Explore the vast range of titles available.

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease. Cells from embryonic, fetal, paediatric and adult human intestinal tissue are analysed at different locations along the intestinal tract to construct a single-cell atlas of the developing and adult human intestinal tract, encompassing all cell lineages.

The enteric nervous system (ENS) is crucial for essential gastrointestinal physiologic functions such as motility, fluid secretion, and blood flow. The gut is colonized by trillions of bacteria that regulate host production of several signaling molecules including serotonin (5-HT) and other hormones and neurotransmitters. Approximately 90% of 5-HT originates from the intestine, and activation of the 5-HT₄ receptor in the ENS has been linked to adult neurogenesis and neuroprotection. Here, we tested the hypothesis that the gut microbiota could induce maturation of the adult ENS through release of 5-HT and activation of 5-HT₄ receptors. Colonization of germ-free mice with a microbiota from conventionally raised mice modified the neuroanatomy of the ENS and increased intestinal transit rates, which was associated with neuronal and mucosal 5-HT production and the proliferation of enteric neuronal progenitors in the adult intestine. Pharmacological modulation of the 5-HT₄ receptor, as well as depletion of endogenous 5-HT, identified a mechanistic link between the gut microbiota and maturation of the adult ENS through the release of 5-HT and activation of the 5-HT₄ receptor. Taken together, these findings show that the microbiota modulates the anatomy of the adult ENS in a 5-HT–dependent fashion with concomitant changes in intestinal transit.

The extrinsic and autonomic nervous system intricately controls the major functions of the gastrointestinal tract through the enteric nervous system; these include motor, secretory, sensory, storage, and excretory functions. Disorders of the nervous system affecting gastrointestinal tract function manifest primarily as abnormalities in motor (rather than secretory) functions. Common gastrointestinal symptoms in neurologic disorders include sialorrhea, dysphagia, gastroparesis, intestinal pseudo-obstruction, constipation, diarrhea, and fecal incontinence. Diseases of the entire neural axis ranging from the cerebral hemispheres to the peripheral autonomic nerves can result in gastrointestinal motility disorders. The most common neurologic diseases affecting gastrointestinal function are stroke, parkinsonism, multiple sclerosis, and diabetic neuropathy. Diagnosis involves identification of the neurologic disease and its distribution, and documentation of segmental gut dysfunction, typically using noninvasive imaging, transit measurements, or intraluminal measurements of pressure activity and coordination of motility. Apart from treatment of the underlying neurologic disease, management focuses on restoration of normal hydration and nutrition and pharmacologic treatment of the gut neuromuscular disorder.

Correct development and maturation of the enteric nervous system (ENS) is critical for survival 1 . At birth, the ENS is immature and requires considerable refinement to exert its functions in adulthood 2 . Here we demonstrate that resident macrophages of the muscularis externa (MMϕ) refine the ENS early in life by pruning synapses and phagocytosing enteric neurons. Depletion of MMϕ before weaning disrupts this process and results in abnormal intestinal transit. After weaning, MMϕ continue to interact closely with the ENS and acquire a neurosupportive phenotype. The latter is instructed by transforming growth factor-β produced by the ENS; depletion of the ENS and disruption of transforming growth factor-β signalling result in a decrease in neuron-associated MMϕ associated with loss of enteric neurons and altered intestinal transit. These findings introduce a new reciprocal cell–cell communication responsible for maintenance of the ENS and indicate that the ENS, similarly to the brain, is shaped and maintained by a dedicated population of resident macrophages that adapts its phenotype and transcriptome to the timely needs of the ENS niche. Resident macrophages of the muscularis externa refine the enteric nervous system (ENS) early in life by pruning synapses and phagocytosing enteric neurons, and later switch to a neuro-supportive function, indicating that the ENS is governed by a dedicated population of resident macrophages that adapt to the timely needs of the ENS.

The enteric nervous system (ENS) is an extensive network comprising millions of neurons and glial cells contained within the wall of the gastrointestinal tract. The major functions of the ENS that have been most studied include the regulation of local gut motility, secretion, and blood flow. Other areas that have been gaining increased attention include its interaction with the immune system, with the gut microbiota and its involvement in the gut–brain axis, and neuro-epithelial interactions. Thus, the enteric circuitry plays a central role in intestinal homeostasis, and this becomes particularly evident when there are faults in its wiring such as in neurodevelopmental or neurodegenerative disorders. In this review, we first focus on the current knowledge on the cellular composition of enteric circuits. We then further discuss how enteric circuits detect and process external information, how these signals may be modulated by physiological and pathophysiological factors, and finally, how outputs are generated for integrated gut function.

