The gut has numerous sensors that detect nutrients, distension, symbiotic and pathogenic microorganisms, toxins and other components of its luminal contents For the digestive system to react appropriately to its environment, the sensory information is communicated to extensive endocrine, neural, immune and nonimmune tissue defence systems More than 20 receptors that face the luminal contents are potential therapeutic targets for diabetes, obesity and digestive disorders; restricting orally active therapeutics to the lumen could reduce off-target actions The sensing mechanism of the gut and the effector systems with which they communicate interact intimately on an anatomical and functional level. Here, John Furness and colleagues discuss how recent discoveries are enabling us to develop a comprehensive understanding of the integrated responses of the gut to the sensory information it receives. The gastrointestinal tract presents the largest and most vulnerable surface to the outside world. Simultaneously, it must be accessible and permeable to nutrients and must defend against pathogens and potentially injurious chemicals. Integrated responses to these challenges require the gut to sense its environment, which it does through a range of detection systems for specific chemical entities, pathogenic organisms and their products (including toxins), as well as physicochemical properties of its contents. Sensory information is then communicated to four major effector systems: the enteroendocrine hormonal signalling system; the innervation of the gut, both intrinsic and extrinsic; the gut immune system; and the local tissue defence system. Extensive endocrine–neuro–immune–organ-defence interactions are demonstrable, but under-investigated. A major challenge is to develop a comprehensive understanding of the integrated responses of the gut to the sensory information it receives. A major therapeutic opportunity exists to develop agents that target the receptors facing the gut lumen.

Alterations in colonic motility are implicated in the pathophysiology of bowel disorders, but high-resolution manometry of human colonic motor function has revealed that our knowledge of normal motor patterns is limited. Furthermore, various terminologies and definitions have been used to describe colonic motor patterns in children, adults and animals. An example is the distinction between the high-amplitude propagating contractions in humans and giant contractions in animals. Harmonized terminology and definitions are required that are applicable to the study of colonic motility performed by basic scientists and clinicians, as well as adult and paediatric gastroenterologists. As clinical studies increasingly require adequate animal models to develop and test new therapies, there is a need for rational use of terminology to describe those motor patterns that are equivalent between animals and humans. This Consensus Statement provides the first harmonized interpretation of commonly used terminology to describe colonic motor function and delineates possible similarities between motor patterns observed in animal models and humans in vitro (ex vivo) and in vivo. The consolidated terminology can be an impetus for new research that will considerably improve our understanding of colonic motor function and will facilitate the development and testing of new therapies for colonic motility disorders.

Key Points The enteric nervous system (ENS) is the largest component of the autonomic nervous system and is uniquely equipped with intrinsic microcircuits that enable it to orchestrate gastrointestinal function independently of central nervous system (CNS) input Because many neurotransmitters, signalling pathways and anatomical properties are common to the ENS and CNS, pathophysiological processes that underlie CNS disease often have enteric manifestations Neuronal connections and the immune system might provide conduits that allow diseases acquired in the gut to spread to the brain Transmissible spongiform encephalopathies, autistic spectrum disorders, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and varicella zoster virus (VZV) infection are examples of disorders with both gastrointestinal and neurological consequences VZV reactivations from latency in enteric and other autonomic neurons that lack cutaneous projections are occult causes of zoster without rash that lead to gastrointestinal disease, meningitis and strokes Research on the gut–brain axis of disease is reasonably new, concepts are changing rapidly, and further investigation is much needed The enteric nervous system is vital for life, and its dysfunction participates not only in digestive disorders, but also in diseases of the central nervous system (CNS). Here, Rao and Gershon discuss the gastrointestinal consequences of neurological disorders, the acquisition of CNS disease in the gut and the spread of pathology along the gut–brain axis. The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut–brain alliance has raised consciousness as a contributor to health, but a gut–brain axis that contributes to disease merits equal attention.

