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The autonomic nervous system orchestrates the functions of the brain and body through the sympathetic and parasympathetic pathways 1 . However, our understanding of the autonomic system, especially the sympathetic system, at the cellular and molecular levels is severely limited. Here we show topological representations of individual visceral organs in the major abdominal sympathetic ganglion complex. Using multi-modal transcriptomic analyses, we identified molecularly distinct sympathetic populations in the coeliac–superior mesenteric ganglia (CG–SMG). Of note, individual CG–SMG populations exhibit selective and mutually exclusive axonal projections to visceral organs, targeting either the gastrointestinal tract or secretory areas including the pancreas and bile tract. This combinatorial innervation pattern suggests functional segregation between different CG–SMG populations. Indeed, our neural perturbation experiments demonstrated that one class of neurons regulates gastrointestinal transit, and another class of neurons controls digestion and glucagon secretion independent of gut motility. These results reveal the molecularly diverse sympathetic system and suggest modular regulation of visceral organ functions by sympathetic populations. Multi-modal transcriptomic analyses of the sympathetic nervous system reveal organ-specific neural innervation and modular regulation of visceral functions.

The classic view portrays Parkinson disease (PD) as a motor disorder resulting from loss of substantia nigra pars compacta dopaminergic neurons. Multiple studies, however, describe prodromal, non-motor dysfunctions that affect the quality of life of patients who subsequently develop PD. These prodromal dysfunctions comprise a wide array of gastrointestinal motility disorders including dysphagia, delayed gastric emptying and chronic constipation. The histological hallmark of PD — misfolded α-synuclein aggregates that form Lewy bodies and neurites — is detected in the enteric nervous system prior to clinical diagnosis, suggesting that the gastrointestinal tract and its neural (vagal) connection to the central nervous system could have a major role in disease aetiology. This Review provides novel insights on the pathogenesis of PD, including gut-to-brain trafficking of α-synuclein as well as the newly discovered nigro–vagal pathway, and highlights how vagal connections from the gut could be the conduit by which ingested environmental pathogens enter the central nervous system and ultimately induce, or accelerate, PD progression. The pathogenic potential of various environmental neurotoxicants and the suitability and translational potential of experimental animal models of PD will be highlighted and appraised. Finally, the clinical manifestations of gastrointestinal involvement in PD and medications will be discussed briefly.Gastrointestinal dysfunction (including dysphagia and constipation) can occur in Parkinson disease (PD), with evidence that they can arise prior to diagnosis of PD. This Review describes new insights into the mechanisms and pathophysiology of the gastrointestinal involvement of PD, including clinical manifestations.

Intestinal type 2 innate lymphoid cells express the neuropeptide receptor NMUR1, which makes them responsive to neuronal neuromedin U, thereby promoting a type 2 cytokine response and accelerated expulsion of the gastro-intestinal nematode Nippostrongylus brasiliensis . Neuron regulation of immune cells Group 2 innate lymphoid cells (ILC2s) are entangled with cholinergic SNAP-25-expressing neurons. David Artis and colleagues report that ILC2s express the neuropeptide receptor NMUR1, making them responsive to neuronal neuromedin. In mice, this promoted a tissue-protective type 2 response and accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis . Elsewhere in this issue, Henrique Veiga-Fernandes and colleagues also provide evidence that ILC2s express Nmur1 and respond to neuromedin expressed by adjacent enteric neurons. In mice, the interaction results in an enhanced and immediate response of ILC2s to infection by the parasite N. brasiliensis . The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair 1 , 2 , 3 . Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses 4 , 5 , 6 , 7 , 8 , 9 , how ILC2 responses are regulated by other stimuli remains poorly understood. Here we demonstrate that ILC2s in the mouse gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU) 10 , 11 . In contrast to other haematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation, and secretion of the type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and G αq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1 −/− mice than in control mice. Furthermore, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU–NMUR1 neuronal signalling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.

