American Journal Of Physiology. Gastrointestinal And Liver Physiology[JOURNAL]
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200 papers
From rodents to chips: preclinical models of inflammatory bowel disease with emphasis on host-microbiome interactions.
Kumar S, Sarkar B
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41721794 · Publisher ↗
Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a chronic relapsing inflammatory disorder with steadily increasing global prevalence, significantly impairing patient quality of lif...
Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a chronic relapsing inflammatory disorder with steadily increasing global prevalence, significantly impairing patient quality of life. Preclinical research in IBD has traditionally relied on animal models to investigate disease etiology, immunopathogenesis, and therapeutic responses. A wide range of experimental models primarily rodents, along with limited use of larger animals such as pigs and nonhuman primates, have been developed to reproduce key clinical, histological, and immunological features of human IBD. These models have played a crucial role in evaluating pharmacological agents, biologics, probiotics, dietary interventions, gene-based therapies, and microbiome-targeted strategies. Notably, accumulating evidence highlights the pivotal role of gut microbiota dysbiosis in disease initiation, progression, and therapeutic responsiveness, making host-microbiome interactions a central component of contemporary IBD research. However, despite their utility, animal models exhibit important limitations related to interspecies differences, incomplete microbiome representation, and poor translational predictability. In response, increasing regulatory pressure from agencies such as the National Institutes of Health (NIH) and FDA to reduce animal experimentation has accelerated the development of human-relevant, nonanimal platforms, including intestinal organoids, in vitro coculture systems, and gut-on-chip technologies. This review critically evaluates existing in vivo IBD models with particular emphasis on their ability to capture immune-microbiome epithelial interactions while also discussing emerging human-derived systems as complementary translational tools. Collectively, the integration of microbiome-responsive and immune-competent-advanced in vitro models represents a promising direction to bridge the gap between experimental findings and clinical application in IBD research.
Regulatory T cells are induced by gut microbiota through differentially regulating costimulatory molecules of enteric glial cells.
Yang J, Zeng Q, Zou M … +2 more , Nie J, Gan H
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41711540 · Publisher ↗
Probiotics have been proven to be effective in inducing and maintaining remission of inflammatory bowel disease (IBD). However, their precise mechanisms remain unclear. Interactions between the gut microbiota and enteric...
Probiotics have been proven to be effective in inducing and maintaining remission of inflammatory bowel disease (IBD). However, their precise mechanisms remain unclear. Interactions between the gut microbiota and enteric glial cells (EGCs) have gained increasing attention. We aimed to investigate whether and how (B.l), as a typical probiotic, exerts anti-inflammatory effects by acting on EGCs. Herein, we demonstrate that EGCs possess bacterial phagocytosis and antigen-presenting functions, and their costimulatory molecule expression is differentially regulated by bacteria. Specifically, B.l significantly upregulates EGC expression of programmed death-ligand 1 (PD-L1), while enterohemorrhagic (EHEC) markedly increases CD86 expression. B.l ameliorates dextran sulfate sodium (DSS)-induced experimental colitis by activating the p38 MAPK signaling pathway, upregulating PD-L1 expression in EGCs, and inducing the conversion of CD4 cells into regulatory T (Treg) cells through the PD-L1/PD-1 pathway. This process promotes Treg cell expansion, inhibits pathogenic T-helper type 17 (Th17) cells, increasing IL-10 production, and reduces TNF-α and IL-1β production. Notably, ablation of EGCs significantly diminishes the efficacy of B.l in alleviating experimental colitis. In conclusion, our findings suggest that B.l induces the conversion of CD4 cells into Treg cells by acting on EGCs and alleviating intestinal inflammation. These findings support the notion that EGCs are not only neural cells but also potential immune cells, which exert immune regulatory functions depending on the type of bacteria and which signaling molecules are being expressed. This study provides new data for elucidating the mechanisms of probiotics in the treatment of IBD. The interactions between gut microbiota and enteric glial cells (EGCs) are increasingly recognized. This study reveals that EGCs possess bacterial phagocytosis and antigen-presentation functions, which are modulated differently by various bacteria. Specifically, (B.l) relieves DSS-induced colitis by enhancing PD-L1 expression on EGCs and promoting Treg cell differentiation through EGC-mediated immune regulation. Understanding the dual role of EGCs as both neural and immune cells expands our comprehension of gut microbiota-neural-immune interaction in intestinal health.
SGK1 signaling: an important modulator of CFTR function and early immune response in mouse intestine.
Muiler C, Santos A, Ameen NA
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41705904 · Full text
Glucocorticoid (GC) and stress-induced serum- and glucocorticoid-inducible kinase 1 (SGK1) signaling rapidly modulate intestinal epithelial transport, yet whether epithelial SGK1 is required to couple GC signaling to fun...
Glucocorticoid (GC) and stress-induced serum- and glucocorticoid-inducible kinase 1 (SGK1) signaling rapidly modulate intestinal epithelial transport, yet whether epithelial SGK1 is required to couple GC signaling to functional cystic fibrosis transmembrane conductance regulator (CFTR) output in vivo has remained unclear. We examined this question using conditional knockout (cKO) and littermate heterozygous controls (cHET) mice treated with dexamethasone (DEX; 2 mg/kg ip) for 1 or 4 h. Outcomes included CFTR protein abundance, immunolocalization (immunoblotting and immunofluorescence), CFTR-ion transport measured by short-circuit current () in Ussing chambers, epithelial expression, intestinal loop fluid accumulation, and CD45 cell signal as a readout of early immune engagement. Acute DEX treatment activated SGK1 signaling and elevated CFTR protein in cHET but also in cKO. However, only cHET exhibited a rise in CFTR-dependent Δ, whereas cKO failed to increase secretion despite higher total CFTR. and were upregulated in cKO but did not restore function. CD45 signal rose transiently at 1 h and normalized by 4 h, consistent with early, self-limited immune engagement. In an intestinal loop assay, short-term DEX treatment did not exacerbate cGMP-evoked fluid accumulation. Together, these data identify epithelial SGK1 signaling as a necessary node that translates acute stress-induced CFTR stabilization into functional secretion and a transient epithelial-immune response. These findings help reconcile expression-function discrepancies and suggest that targeting SGK1 or its downstream steps may be required to achieve functional CFTR gains under acute stress in the intestine. Glucocorticoids rapidly boost intestinal CFTR expression, function, and trafficking through SGK1 and link stress signaling to epithelial secretion and immune control. Deleting blocked glucocorticoid-driven CFTR activation and altered early immune cell recruitment, uncovering SGK1 as a critical regulator of intestinal adaptation to acute stress.
