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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.

The intestinal lumen is filled with diverse chemical and physical stimuli. Intestinal epithelial cells sense these stimuli and signal to enteric neurons which coordinate a range of physiologic processes required for normal digestive tract function. Yet, the neuro-epithelial connections remain poorly resolved, in part because the tools for orchestrating interactions between these cellular compartments are lacking. We describe the development of a two-compartment microfluidic device for co-culturing enteric neurons with intestinal epithelial cells. The device contains epithelial and neuronal compartments connected by microgrooves. The epithelial compartment was designed for cell seeding via injection and confinement of intestinal epithelial cells derived from human intestinal organoids. We demonstrated that organoids planarized effectively and retained epithelial phenotype for over a week. In the second chamber we dissociated and cultured intestinal myenteric neurons including intrinsic primary afferent neurons (IPANs) from transgenic mice that expressed the fluorescent protein tdTomato. IPANs extended projections into microgrooves, surrounded and frequently made contacts with epithelial cells. The density and directionality of neuronal projections were enhanced by the presence of epithelial cells in the adjacent compartment. Our microfluidic device represents a platform that may, in the future, be used to dissect structure and function of neuro-epithelial connections in the gut and other organs (skin, lung, bladder, and others) in health and disease.

Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear. Piezo2 mechanosensitive ion channels are important for some specialized epithelial mechanosensors, and they are expressed in mouse and human EC cells. Here, we use EC and EE cell lineage tracing in multiple mouse models to show that Piezo2 is expressed in a subset of murine EE and EC cells, and it is distributed near serotonin vesicles by superresolution microscopy. Mechanical stimulation of a subset of isolated EE cells leads to a rapid inward ionic current, which is diminished by Piezo2 knockdown and channel inhibitors. In these mechanosensitive EE cells force leads to Piezo2-dependent intracellular Ca2+ increase in isolated cells as well as in EE cells within intestinal organoids, and Piezo2-dependent mechanosensitive serotonin release in EC cells. Conditional knockout of intestinal epithelial Piezo2 results in a significant decrease in mechanically stimulated epithelial secretion. This study shows that a subset of primary EE and EC cells is mechanosensitive, uncovers Piezo2 as their primary mechanotransducer, defines the molecular mechanism of their mechanotransduction and mechanosensitive serotonin release, and establishes the role of epithelial Piezo2 mechanosensitive ion channels in regulation of intestinal physiology.

Mast cells constitutively express ß-catenin and expand in solid tumors such as colon and skin cancer. However, the role of ß-catenin signaling in mast cells and the cause or effect of mast cell expansion and tumor growth has yet to be established. In earlier studies we used mast cell depletion and protease staining approaches, to provide evidence for a causative role of mast cells in small bowel polyposis, and related specific phenotypes and distributions of tumor infiltrating mast cells to stages of tumor growth. Here we report that, stabilization of ß-catenin expands mast cells to promote high incidence of colon polyposis and infrequent small bowel polyps and skin cancer. Expression of a dominant acting ß-catenin in mast cells (5CreCAT) stimulated maturation and expression of granule stored proteases. Both mucosal and connective tissue type mast cells accumulated in colonic small bowel polyps independent of gender, and mice developed chronic systemic inflammation with splenomegaly. Reconstitution of polyposis-prone mice with bone marrow from 5CreCAT mice resulted in focal expansion of connective tissue like mast cells, which are normally rare in benign polyps and characteristically expand during adenoma-to-carcinoma transition. Our findings highlight a hitherto unknown contribution of ß-catenin signaling in mast cells to their maturation and to increased risk of colon cancer.