Serotonin (5-HT) has been recognized for decades as an important signalling molecule in the gut, but it is still revealing its secrets. Mawe and Hoffman outline the conventional and nonconventional actions of 5-HT, and describe potential therapeutic strategies targeting this molecule and its receptors. Serotonin (5-HT) has been recognized for decades as an important signalling molecule in the gut, but it is still revealing its secrets. Novel gastrointestinal functions of 5-HT continue to be discovered, as well as distant actions of gut-derived 5-HT, and we are learning how 5-HT signalling is altered in gastrointestinal disorders. Conventional functions of 5-HT involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion and vasodilation. Activation of extrinsic vagal and spinal afferent fibres results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5-HT also exerts nonconventional actions such as promoting inflammation and serving as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, originating in the gut, promotes haemostasis, influences bone development and serves many other functions. 5-HT 3 receptor antagonists and 5-HT 4 receptor agonists have been used to treat functional disorders with diarrhoea or constipation, respectively, and the synthetic enzyme tryptophan hydroxylase has also been targeted. Emerging evidence suggests that exploiting epithelial targets with nonabsorbable serotonergic agents could provide safe and effective therapies. We provide an overview of these serotonergic actions and treatment strategies. Key Points Serotonin (5-HT) is an important gastrointestinal signalling molecule that conveys signals from the lumen of the gut to intrinsic and extrinsic sensory neurons, and contributes to synaptic signals in the enteric nervous system Fundamental properties of mucosal 5-HT signalling are altered in response to inflammation and in functional gastrointestinal disorders Actions of 5-HT released from mucosal enterochromaffin cells include stimulation of intrinsic reflexes such as peristalsis, segmentation, secretion and vasodilation 5-HT can also activate signals sent to the CNS that stimulate digestive reflexes and can cause abdominal pain and discomfort, satiety or nausea Mucosal 5-HT can promote intestinal inflammation, and 5-HT in the muscularis propria can promote survival of neurons and interstitial cells of Cajal, and promote neural regeneration As the colonic epithelium is rich in 5-HT-related targets, nonabsorbable drugs that target 5-HT 3 receptors, 5-HT 4 receptors and tryptophan hydroxylase could serve as safe and effective therapies

Parkinson’s disease (PD) is a complex neurological disorder classically characterized by impairments in motor system function associated with loss of dopaminergic neurons in the substantia nigra. After almost 200 years since the first description of PD by James Parkinson, unraveling the complexity of PD continues to evolve. It is now recognized that an interplay between genetic and environmental factors influences a diverse range of cellular processes, reflecting on other clinical features including non-motor symptoms. This has consequently highlighted the extensive value of early clinical diagnosis to reduce difficulties of later stage management of PD. Advancement in understanding of PD has made remarkable progress in introducing new tools and strategies such as stem cell therapy and deep brain stimulation. A link between alterations in gut microbiota and PD has also opened a new line. Evidence exists of a bidirectional pathway between the gastrointestinal tract and the central nervous system. Probiotics, prebiotics and synbiotics are being examined that might influence gut-brain axis by altering gut microbiota composition, enteric nervous system, and CNS. This review provides status on use of probiotics for PD. Limitations and future directions will also be addressed to promote further research considering use of probiotics for PD.

The gastrointestinal tract contains its own set of intrinsic neuroglial circuits — the enteric nervous system (ENS) — which detects and responds to diverse signals from the environment. Here, we address recent advances in the understanding of ENS development, including how neural-crest-derived progenitors migrate into and colonize the bowel, the formation of ganglionated plexuses and the molecular mechanisms of enteric neuronal and glial diversification. Modern lineage tracing and transcription-profiling technologies have produced observations that simultaneously challenge and affirm long-held beliefs about ENS development. We review many genetic and environmental factors that can alter ENS development and exert long-lasting effects on gastrointestinal function, and discuss how developmental defects in the ENS might account for some of the large burden of digestive disease.

Satiation is the process by which eating and drinking reduce appetite. For thirst, oropharyngeal cues have a critical role in driving satiation by reporting to the brain the volume of fluid that has been ingested 1 – 12 . By contrast, the mechanisms that relay the osmolarity of ingested fluids remain poorly understood. Here we show that the water and salt content of the gastrointestinal tract are precisely measured and then rapidly communicated to the brain to control drinking behaviour in mice. We demonstrate that this osmosensory signal is necessary and sufficient for satiation during normal drinking, involves the vagus nerve and is transmitted to key forebrain neurons that control thirst and vasopressin secretion. Using microendoscopic imaging, we show that individual neurons compute homeostatic need by integrating this gastrointestinal osmosensory information with oropharyngeal and blood-borne signals. These findings reveal how the fluid homeostasis system monitors the osmolarity of ingested fluids to dynamically control drinking behaviour. Drinking behaviour in mice is regulated by a signal derived from the water and salt content of the gastrointestinal tract that is transmitted to forebrain neurons that control thirst via the vagus nerve.