Sex-specific differences in liver DNA methylation patterns and epigenetic aging in mice.
Apelian S, Mamillapalli R, Ucar A … +2 more , Gawde N, Taylor HS
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41697067 · Publisher ↗
Biological sex has been shown to influence aging outcomes, contributing to distinct trajectories in disease susceptibility and lifespan. DNA methylation patterns provide a quantitative measure of biological aging. This s...
Biological sex has been shown to influence aging outcomes, contributing to distinct trajectories in disease susceptibility and lifespan. DNA methylation patterns provide a quantitative measure of biological aging. This study investigated whether aged male and female mice display distinct liver DNA methylation patterns and differences in epigenetic aging. Liver samples were collected from 17 aged c57BL/6 mice (6 males, 11 females). Genomic DNA was extracted and bisulfite-converted before targeted enrichment of 2,045 murine age-associated CpG loci. Biological age (DNAge) was estimated using a previously developed DNA methylation-based predictor generated through elastic net regression. The difference (ΔDNAge) between DNAge and chronological age was computed. Sex-specific differences were assessed by comparing site-specific methylation ratios, ΔDNAge values, and through principal component analysis (PCA) and multiple linear regression. Twelve CpG sites across six genes (, , , , , and ) showed significant sex-associated differences in methylation. demonstrated the largest and most consistent sex-associated effect, with all three associated CpG sites showing higher methylation in males (regression coefficients: -0.204, -0.281, and -0.294). exhibited consistent lower methylation ratios in females, whereas the other genes showed higher methylation in females. There were no sex differences in biological age or ΔDNAge ( = 0.596). Although the epigenetic clock did not reveal differences between sexes in aging, aged mice did exhibit sex-specific liver methylation patterns different from those reported in younger mice, suggesting that sex-dependent epigenetic changes may emerge later in life and may reflect sexual dimorphism in liver function with age. Males and females are known to age differently and develop certain diseases at different rates. Here, we examined the livers of aged male and female mice to see if they show different DNA methylation patterns. We found that aged male and female mice had distinct DNA methylation patterns at specific genes. Interestingly, most of these methylation differences were not present in younger mice, suggesting that sex differences in the genome may change with age.
Tools and advanced imaging technologies for assessing intestinal epithelial barrier integrity: a systematic review.
Vieujean S, Atreya R, Buda A … +19 more , Caradec J, Citi S, Danese S, Dewit O, Friedrich M, Ghosh S, Iacucci M, Jairath V, Kaser A, Leong RW, Neurath MF, Pierre N, Pohin M, Rath T, Rivière P, Travis S, Westcott J, Zeissig S, Peyrin-Biroulet L
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41677575 · Publisher ↗
The intestinal epithelium is a key component of the intestinal barrier, which is the largest and most complex barrier of the human body, regulating nutrient absorption while restricting the entry of harmful antigens. Bre...
The intestinal epithelium is a key component of the intestinal barrier, which is the largest and most complex barrier of the human body, regulating nutrient absorption while restricting the entry of harmful antigens. Breakdown of this barrier facilitates microbial and dietary antigenic translocation, triggering local immune system activation and inflammation. Although barrier alteration alone may not be sufficient to initiate disease, accumulating evidence highlights its critical role in the pathogenesis and progression of a wide range of gastrointestinal and systemic disorders. Early identification of intestinal epithelium and barrier alterations could enable timely therapeutic approaches. This systematic review provides an overview of current in vivo (both noninvasive and invasive) and ex vivo/in vitro approaches used to assess intestinal epithelial barrier alterations. Noninvasive in vivo approaches rely mainly on urinary detection of orally ingested probes, but their clinical utility is limited by lack of standardization and specificity. Circulating and fecal constitutive markers derived from the intestinal barrier, which reflect epithelial alterations, together with indicators of microbial translocation, provide complementary insights but remain insufficiently validated. Advanced invasive endoscopic modalities such as confocal laser endomicroscopy enable near-histological, real-time visualization but are costly and largely used as research tools in specialist centers. In vitro, transepithelial electrical resistance assessment remains the reference standard, though novel technologies (including impedance spectroscopy and organic electrochemical transistors) offer enhanced sensitivity and resolution. Despite progress, major gaps remain, including the absence of a standardized definition of epithelial barrier breakdown, the lack of a practical diagnostic tool, methodological heterogeneity, unvalidated thresholds, and limited prospective validation.
WNT3a induces external anal sphincter fibrosis and dysfunction in rabbits.
Thippeswamy J, Mamachan M, Shin J … +4 more , Halekote Rudramurthy S, Panner Selvam MK, Rajasekaran M, Mittal RK
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41677453 · Full text
Injury and aging of the external anal sphincter (EAS) muscle lead to fibrosis and muscle dysfunction, major contributors to fecal incontinence. Activation of the WNT/β-catenin signaling pathway has been linked to fibrosi...