One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions.Enteric glia regulate homeostasis in the enteric nervous system and influence gastrointestinal function. This Review provides an update on enteric glial biology and the underlying mechanisms by which enteric glia regulate gastrointestinal function and disease, with a focus on neuronal and immune interactions.

The enteric nervous system (ENS) is the largest division of the peripheral nervous system and closely resembles components and functions of the central nervous system. Although the central role of the ENS in congenital enteric neuropathic disorders, including Hirschsprung disease and inflammatory and functional bowel diseases, is well acknowledged, its role in systemic diseases is less understood. Evidence of a disordered ENS has accumulated in neurodegenerative diseases ranging from amyotrophic lateral sclerosis, Alzheimer disease and multiple sclerosis to Parkinson disease as well as neurodevelopmental disorders such as autism. The ENS is a key modulator of gut barrier function and a regulator of enteric homeostasis. A ‘leaky gut’ represents the gateway for bacterial and toxin translocation that might initiate downstream processes. Data indicate that changes in the gut microbiome acting in concert with the individual genetic background can modify the ENS, central nervous system and the immune system, impair barrier function, and contribute to various disorders such as irritable bowel syndrome, inflammatory bowel disease or neurodegeneration. Here, we summarize the current knowledge on the role of the ENS in gastrointestinal and systemic diseases, highlighting its interaction with various key players involved in shaping the phenotypes. Finally, current flaws and pitfalls related to ENS research in addition to future perspectives are also addressed.Although the role of the enteric nervous system in congenital enteric neuropathic disorders is well acknowledged, its role in systemic diseases is less understood. Here, the authors focus on diseases in which the enteric nervous system has so far not been considered to have a major role and on its emerging role in neurodegeneration, cancer and diabetes.

Organoids formed by combining pluripotent-stem-cell-derived human neural crest cells with pluripotent-stem-cell-derived intestinal tissue show functional interstitial cells of Cajal and undergo waves of contraction; these tissues reveal insights into the molecular defects characterizing Hirschsprung's disease. The enteric nervous system (ENS) of the gastrointestinal tract controls many diverse functions, including motility and epithelial permeability. Perturbations in ENS development or function are common, yet there is no human model for studying ENS-intestinal biology and disease. We used a tissue-engineering approach with embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining human-PSC-derived neural crest cells (NCCs) and developing human intestinal organoids (HIOs). NCCs recombined with HIOs in vitro migrated into the mesenchyme, differentiated into neurons and glial cells and showed neuronal activity, as measured by rhythmic waves of calcium transients. ENS-containing HIOs grown in vivo formed neuroglial structures similar to a myenteric and submucosal plexus, had functional interstitial cells of Cajal and had an electromechanical coupling that regulated waves of propagating contraction. Finally, we used this system to investigate the cellular and molecular basis for Hirschsprung's disease caused by a mutation in the gene PHOX2B . This is, to the best of our knowledge, the first demonstration of human-PSC-derived intestinal tissue with a functional ENS and how this system can be used to study motility disorders of the human gastrointestinal tract.

ObjectivesProteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity.DesignTrypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (PRSS1, 2 and 3) were detected by reverse transcription-PCR, and trypsin-3 protein expression was studied by western blot analysis and immunohistochemistry. Electrophysiological recordings and Ca2+ imaging in response to trypsin-3 were performed in mouse primary afferent and in human submucosal neurons, respectively. Visceromotor response to colorectal distension was recorded in mice administered intracolonically with trypsin-3.ResultsWe showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a protease-activated receptor-2-dependent mechanism.ConclusionsIn IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity.

Pathological studies on Parkinson's disease (PD) patients suggest that PD pathology progresses from the enteric nervous system (ENS) and the olfactory bulb into the central nervous system. We have previously shown that environmental toxins acting locally on the ENS mimic this PD-like pathology progression pattern in mice. Here, we show for the first time that the resection of the autonomic nerves stops this progression. Moreover, our results show that an environmental toxin (i.e. rotenone) promotes the release of alpha-synuclein by enteric neurons and that released enteric alpha-synuclein is up-taken by presynaptic sympathetic neurites and retrogradely transported to the soma, where it accumulates. These results strongly suggest that pesticides can initiate the progression of PD pathology and that this progression is based on the transneuronal and retrograde axonal transport of alpha-synuclein. If confirmed in patients, this study would have crucial implications in the strategies used to prevent and treat PD.