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.

Cholinergic Regulation of Ghrelin and Peptide YY Release May Be Impaired in Obesity Christina Maier 1 , Michaela Riedl 1 , Greisa Vila 1 , Peter Nowotny 1 , Michael Wolzt 2 , Martin Clodi 1 , Bernhard Ludvik 1 and Anton Luger 1 1 Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria 2 Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria Corresponding author: Christina Maier, christina.maier{at}meduniwien.ac.at Abstract OBJECTIVE— Ghrelin and peptide YY (PYY) are both hormones derived from the gastrointestinal tract involved in appetite regulation. The cholinergic part of the vagal nerve is involved in the regulation of glucose and insulin. The aim of this study was to examine the effects of the cholinergic antagonist atropine on ghrelin, PYY, glucose, and insulin under basal conditions and after meal ingestion in lean and obese subjects. REASEARCH DESIGN AND METHODS— Eight lean and eight obese subjects were included in a randomized, double-blind, placebo-controlled crossover study with 4 study days in randomized order (atropine/placebo ± breakfast). Plasma ghrelin, PYY, insulin, and glucose were measured. Hunger and satiety feelings were rated on a 10-cm visual analog scale. RESULTS— In lean individuals, atropine led to a decrease in ghrelin concentrations comparable and nonadditive with breakfast ingestion and a significant decrease in both basal and meal-induced PYY concentrations. In obese subjects, atropine did not significantly change ghrelin or PYY concentrations, whereas it induced a comparable increase in heart rate and meal-induced glucose concentrations in the two study groups. Only lean, not obese, subjects experienced sustained feelings of satiety after breakfast. CONCLUSIONS— The impaired cholinergic regulation of the postprandial drop in ghrelin concentrations and rise in PYY concentrations might be part of the deregulated food intake in obese subjects. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 20 June 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 17, 2008. Received June 4, 2007. DIABETES

Neurogastroenterology encompasses control of digestion through the enteric nervous system, the central nervous system and integrative centers in sympathetic ganglia. In this Review, John Furness provides a broad overview of the rapidly developing field of neurogastroenterology, with a focus on the roles of the enteric nervous system in the control of the musculature of the gastrointestinal tract and transmucosal fluid movement. Neurogastroenterology is defined as neurology of the gastrointestinal tract, liver, gallbladder and pancreas and encompasses control of digestion through the enteric nervous system (ENS), the central nervous system (CNS) and integrative centers in sympathetic ganglia. This Review provides a broad overview of the field of neurogastroenterology, with a focus on the roles of the ENS in the control of the musculature of the gastrointestinal tract and transmucosal fluid movement. Digestion is controlled through the integration of multiple signals from the ENS and CNS; neural signals also pass between distinct gut regions to coordinate digestive activity. Moreover, neural and endocrine control of digestion is closely coordinated. Interestingly, the extent to which the ENS or CNS controls digestion differs considerably along the digestive tract. The importance of the ENS is emphasized by the life-threatening effects of certain ENS neuropathies, including Hirschsprung disease and Chagas disease. Other ENS disorders, such as esophageal achalasia and gastroparesis, cause varying degrees of dysfunction. The neurons in enteric reflex pathways use a wide range of chemical messengers that signal through an even wider range of receptors. These receptors provide many actual and potential targets for modifying digestive function. Key Points The enteric nervous system (ENS) is an extensive reflex control system for digestive function that works with the central nervous system (CNS) and neural pathways that pass through sympathetic ganglia The ENS of the small intestine and colon has complete reflex pathways that control patterns of contractile activity, local blood flow and transmucosal movement of fluids The CNS has essential roles in control of esophageal, stomach and colorectal functions Control of transmucosal fluid movement by the ENS and CNS is closely integrated The ENS interacts with both the gut endocrine and immune systems and has roles in modifying nutrient absorption and maintaining the mucosal barrier Enteric neuropathies in which control of muscle contractile activity or neural control of transmucosal fluid movement fail are life-threatening