Injury and aging of the external anal sphincter (EAS) muscle lead to fibrosis and muscle dysfunction, major contributors to fecal incontinence. Activation of the WNT/β-catenin signaling pathway has been linked to fibrosis in various tissues, including skeletal muscle. This study examined whether the WNT agonist Wnt3a induces fibrosis and dysfunction in the EAS muscle. Adult female New Zealand White rabbits received four local injections of Wnt3a or saline into the EAS muscle. Anal canal pressure was measured by manometry every 2 wk for 8 wk, followed by histological, immunofluorescent, immunohistochemistry (IHC), Western blot, and proteomic analyses of the EAS muscle. Rabbits treated with Wnt3a exhibited a significant reduction in anal canal pressure 8 wk postinjection ( ≤ 0.05) compared with controls. Histologic evaluation revealed increased connective tissue ( = 0.06), significant collagen deposition, and decreased muscle area and fiber thickness ( ≤ 0.05). Western blot analysis showed elevated levels of β-catenin, nuclear active β-catenin (PY489), Smad1/2/3, signal transducer and activator of transcription 3 (Stat3), transforming growth factor-β (TGF-β), and vimentin ( ≤ 0.05), with p-Stat3, p-Smad3, and collagen-4 trending upward. Immunofluorescence and IHC confirmed increased β-catenin, collagen-4, and TGF-β levels, and proteomic data indicated altered pathways related to muscle contraction, fibrosis, and atrophy. These findings demonstrate that direct administration of a WNT agonist promotes EAS fibrosis and dysfunction, mirroring changes associated with aging and injury. Local application of WNT antagonists may represent a therapeutic strategy to prevent anal sphincter dysfunction following injury. In the current study, for the first time we investigated the effects of a local injection of Wnt3a-an agonist of the WNT signaling pathway-on EAS function, muscle replacement by fibrosis, and the activation of downstream WNT signaling pathways. Wnt3a injection resulted in impaired EAS function and replacement of muscle with fibrosis. Notably, the downstream signaling remained active even 8 wk after the Wnt3a injection.
Brown adipose tissue inactivation exacerbates alcohol-induced liver steatosis, inflammation, and fibrosis.
Zhang Q, Zhang Z, Rui L
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41677414 · Full text
Alcohol-induced liver fibrosis is a devastating manifestation of alcohol-related liver disease (ALD). However, conventional mouse models fail to recapitulate this fibrotic phenotype, limiting their translational relevanc...
Alcohol-induced liver fibrosis is a devastating manifestation of alcohol-related liver disease (ALD). However, conventional mouse models fail to recapitulate this fibrotic phenotype, limiting their translational relevance. Mice develop and retain robust brown adipose tissue (BAT) for thermoregulation, which confers protection against hepatic steatosis. Here, we identify BAT as a key protective tissue against alcohol-induced liver fibrosis in mice. BAT was inactivated in mice via denervation or surgically ablated, followed by 8 wk of chronic plus binge alcohol exposure. Both BAT denervation and ablation markedly exacerbated hepatic steatosis, injury, and inflammation compared with sham controls. Remarkably, BAT inactivation or ablation induced robust hepatic stellate cell (HSC) activation and liver fibrosis in both sexes, as evidenced by increased α-smooth muscle actin expression, enhanced Sirius red and Masson's trichrome staining, and elevated hydroxyproline content. These fibrotic changes were absent in sham-operated controls. Mechanistically, BAT-conditioned medium-containing BAT-secreted batokines-induced lipid accumulation, oxidative stress, and cell injury in hepatocyte cultures. Furthermore, batokines directly targeted cultured macrophages and HSCs and suppressed their activities. Collectively, these results unveil a hepatoprotective role of BAT and batokines in ALD progression and establish a physiologically and translationally relevant mouse model of ALD by combining BAT inactivation with chronic plus binge alcohol exposure. Brown adipose tissue confers resistance to alcohol-related liver disease through secreting batokines. Inactivation of brown fat exacerbates alcohol-induced liver steatosis, inflammation, and fibrosis.
MrgprC11 expression and function in vagal afferent nerves in the esophagus.
Yu X, Huang Y, Patil MJ … +7 more , Xing Y, Ru F, Kawamoto R, Han L, Undem BJ, Dong X, Yu S
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41671080 · Publisher ↗
Noxious stimulation-induced esophageal nociception plays a crucial role in generating esophageal pain and heartburn, but the underlying mechanism remains unclear. MrgprC11 is a recently discovered member belonging to Mas...
Noxious stimulation-induced esophageal nociception plays a crucial role in generating esophageal pain and heartburn, but the underlying mechanism remains unclear. MrgprC11 is a recently discovered member belonging to Mas1-related G protein-coupled receptor (Mrgpr) family, which is selectively expressed in afferent DRG neurons and distinctively encodes somatic pain and itch sensations. Whether MrgprC11 is also functionally expressed in esophageal afferent neurons and mediates esophageal nociception has yet to be defined. We first compared MrgprC11 mRNA expressions in the esophagus, DRG, and vagal ganglia by RT-PCR. MrgprC11-positive nerve fiber distributions were revealed by confocal imaging in the whole mount esophageal tissues using the MrgprC11 mouse. We then addressed the MrgprC11 agonist bovine adrenal medulla peptide 8-22 (BAM8-22)-evoked functional responses in vagal afferent neurons by two-photon imaging using pirt-GCaMP6 mice and in esophageal vagal C-fibers by extracellular recording from wild-type and mice. MrgprC11 mRNA expression was identified in the DRG and vagal ganglia, but not the esophagus. MrgprC11-positive nerve fibers were richly distributed in the wall of the esophagus. MrgprC11 agonist BAM8-22 elicited a significant increase in calcium influx in vagal afferent neurons. When applied to the esophageal vagal C-fiber nerve terminals in extracellular recordings, BAM8-22-evoked action potential discharges in the C-fibers only in wild-type but not in mice. Following activation, esophageal distension-induced action potential discharges were significantly enhanced in wild-type but not in knockout animals. The present study demonstrated a functional role of MrgprC11 in mediating activation and sensitization of esophageal vagal afferent C-fibers, revealing a new mechanism and potential target for esophageal nociception. MrgprC11 belongs to the recently discovered Mrgpr family and plays a crucial role in somatic sensory transduction. Its functional expression in visceral esophageal afferent nerves has yet to be defined. The present study demonstrated a functional role of MrgprC11 in mediating activation and sensitization of esophageal vagal afferent C-fibers, revealing a novel nociceptive sensory transduction mechanism in the esophagus.
