American Journal Of Physiology. Gastrointestinal And Liver Physiology[JOURNAL]
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200 papers
Could physical exercise improve mental health in the context of chronic liver disease?
Wallace CJK, Audet MC
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40380078 · Publisher ↗
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Enteric glia promotes the survival of CD4 and CD8 T cells in plexitis: a new player in Crohn's disease recurrence?
Le Berre C, Durand T, Pabois J … +6 more , Brossaud R, Aymeric L, Neunlist M, Bourreille A, Naveilhan P, Neveu I
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40375619 · Publisher ↗
The accumulation of immune cells in and around enteric ganglia, called plexitis, is associated with postoperative recurrence in Crohn's disease. Interaction between T cells and enteric glia is increased at the proximal r...
The accumulation of immune cells in and around enteric ganglia, called plexitis, is associated with postoperative recurrence in Crohn's disease. Interaction between T cells and enteric glia is increased at the proximal resection margin in patients with Crohn's disease who suffer from postoperative recurrence. However, little is known about the T cells that interact with enteric glia and contribute to the formation of plexitis. In this work, the number of CD4 and CD8 T cells interacting with enteric glia was quantified in sections of the proximal (ileal) resection margin of patients with Crohn's disease, and in cocultures prepared with rat and human enteric glia. The molecules implicated in these interactions were investigated, as well as the impact of enteric glia on T cell survival. Analyses indicated that both CD4 and CD8 cells were present and in contact with enteric glia in plexitis in patients with Crohn's disease. In vitro studies demonstrated that the adhesion of both human and rat CD4 and CD8 cells to enteric glia was increased after pretreatment of the glial cells with IL1β/TNFα, and that this adhesion was lymphocyte function-associated antigen 1 (LFA-1)-dependent. The interactions between T cells and enteric glia increased the survival of CD4 and CD8 T cells in an ICAM-1/LFA-1-independent manner. In conclusion, both CD4 and CD8 T lymphocytes are present and in contact with enteric glia in plexitis. The in vitro studies demonstrate that they adhere to human and rat enteric glia through LFA-1 and show that interactions with enteric glia promote their survival, independently of LFA-1. Both CD4 and CD8 T cells adhere to enteric glial cells in patients with Crohn's disease, contributing to the development of plexitis associated with postoperative recurrence. The adhesion of CD4 and CD8 T cells to enteric glial cells is dependent on ICAM-1/LFA-1. Enteric glial cells promote the survival of CD4 and CD8 T cells independently of ICAM-1/LFA-1.
Elucidation of roles of serine/threonine phosphatases PP1 and PP2A in mediating CCK-stimulated growth and enzyme secretion in pancreatic acinar cells.
Ramos-Alvarez I, Jensen RT
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40375576 · Full text
Serine/threonine phosphatases, protein phosphatases 1 and 2A (PP1 and PP2A), play important roles in mediating cellular signaling in different tissues to different stimuli, including glycogen metabolism, protein synthesi...