Aim This study aims to determine mechanisms of action of the gasotransmitter hydrogen sulfide (H 2 S) on contractile activity in longitudinal muscle of rat ileum. Methods Ileal longitudinal muscle strips were prepared to measure isometric contractions. Effects of sodium hydrosulfide (NaHS), a donor of H 2 S, were evaluated on spontaneous contractile activity and after enhanced contractile activity with bethanechol. l -cysteine was evaluated as a potential endogenous donor of H 2 S. We evaluated involvement of extrinsic nerves, enteric nervous system, visceral afferent nerves, nitric oxide, and K ATP + channel and K Ca + channel activity on the action of H 2 S using non-adrenergic/non-cholinergic conditions, tetrodotoxin, capsaicin, l -N G -nitro arginine ( l -NNA), glibenclamide, and apamin, respectively, as well as electrical field stimulation. Result NaHS dose-dependently and reversibly inhibited spontaneous and bethanechol-stimulated contractile activity ( p  < 0.05). l -cysteine had no inhibitory effect. Non-adrenergic/non-cholinergic conditions, tetrodotoxin, capsaicin, l -NNA, glibenclamide, or apamin had no major effect on total contractile activity by NaHS, although both tetrodotoxin and apamin decreased the frequency of bethanechol-enhanced contractile activity ( p  < 0.05). We could not demonstrate H 2 S release by electrical field stimulation but did show that inhibition of cystathionine β synthase, an endogenous source of H 2 S, augmented the inhibitory effect of low-frequency electrical field stimulation. Conclusion H 2 S inhibits contractile activity of ileal longitudinal muscle dose-dependently but not through pathways mediated by the extrinsic or enteric nervous system, visceral afferent nerves, nitric oxide, K ATP + channels, or K Ca + channels.

Specific small-intestinal bacteria, particularly Enterobacteriaceae, can trigger abdominal pain by activating gut sensory and nerve cells, revealing how microbiota contribute to gastrointestinal symptoms.

The objective of this study was to determine whether constipation-predominant irritable bowel syndrome (IBS-C) is associated with changes in intestinal barrier and secretory function. A total of 19 IBS-C patients and 18 healthy volunteers (all females) underwent saccharide excretion assay (0.1 g C mannitol and 1 g lactulose), measurements of duodenal and colonic mucosal barrier (transmucosal resistance (TMR), macromolecular and Escherichia coli Bio-Particle translocation), mucosal secretion (basal and acetylcholine (Ach)-evoked short-circuit current (Isc)), in vivo duodenal mucosal impedance, circulating endotoxins, and colonic tight junction gene expression. There were no differences in the in vivo measurements of barrier function between IBS-C patients and healthy controls: cumulative excretion of C mannitol (0-2 h mean (s.e.m.); IBS-C: 12.1 (0.9) mg vs. healthy: 13.2 (0.8) mg) and lactulose (8-24 h; IBS-C: 0.9 (0.5) mg vs. healthy: 0.5 (0.2) mg); duodenal impedance IBS-C: 729 (65) Ω vs. healthy: 706 (43) Ω; plasma mean endotoxin activity level IBS-C: 0.36 (0.03) vs. healthy: 0.35 (0.02); and in colonic mRNA expression of occludin, zonula occludens (ZO) 1-3, and claudins 1-12 and 14-19. The ex vivo findings were consistent, with no group differences: duodenal TMR (IBS-C: 28.2 (1.9) Ω cm vs. healthy: 29.8 (1.9) Ω cm ) and colonic TMR (IBS-C: 19.1 (1.1) Ω cm vs. healthy: 17.6 (1.7) Ω cm ); fluorescein isothiocyanate (FITC)-dextran (4 kDa) and E. coli Bio-Particle flux. Colonic basal Isc was similar, but duodenal basal Isc was lower in IBS-C (43.5 (4.5) μA cm ) vs. healthy (56.9 (4.9) μA cm ), P=0.05. Ach-evoked ΔIsc was similar. Females with IBS-C have normal colonic barrier and secretory function. Basal duodenal secretion is decreased in IBS-C.