Esophageal mucosal mast cell density and degranulation are increased in gastroesophageal reflux disease.
Leech T, Peiris M
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41665165 · Publisher ↗
Gastroesophageal reflux disease (GERD) is a chronic condition encompassing visceral pain-experienced as heartburn and, in some cases, inflammation of the esophageal mucosa. Although mast cell dysregulation has been descr...
Gastroesophageal reflux disease (GERD) is a chronic condition encompassing visceral pain-experienced as heartburn and, in some cases, inflammation of the esophageal mucosa. Although mast cell dysregulation has been described in disorders of gut-brain interaction, it has been understudied in GERD. We aimed to characterize mast cell localization and degranulation in GERD esophageal mucosa. Distal esophageal biopsies were collected from healthy control subjects (HC; = 10) and subjects with functional heartburn (FH; = 9), nonerosive reflux disease (NERD; = 13), and erosive reflux disease (ERD; = 12). Immunohistochemistry was used to visualize tryptase expression in the esophageal mucosa. The localization of tryptase+ mast cells was identified as intraepithelial or papillary, and the degranulation state of individual mast cells was determined based on the tryptase staining pattern. There was an increased density of mast cells in the esophageal papillae and epithelium of patients with ERD compared with HCs. The density of degranulated intraepithelial mast cells was significantly higher in subjects with FH and subjects with ERD compared with HCs, with a trend toward an increase in NERD. In NERD and ERD, the density of degranulated mast cells in papillae was significantly higher than in HCs. In FH, the density of intraepithelial mast cells positively correlated with reflux disease questionnaire (RDQ) score. Mast cells are more numerous in the esophageal mucosa of subjects with ERD, and activity is increased in subjects with FH, NERD, and ERD. This could contribute to mucosal inflammation, barrier dysfunction, and visceral hypersensitivity in patients with GERD. Future studies should investigate the role of mucosal mast cells in GERD, representing a possible future treatment target. This is the first study to characterize mast cell localization and degranulation in subjects with pH-phenotyped FH, NERD, and ERD compared with healthy controls, showing elevated mast cell numbers in ERD, with increased degranulation in all patient groups (FH, NERD, and ERD). These findings suggest that mast cell activation may contribute to mucosal inflammation and symptom generation in GERD, particularly FH.
New approach methodologies in Crohn's disease link molecular disease subtypes to clinical outcomes.
Penrose HM, Sinha S, Tindle C … +5 more , Zablan K, Le HN, Neill J, Ghosh P, Boland BS
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41665110 · Full text
Current clinical decision-making is hindered by the absence of predictive preclinical models that faithfully bridge molecular diversity to patient outcomes. Here, we apply the principle of abstraction-deriving essential...
Current clinical decision-making is hindered by the absence of predictive preclinical models that faithfully bridge molecular diversity to patient outcomes. Here, we apply the principle of abstraction-deriving essential features from human tissues to build next-generation new approach methodologies (NAMs) that transform patient-derived organoids (PDOs) into predictive vehicles for Crohn's disease (CD). From our living biobank of adult stem cell-derived colonic PDOs, we previously defined two molecular CD subtypes: immune-deficient infectious CD (IDICD) and stress and senescence-induced fibrostenotic CD (S2FCD), each defined by unique genomic, transcriptomic, and functional profiles with matched therapeutic vulnerabilities. In this study, we prospectively anchored PDO-derived molecular phenotypes to real-world clinical outcomes, revealing that S2FCD maps to baseline and progressive colonic disease activity, whereas IDICD tracks with prior ileocecal surgery, penetrating disease behavior, as well as baseline and progressive ileal disease activity. By abstracting NAMs from human tissues and cycling insights between small-"n" organoids and Phase 3-sized datasets, this framework recasts PDOs as dynamic, predictive platforms that capture the past, present, and future of disease behavior. Beyond oncology, this work establishes PDOs as vehicles for prospective clinical trial-like studies in inflammatory diseases and highlights colonic immune dysfunction as a potential driver of ileal CD. In this prospective study, Penrose et al. evaluate a living biobank of genotyped and phenotyped patient-derived organoids (PDOs) as predictive tools in Crohn's disease, demonstrating their ability to faithfully capture past, present, and future disease behavior. By positioning PDOs as new approach methodologies (NAMs), this work extends PDO-informed precision medicine beyond oncology and into complex inflammatory disorders, translating molecular diversity into actionable clinical insights.
Highly Ca-permeable transient receptor potential vanilloid 6 contributes to the protection against colitis by regulating epithelial barrier function.
Murayama Y, Yasuda H, Saito M … +3 more , Hayashi S, Matsumoto K, Kato S
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41643217 · Publisher ↗
Transient receptor potential vanilloid 6 (TRPV6) is a highly Ca-permeable cation channel predominantly expressed in the intestinal epithelium. It plays a crucial role in maintaining systemic calcium homeostasis by regula...