Maintenance of gastrointestinal health is challenging as it requires balancing multifaceted processes within the highly complex and dynamic ecosystem of the gastrointestinal tract. Disturbances within this vibrant environment can have detrimental consequences, including the onset of gastrointestinal cancers. Globally, gastrointestinal cancers account for ~19% of all cancer cases and ~22.5% of all cancer-related deaths. Developing new ways to more readily detect and more efficiently target these malignancies are urgently needed. Whereas members of the tumour microenvironment, such as immune cells and fibroblasts, have already been in the spotlight as key players of cancer initiation and progression, the importance of the nervous system in gastrointestinal cancers has only been highlighted in the past few years. Although extrinsic innervations modulate gastrointestinal cancers, cells and signals from the gut’s intrinsic innervation also have the ability to do so. Here, we shed light on this thriving field and discuss neural influences during gastrointestinal carcinogenesis. We focus on the interactions between neurons and components of the gastrointestinal tract and tumour microenvironment, on the neural signalling pathways involved, and how these factors affect the cancer hallmarks, and discuss the neural signatures in gastrointestinal cancers. Finally, we highlight neural-related therapies that have potential for the management of gastrointestinal cancers.The influence of nerves on cancer is beginning to be understood. This Review discusses emerging insights into the role of the nervous system in gastrointestinal cancer and of nerves as components of the tumour microenvironment, highlighting underlying mechanisms and its potential as a therapeutic target.

Key Points Gastrointestinal infection and inflammation are key risk factors for the development of numerous clinical gastrointestinal disorders that present with symptoms such as altered motility or secretion, abdominal discomfort and pain Neuronal processing along the gut–brain axis is crucial for the function and modulation of key gastrointestinal processes; findings suggest that this processing can be altered by gut inflammation or infection Inflammation or infection causes specific changes in enteric neuronal excitability, which can persist after inflammation has resolved; in some experimental models, inflammation also causes a rapid loss of myenteric neurons and viscerofugal neurons Inflammation causes a specific hypersensitivity of visceromotor sympathetic neurons in prevertebral ganglia, which persists long after inflammation has resolved Extrinsic gut sensory afferents express pronociceptive channels and receptors that can be activated in response to inflammatory and immune mediators, leading to acute neuronal hyperexcitability, visceral hypersensitivity and neurogenic inflammation Inflammation causes lowering of mechanical activation thresholds of high-threshold or low-threshold afferents, which leads to hyperexcitability in afferent neuronal cell bodies, and increased activation of nociceptive pathways in the central nervous system Neuronal processing along the gut–brain axis is crucial for the function and modulation of key gastrointestinal processes, and evidence suggests that this processing can be altered by gut inflammation or infection. This Review discusses the current body of evidence for neuroplasticity (the structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most individuals are unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such changes are evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time course of neuroplasticity must be fully appreciated.

In 2021, transcriptome analysis of the mouse and human gut advanced our understanding of the cellular composition, development and surrounding non-neural context of the enteric nervous system (ENS). A role for the ENS in tuning regulatory T cell proportions contributed insights into the dependency between the ENS, immune system and microbiota.Key advancesSingle-cell transcriptome analysis and histochemistry revealed 12 myenteric neuron classes in the mouse small intestine and a conceptually new step-wise principle for their embryonic diversification5.A monumental single-cell transcriptome atlas of the human gut across time and space described the development of the enteric nervous system (ENS) and the non-neural cellular context of the fetal, paediatric and adult ENS7.Enteric neurons tune the number and phenotypes of regulatory T cells by secretion of IL-6; in turn, the structure and activity of the ENS is modulated by microbial signals, altogether suggesting tripartite interactions between the ENS, immune system and microbiota, of relevance for intestinal tolerance10.

Optical clearing with high-refractive-index (high- n ) reagents is essential for 3D tissue imaging. However, the current liquid-based clearing condition and dye environment suffer from solvent evaporation and photobleaching, causing difficulties in maintaining the tissue optical and fluorescent features. Here, using the Gladstone-Dale equation [( n −1)/density=constant] as a design concept, we develop a solid (solvent-free) high- n acrylamide-based copolymer to embed mouse and human tissues for clearing and imaging. In the solid state, the fluorescent dye-labeled tissue matrices are filled and packed with the high- n copolymer, minimizing scattering in in-depth imaging and dye fading. This transparent, liquid-free condition provides a friendly tissue and cellular environment to facilitate high/super-resolution 3D imaging, preservation, transfer, and sharing among laboratories to investigate the morphologies of interest in experimental and clinical conditions. Current liquid-based optical clearing protocols can suffer from solvent evaporation and photobleaching. Here, the authors develop a solid high-refractive-index polymer to embed mouse and human tissues for clearing and antifade high-resolution 3D imaging.

The stability of the neuronal circuits and cells of the enteric nervous system can no longer be taken for granted; new evidence suggests astounding rates of apoptosis and neurogenesis.