Background Nutritional interventions often fail to prevent growth failure in childhood and adolescent malnutrition and the mechanisms remain unclear. Recent studies revealed altered microbiota in malnourished children and anorexia nervosa. To facilitate mechanistic studies under physiologically relevant conditions, we established a mouse model of growth failure following chronic dietary restriction and examined microbiota in relation to age, diet, body weight, and anabolic treatment. Methods Four-week-old female BALB/c mice (n = 12/group) were fed ad libitum (AL) or offered limited food to abolish weight gain (LF). A subset of restricted mice was treated with an insulin-like growth factor 1 (IGF1) analog. Food access was restored in a subset of untreated LF (LF-RF) and IGF1-treated LF mice (TLF-RF) on day 97. Gut microbiota were determined on days 69, 96–99 and 120 by next generation sequencing of the V3–5 region of the 16S rRNA gene. Microbiota–host factor associations were analyzed by distance-based PERMANOVA and quantified by the coefficient of determination R 2 for age, diet, and normalized body weight change (Δbwt). Microbial taxa on day 120 were compared following fitting with an overdispersed Poisson regression model. The machine learning algorithm Random Forests was used to predict age based on the microbiota. Results On day 120, Δbwt in AL, LF, LF-RF, and TLF-RF mice was 52 ± 3, –6 ± 1*, 40 ± 3*, and 46 ± 2 % (*, P  < 0.05 versus AL). Age and diet, but not Δbwt, were associated with gut microbiota composition. Age explained a larger proportion of the microbiota variability than diet or Δbwt. Random Forests predicted chronological age based on the microbiota and indicated microbiota immaturity in the LF mice before, but not after, refeeding. However, on day 120, the microbiota community structure of LF-RF mice was significantly different from that of both AL and LF mice. IGF1 mitigated the difference from the AL group. Refed groups had a higher abundance of Bacteroidetes and Proteobacteria and a lower abundance of Firmicutes than AL mice. Conclusions Persistent growth failure can be induced by 97-day dietary restriction in young female mice and is associated with microbiota changes seen in lean mice and individuals and anorexia nervosa. IGF1 facilitates recovery of body weights and microbiota.

Electrophysiology is the study of the electrical properties of biological tissues, which involves the movement of ions across cell membranes. The analysis of the movement of electrical charges through the body has a wide range of biomedical applications, such as diagnosing and planning treatment in cardiovascular, nervous systems, muscular, and gastrointestinal disorders. The dielectric properties of biological tissues change according to the water content in the tissue and are measured as permittivity and conductivity relative to the frequency of the electrical field. This principle has been applied in diagnostics and therapeutics using microwave energysuch as imaging and ablation, etc. This review article summarizes the potential use of measuring dielectric properties using microwave imaging and how it can augment electrophysiological studies in medicine.

The majority of diarrheal episodes are associated with Escherichia coli, or Shigella, Campylobacter or Samonella spp., however, infection with the bacterium Vibrio cholerae is perhaps the most renowned because it produces diarrhea that can lead to severe dehydration and death, sometimes within hours of the first symptoms, and outbreaks reach epidemic proportions prior to the discovery of the contaminated source. Cholera has traditionally been considered to act by increasing cAMP levels in epithelial cells to evoke secretion (Vanden Broeck et al., 2007), but newer lines of evidence point to enteroendocrine-mediated initiation of secretory reflexes within the enteric nervous system (ENS) as a primary cause (Farthing, 2002), the most compelling data of which is that tetrodotoxin, and 5-hydroxytryptamine (5-HT)3 receptor antagonists block cholera toxin-induced secretory diarrhea (Beubler et al., 1989; Jodal, 1990). [...]Banwell and Sherr (1973) observed that a small intestinal loop exposed to V. cholerae became flaccid but a later myoelectrical analysis of infected open loops of rabbit intestine revealed increases in migrating action potential complexes 4 h post-inoculation with cholera toxin (Mathias et al., 1976; Mathias et al., 1977). Interestingly, when the 5-HT3 receptor antagonist, granisetron, was administered to these rats to reduce the secretory effect of cholera toxin, there was a significant increase in contractions (Kordasti et al., 2006).