Transient receptor potential vanilloid 6 (TRPV6) is a highly Ca-permeable cation channel predominantly expressed in the intestinal epithelium. It plays a crucial role in maintaining systemic calcium homeostasis by regulating Ca absorption in the intestine. However, its local physiological and pathophysiological roles in the intestine remain unexplored. The exact cause of inflammatory bowel disease is not fully understood; however, disruption of the intestinal epithelial barrier is a key pathogenic mechanism. In this study, we aimed to elucidate the role of TRPV6 in the pathogenesis of colitis. Experimental colitis was induced in TRPV6-deficient [knockout (KO)] and wild-type (WT) mice by administering 2% dextran sulfate sodium (DSS) solution in drinking water for 7 days. DSS treatment resulted in weight loss, diarrhea/bloody stool, histological colonic injury, and colon shortening. The systemic symptoms and colonic injury were significantly worse in TRPV6KO mice than in WT mice. DSS treatment increased tumor necrosis factor-α, interleukin-1β, interleukin-6 mRNA expressions, and myeloperoxidase activity, and these responses were significantly enhanced in TRPV6KO mice compared with WT mice. Under normal (no DSS-treated) conditions, TRPV6KO mice exhibited increased intestinal permeability compared with WT mice. No difference was observed in the number of goblet cells between WT and TRPV6KO mice; however, the expression of intercellular junction proteins, including E-cadherin, claudin-3, and occludin, was significantly suppressed in TRPV6KO mice compared with WT mice. These findings suggest that TRPV6 protects against DSS-induced colitis, potentially by regulating epithelial barrier function through intracellular junction protein expressions. This study is the first to reveal the local role of TRPV6 in the intestine. TRPV6KO exacerbated dextran sulfate sodium-induced colitis and increased intestinal permeability compared with wild-type mice. Furthermore, intercellular junction protein expression was lower in TRPV6KO mice. TRPV6 protects against colitis by maintaining epithelial barrier function by regulating intercellular junction protein expression. Thus, TRPV6 may be a novel therapeutic candidate for treating inflammatory bowel disease.
A pilot, randomized, placebo-controlled trial of rimegepant on visceral sensation and symptoms in nonconstipation IBS pain.
Halawi H, Matar A, Wang I … +5 more , Jencks KJ, Busciglio I, Eckert D, Harmsen WS, Camilleri M
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41637861 · Publisher ↗
Visceral hypersensitivity is a pivotal mechanism in pain associated with irritable bowel syndrome (IBS). Calcitonin gene-related peptide (CGRP) is expressed by visceral afferents. The aim of this study was to evaluate th...
Visceral hypersensitivity is a pivotal mechanism in pain associated with irritable bowel syndrome (IBS). Calcitonin gene-related peptide (CGRP) is expressed by visceral afferents. The aim of this study was to evaluate the efficacy of rimegepant, a CGRP antagonist, on abdominal pain, rectal compliance and sensation, gut transit, and safety in participants with nonconstipation IBS with pain. We conducted a pilot, randomized, double-blind, placebo-controlled, parallel-group design trial (NCT06221111) of oral rimegepant 75 mg every other day (as approved for migraine prophylaxis) in adults with nonconstipation IBS pain. The trial consisted of three periods: 2-wk run-in, 4-wk treatment, and 4-wk post-treatment with diary recording of daily abdominal pain (primary endpoint) and bowel movements (BMs). Rectal compliance and sensation were measured using barostat distensions and gastrointestinal and colonic transit by scintigraphy. Statistical analysis compared rimegepant with placebo using analysis of covariance with sex, level of anxiety, and baseline measurements as covariates. Twenty-four participants were randomized to rimegepant ( = 12) or placebo ( = 12); baseline demographics, rectal sensation, and compliance were similar between the groups. Rimegepant did not significantly reduce abdominal pain, daily BM frequency, or BM consistency relative to baseline. Compared with placebo, rimegepant significantly reduced sensations of gas, urgency, and pain during 24 mmHg, and gas and urgency sensations during 36 mmHg rectal distension (all ≤ 0.05 unadjusted). Rimegepant decreased rectal compliance. No significant effects were noted during washout. There were no serious adverse events or adverse events of ≥ Grade 3 severity. Rimegepant's effects on rectal sensation suggest further studies in nonconstipation IBS pain are warranted. Clinical Trial Registry Number: NCT06221111. This pilot, randomized, double-blind trial in a relatively small sample of patients with IBS-related pain shows rimegepant significantly reduced sensations of gas, urgency, and pain during rectal distention and decreased rectal compliance. Decrease in compliance implies that changes in physical properties or distensibility of rectum did not contribute to alterations in rectal sensation. Same dose of rimegepant did not significantly impact daily abdominal pain, BM frequency, or colonic transit. There were no serious adverse events.
Late-in-life treadmill training mitigates gut microbiome imbalances and cardiovascular disease risk in mice.
Cho JM, Park SK, Satheesh Babu AK … +9 more , Mookherjee S, Hansen M, Petersen C, Zhong Y, Jalili T, Robeson MS, Wankhade UD, Anandh Babu PV, Symons JD
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41632533 · Full text
Primary aging associates with an imbalanced gut microbiome and cardiovascular disease (CVD) risk in mice and humans. Strong evidence from clinical and preclinical studies supports that habitual physical exercise improves...
Primary aging associates with an imbalanced gut microbiome and cardiovascular disease (CVD) risk in mice and humans. Strong evidence from clinical and preclinical studies supports that habitual physical exercise improves cardiovascular function and intestinal health in adults. Here we tested the hypothesis that exercise training, even when initiated late-in-life, reestablishes a beneficial and cooperative intestinal microbiome to an extent that associates with reduced risk for CVD. At 21 mo of age, male C57BL/6 mice started a progressive resistance treadmill training program 6 days per week (Old + ETR) for 12 wk. Twenty-one-month-old (Old) and 4-mo-old (Adult) male mice remained sedentary. First, reductions in exercise capacity and soleus muscle citrate synthase activity displayed by Old vs. Adult mice were restored in Old + ETR animals. Next, systolic function [fractional shortening (FS)], diastolic function (E/A ratio), and overall left-ventricular function [myocardial performance index (MPI)] otherwise depressed in Old vs. Adult mice were normalized in Old + ETR animals. Third, elevated trimethylamine (TMA) and TMA -oxide (TMAO), and heightened inflammatory markers [e.g., interferon (IFN)-γ and keratinocyte-derived chemokine (KC)], observed in Old vs. Adult mice were lowered in Old + ETR animals. Importantly, the abundance of beneficial microbial features, including , Muribaculaceae, , and the gut group, otherwise depressed by aging, was normalized in Old + ETR mice. Finally, the gut group was positively correlated with FS, and Parabacteroides was negatively correlated with IFN-γ. These findings support that late-in-life exercise training beneficially remodels the gut microbiome to an extent that associates with reduced CVD risk in male mice. It is unknown whether exercise training, if started late-in-life, reestablishes a beneficial and cooperative intestinal microbiome. Here we demonstrate that a 12-wk treadmill running program in older mice rejuvenates the gut microbiome and attenuates markers of cardiovascular disease (CVD) risk. Notably, specific microbial taxa correlate with activity-induced improvements in overall myocardial performance and inflammation, highlighting the importance of gut health on CVD and illustrating the restorative benefits that can be attained from a low-cost lifestyle intervention.
Bolus pressure and bolus mismatch in patients with dysphagia and preserved esophageal peristalsis.
Seo M, Joo S, Mittal RK
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41617497 · Publisher ↗
Dysphagia is common in patients with preserved contraction phase of esophageal peristalsis, such as those diagnosed with functional dysphagia (FD) or esophagogastric junction outflow obstruction (EGJOO); it amounts to ≥5...
Dysphagia is common in patients with preserved contraction phase of esophageal peristalsis, such as those diagnosed with functional dysphagia (FD) or esophagogastric junction outflow obstruction (EGJOO); it amounts to ≥50% patients undergoing high-resolution manometry impedance (HRMZ) study. We aimed to characterize the distension phase of esophageal peristalsis (bolus domain) and identify abnormalities that may contribute to dysphagia in these patients. HRMZ recordings from 35 healthy controls, 35 patients with FD, and 35 patients with EGJOO were analyzed. Distension-contraction plots were used to assess the luminal cross-sectional area, bolus pressure, and regions without bolus ("no-bolus areas") within the bolus domain of peristalsis. The proportion of no-bolus area was compared among groups, and receiver operating characteristic (ROC) analysis evaluated diagnostic performance. Esophageal wall compliance during the distension phase was also determined. Both FD and EGJOO groups exhibited a significantly greater proportion of no-bolus area within the bolus domain compared with controls, particularly in the distal esophagus ( < 0.001). Pressure peaks frequently occurred in the absence of bolus, indicating pseudo-bolus pressures. Ultrasound imaging revealed transient luminal collapse against the manometry catheter in the "pseudo-bolus" zone. Esophageal wall compliance was reduced in both patient groups. ROC analysis demonstrated that the percentage of no-bolus area discriminated patients from controls with high accuracy (area under the curve 0.83 for FD, 0.88 for EGJOO). We propose that impaired esophageal distensibility and transient luminal collapse within the bolus domain cause functional obstruction and possibly dysphagia. This study introduces a novel impedance-based method to analyze the bolus domain of esophageal peristalsis, emphasizing bolus pressure and bolus mismatch. Patients with functional dysphagia and EGJOO demonstrated impaired esophageal distension, reduced wall compliance, and frequent pseudo-bolus pressures from transient luminal collapse during peristalsis. These findings suggest that dysphagia may result from dynamic obstruction due to esophageal collapse during peristalsis rather than fixed outflow obstruction, highlighting bolus domain mechanics as a complementary diagnostic tool.
Esophageal symptom burden remains high and associates with failed swallows after 5 years in patients with ineffective esophageal motility.
Koop AH, Nimma IR, Avaiya K … +3 more , Al Jawish M, Acuna EV, Lacy BE
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41617482 · Publisher ↗
Ineffective esophageal motility (IEM) is a motor disorder of the esophagus diagnosed by high-resolution esophageal manometry (HRM) and associated with symptoms of gastroesophageal reflux disease (GERD) and dysphagia; how...
Ineffective esophageal motility (IEM) is a motor disorder of the esophagus diagnosed by high-resolution esophageal manometry (HRM) and associated with symptoms of gastroesophageal reflux disease (GERD) and dysphagia; however, the long-term significance is unclear. The goal of this study was to assess esophageal symptoms in patients with IEM diagnosed 5 or more years earlier. Adult patients diagnosed with IEM ≥5 years earlier by HRM were included and sent validated esophageal symptom questionnaires including the Gastroesophageal Reflux Disease Questionnaire (GerdQ), Gastroesophageal Reflux Disease Health-related Quality of Life (GERD-HRQL) Questionnaire, and the Brief Esophageal Dysphagia Questionnaire (BEDQ). Symptom scores were assessed by esophageal motor function including the number of intact, failed, and ineffective swallows. Statistical analysis was performed using Fisher's exact test, Mann-Whitney test, and Spearman correlation coefficients. Forty-seven patients were included, and 26 (55.3%) were positive for GERD by the GerdQ score, 21 (44.7%) by GERD-HQRL, and 35 (74.5%) for dysphagia by BEDQ score. Presence of ≥7 swallows with failed peristalsis was associated with a greater GerdQ score (9 vs. 7, = 0.029) and dissatisfaction with current symptoms; ≥8 failed swallows was associated with worse dysphagia by the BEDQ score (21.5 vs. 12, = 0.037). Number of failed swallows correlated with GerdQ (ρ = 0.46, = 0.0011) and GERD-HRQL scores (ρ = 0.43, = 0.0025). In this cross-sectional survey study of patients with IEM diagnosed five or more years earlier, at least 45% reported GERD symptoms, 75% dysphagia symptoms; the number of swallows with failed peristalsis was associated with worse GERD and dysphagia symptoms. Patients with ineffective esophageal motility continue to experience significant symptoms years after diagnosis. In this survey of 47 patients diagnosed ≥5 years earlier, 45% reported GERD symptoms and 75% reported dysphagia. Greater numbers of failed swallows correlated with worse GERD and dysphagia scores, highlighting the long-term clinical impact of IEM and its association with esophageal symptom burden.
Elucidation of daily timed-palatable meal-anticipatory activity in the circadian system of mice.
Taufique SKT, Eischeid A, Magaña I … +4 more , Ehichioya DE, Farah S, Obata Y, Yamazaki S
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41592555 · Full text
Anticipation of daily recurring changes in the environment is critical for survival. When food access is limited to a few hours during the daytime, nocturnal rodents exhibit food-anticipatory activity, which appears a fe...
Anticipation of daily recurring changes in the environment is critical for survival. When food access is limited to a few hours during the daytime, nocturnal rodents exhibit food-anticipatory activity, which appears a few hours before scheduled mealtime. The rodents are also known to exhibit anticipatory activity for time-restricted palatable meals under ad libitum access to chow. When 1 h of chocolate chip access was given during the day, mice exhibited robust anticipatory activity. In contrast, despite the peanut butter-fed mice eating two times the calories of peanut butter than the chocolate-fed mice did of chocolate chips, we observed only negligible anticipatory activity for daily 1-h peanut butter administration. In ex vivo explants, the phase of the liver in mice subjected to timed-chocolate chip access was significantly advanced, similarly to that in mice subjected to 4-h restricted feeding during the day. Similar to anticipatory activity, negligible phase changes in the liver were observed in the mice given 1 h of peanut butter access during the day. Therefore, robustness of palatable meal-anticipatory activity and phase advance in the liver are unlikely to be in direct response to increased calorie intake during the day. We measured food-seeking nose-poking behavior during food deprivation following daily 1-h chocolate chip access. Mice expressed anticipatory food seeking around the time that they had previously been given daily chocolate chips. This suggests that the time of chocolate chip access is encoded to the same circadian pacemaker that controls food-anticipatory activity. Anticipatory activity for daily chocolate chip access is stronger than that for daily peanut butter access. Mice given daily chocolate chip access, but not peanut butter access, exhibited altered circadian organization among peripheral clocks. During food deprivation, mice exhibited anticipatory food-seeking behavior at the time they had previously been given chocolate chip access, suggesting that the time of palatable meals is encoded in the circadian pacemaker controlling food-anticipatory activity.
Inhibitory effects of somatostatin on glucagon-like peptide-1-mediated acceleration of peristalsis in the rat proximal colon.
Nakamori H, Hosoi F, Hashitani H
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41592554 · Publisher ↗
Colonic motility is controlled by the enteric nervous system that is modulated not only by autonomic neurotransmitters but also by substances released from enteroendocrine cells. Glucagon-like peptide-1 (GLP-1) secreted...
Colonic motility is controlled by the enteric nervous system that is modulated not only by autonomic neurotransmitters but also by substances released from enteroendocrine cells. Glucagon-like peptide-1 (GLP-1) secreted from L cells accelerates peristalsis of the proximal colon, whereas somatostatin released from D cells inhibits GLP-1 secretion via the activation of somatostatin receptor subtype 5 (SST). Here, effects of somatostatin on GLP-1-mediated acceleration of colonic peristalsis were investigated. Cannulated segments of rat proximal colon were serosally perfused with oxygenated physiological salt solution and luminally perfused with degassed solution. Colonic wall motion was imaged and converted into spatiotemporal maps. Distributions of somatostatin and SST receptors were assessed via immunohistochemistry. Intraluminal administration of somatostatin alone did not affect oro-aboral propagating peristaltic contractions, but prevented luminal-applied GLP-1 (30 nM)-induced acceleration of peristaltic waves. Somatostatin also prevented the prokinetic action of endogenous GLP-1 that was released upon the stimulation by luminal-applied short-chain fatty acids (SCFA, 3 mM) or lipopolysaccharide. In colonic segments that had been pretreated with selective SST receptor antagonist 1, a lower concentration of GLP-1 (10 nM) or SCFA (300 µM) became capable of accelerating peristaltic waves. GLP-1-positive epithelial cells coexpressed SST receptors, whereas GLP-1 receptor-positive epithelial cells and afferent neurons contained somatostatin. Thus, L cell-derived GLP-1 that accelerates colonic peristalsis may simultaneously stimulate D cells and afferents to release somatostatin that serves as a break on prokinetic actions of GLP-1 by activating SST receptors on L cells. This interplay between GLP-1 and somatostatin would prevent excessive colonic motility. Somatostatin inhibited the prokinetic action of glucagon-like peptide-1 (GLP-1), short-chain fatty acids, and lipopolysaccharide. The inhibitory effect of somatostatin was mediated by the activation of somatostatin receptor subtype 5 that was expressed on L cells. Sources of somatostatin were D cells and intrinsic primary afferent neurons, both of which expressed GLP-1 receptors. Thus, colonic peristalsis may well be regulated by the functional interaction between excitatory GLP-1 and inhibitory somatostatin.
Role of interstitial cells of Cajal in regulating tone and responses to enteric motor neurons in the murine pyloric sphincter.
Lee JY, Koh SD, Baker SA … +1 more , Sanders KM
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41569746 · Publisher ↗
Gastric slow waves fail to propagate through the pyloric sphincter (PS), thus isolating the specialized motility patterns of the stomach and small intestine. We investigated the role of interstitial cells of Cajal (ICC)...
Gastric slow waves fail to propagate through the pyloric sphincter (PS), thus isolating the specialized motility patterns of the stomach and small intestine. We investigated the role of interstitial cells of Cajal (ICC) in PS of mice. Ca waves in ICC, events responsible for electrical slow waves, propagated along the gastric wall but failed to propagate into the PS. ICC in PS fired localized Ca transients and displayed low expression of voltage-dependent Ca conductances. These are properties of intramuscular ICC (ICC-IM) that cannot regenerate and propagate slow waves. A T-type Ca channel antagonist had no effect on Ca transients, but these events were blocked by thapsigargin and cyclopiazonic acid, suggesting that they result from Ca release. PS ICC expressed ANO1, a Ca-activated Cl conductance. Ca released from stores activates ANO1 channels, thus exerting a depolarizing influence on PS. Ani9, a selective antagonist of ANO1 channels, hyperpolarized cells and reduced contractile tone. Electrical field stimulation (EFS) of intrinsic neurons yielded inhibitory junction potentials (IJPs), and cessation of EFS resulted in poststimulus depolarization and contraction. -nitro-l-arginine (L-NNA) abolished relaxation responses to EFS and switched responses to contractions. Application of atropine or Ani9 (in the presence of L-NNA) abolished contraction during EFS. Our results describe new and fundamental functions of ICC-IM in the PS. The inability of these cells to propagate slow waves provides the insulator function of PS muscles and localized Ca transients, and activation of ANO1 regulates PS tone and mediates inputs from enteric neurons. The pyloric sphincter is an electrical insulator between the stomach and small intestine, isolating and maintaining the unique motility patterns of these organs. Using Ca imaging techniques, this study demonstrates why slow waves do not propagate between organs and how interstitial cells of Cajal serve to regulate pyloric tone and responses to enteric motor neurons.
Exploratory study characterizing gastrointestinal physiological changes during controlled human hookworm infection.
Mules TC, Camberis M, Lavender B … +9 more , Payne K, Yumnam B, Vacca F, Noble SL, Tang JS, Te Kawa T, Wheller G, Le Gros G, Inns S
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41553728 · Publisher ↗
Hookworm infects over 400 million people globally and causes gastrointestinal morbidity, yet its physiological effects remain poorly defined. Controlled human hookworm infection is also being explored as a therapy for gu...
Hookworm infects over 400 million people globally and causes gastrointestinal morbidity, yet its physiological effects remain poorly defined. Controlled human hookworm infection is also being explored as a therapy for gut diseases. We performed an exploratory study to evaluate the impact of experimental infection on gastrointestinal transit, motility, and luminal pH in 10 healthy adults (mean age 41 yr, 60% females) infected with 30 larvae via skin application. Assessments using the SmartPill Wireless Motility Capsule were performed at baseline, (acute infection), and or (chronic infection). Parameters included gastric emptying time, small bowel and colonic transit, whole gut transit, intraluminal pressures, contraction frequency, motility index, and segmental pH, analyzed with paired tests or ANOVA. All participants developed patent infections. No significant differences were observed in gastric emptying, small bowel, colonic, or whole gut transit times, nor in motility indices or contraction frequencies. However, during acute infection, duodenal (6.14 ± 0.19 vs. 5.80 ± 0.24, < 0.05) and small bowel pH (6.96 ± 0.37 vs. 6.50 ± 0.37, < 0.05) were significantly reduced compared with baseline, normalizing by the chronic phase. No other significant pH alterations were detected. Thus, these data suggest that controlled infection in healthy adults induces a transient reduction in duodenal and small-intestinal pH without affecting gastrointestinal transit or motility. This acidification may contribute to acute-phase symptoms and nutrient malabsorption in endemic settings, whereas the absence of sustained motility disturbance supports the safety of controlled hookworm infection for therapeutic investigation. This exploratory study using SmartPill technology found that controlled hookworm infection in healthy adults caused a transient drop in duodenal and small-intestinal pH during the acute phase, but no lasting changes in gut motility or transit. The findings, the first of their kind in humans, suggest that the physiological effects of controlled doses of hookworm are subtle and short-lived, offering reassurance for therapeutic trials while highlighting a potential mechanism for symptoms and malabsorption in endemic regions.
Inflammatory pain alters colorectal motility via spinal oxytocinergic pathways.
Sawamura T, Mori A, Yuki N … +6 more , Takashima K, Horii Y, Yoshimura M, Ueta Y, Shiina T, Shimizu Y
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41546560 · Publisher ↗
Gastrointestinal motility is regulated primarily by the enteric and the central nervous systems. Our previous studies revealed that central circuits regulating colorectal motility partially overlap with those involved in...
Gastrointestinal motility is regulated primarily by the enteric and the central nervous systems. Our previous studies revealed that central circuits regulating colorectal motility partially overlap with those involved in pain modulation, suggesting functional interactions between the nociceptive modulatory pathway and the autonomic regulatory pathway of colorectal motility. Here, we examined whether peripheral inflammatory pain alters the neural components of the descending pathway regulating colorectal motility. Complete Freund's adjuvant (CFA) was administered unilaterally into the hind paw of rats to induce inflammation. Colorectal motility was assessed in vivo under anesthesia with α-chloralose and ketamine. In sham-treated rats, intraluminal administration of capsaicin, a noxious stimulus to the colorectal lumen, enhanced colorectal motility. In contrast, the capsaicin-induced colorectal motility response was suppressed in rats 3 days after CFA treatment. This suppression was rescued by the intrathecal administration of a GABA receptor antagonist or an oxytocin (OXT) receptor antagonist. Furthermore, spinal OXT administration and chemogenetic activation of OXT neurons in naïve rats elicited a marked inhibition of capsaicin-induced motility responses of the colorectum. Notably, the inhibitory effect of activated OXT neurons was abolished by the intrathecal administration of a GABA receptor antagonist. These results indicate that the descending OXT pathway becomes operative in response to persistent pain caused by peripheral inflammation and that the inhibitory effect on colorectal motility may involve local GABAergic transmission within the spinal cord. These changes may reduce parasympathetic outflow to the colorectum and contribute to defecation disorders involving central neural mechanisms. This study focused on the remodeling of the neural pathways regulating colorectal motility and examined whether peripheral inflammation outside the gastrointestinal tract affects this process. In rats administered a complete Freund's adjuvant into their hind paw, colorectal motility responses induced by intracolonic administration of capsaicin were suppressed. This suppression involved oxytocinergic and GABAergic transmission in the spinal cord. These results demonstrate that inflammatory pain in the hind paw induces remodeling of the neural pathways regulating colorectal motility.
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