Serine/threonine phosphatases, protein phosphatases 1 and 2A (PP1 and PP2A), play important roles in mediating cellular signaling in different tissues to different stimuli, including glycogen metabolism, protein synthesis/growth, and secretion. However, the roles of PP1/PP2A in pancreatic acinar cell secretion/growth are both unclear and controversial. To address this issue, in the present study, we examined the ability of gastrointestinal hormones/growth factors (GFs) to activate PP1 and PP2A and the signaling cascades involved in rat pancreatic acini and the pancreatic acinar tumor cell line, AR42J cells. PP1 and PP2A were both detected in pancreatic acini and AR42J cells. In acini, PP1 and PP2A were activated by pancreatic secretagogues-stimulating phospholipase C (bombesin, CCK-8, and carbachol) and endothelin and by pancreatic GFs (insulin, hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, platelet-derived growth factor, and insulin-like growth factor 1). Full CCK-8 activation of PP1/PP2A required activation of both high- and low-affinity CCK1-receptor states. Using specific PP1 and PP2 assays, in both acini and AR42J cells, experimental conditions were established, where calyculin A, a known nonselective PP1/PP2A inhibitor, inhibited activation of both, whereas okadaic acid and fostriecin inhibited only PP2A activation and tautomycetin inhibited only PP1 activation. Under these conditions, CCK-stimulated enzyme secretion and stimulation of p44/42, a key mediator of growth, required PP2A activation, without activation of PP1. Using specific siRNA for PP1/PP2A in AR42J cells, similar results were found. These results establish that only PP2A activation is essential for CCK-mediated stimulation of growth and enzyme secretion in pancreatic acinar cells and pancreatic acinar AR42J tumor cells. Despite more than 10 studies, the roles of the serine/threonine phosphatases, PP1/PP2A, in pancreatic acinar cell-secretion/growth remain controversial. This study demonstrates that both PP1/PP2A are present in rat pancreatic acini and in pancreatic acinar tumor-AR42J cells. Both phosphatases are activated by pancreatic secretagogues, stimulating PLC, and by pancreatic growth factors. Using specific inhibitory conditions for PP1/PP2A (inhibitors, siRNA studies), only PP2A activation is needed for CCK-8-stimulated enzyme secretion and growth signaling cascades in pancreatic acinar cells.
Generation of gastric proton pump knockouts in : a fish model for insights into the mechanisms of acidification by oxynticopeptic cells.
Ferreira PG, Vogl AW, Castro LFC … +1 more , Wilson JM
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40372704 · Publisher ↗
The gastric proton pump H/K-ATPase (HKA) is the highly conserved acid secretory mechanism of the gnathostome stomach. HKA is a heterodimeric pump composed of α and β-subunits. In this study, we have explored the involvem...
The gastric proton pump H/K-ATPase (HKA) is the highly conserved acid secretory mechanism of the gnathostome stomach. HKA is a heterodimeric pump composed of α and β-subunits. In this study, we have explored the involvement of this enzyme in the transcriptional regulation of pathways linked to acid secretion (Cl and K movement across the cell membrane) and peptic digestion (pepsinogens) in the stomach of the teleost . To this end, we generated the first nonmammalian knockout line for the gastric proton pump, (HKA-α-subunit), in using CRISPR-Cas9 gene editing. Homozygous mutant fish appeared healthy but were achlorhydric. The transcript and protein levels of the HKA-β-subunit remained unaltered despite the absence of α-subunit protein. Pepsinogen ( and ) transcript levels were reduced, together with , (involved in apical K recycling), and (involved in the acid-coupled Cl secretion mechanism) mRNA levels. The and transcript levels were significantly increased in knockout stomachs. The gastric morphology and cytology of characterized through bright-field and electron microscopy show that the lumen of the gastric glands of fish was dilated and the oxynticopeptic cells had large cytoplasmic inclusions that were absent in wild-type animals. The tubulovesicular system of knockouts was less developed relative to wild-type animals. Our findings provide novel evidence of the highly conservative nature of the gastric acid-peptic pathways across diverse vertebrates. Furthermore, this work highlights the potential for the use of nontraditional models in biomedical research. We have knocked out stomach acidification in a nonmammalian gnathostome for the first time using CRISPR-Cas9 gene editing in the teleost fish targeting the gastric proton pump. This offers a novel and insightful alternative to murine models, having larger offspring numbers, rapid development, and ease of maintenance. In accordance, we present the first demonstration in a knockout animal of how diverse chloride and potassium transporters dynamically respond to-and are directly altered by-acidification.
Host-microbial interactions in the esophagus.
Ebigbo N, Souza RF
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40343857 · Publisher ↗
Host-microbial interactions within the gastrointestinal tract are increasingly recognized as contributors to health and disease, yet our understanding of these interactions in the esophagus remains limited. Dysbiosis of...
Host-microbial interactions within the gastrointestinal tract are increasingly recognized as contributors to health and disease, yet our understanding of these interactions in the esophagus remains limited. Dysbiosis of the esophageal microbiome has been linked to esophageal disorders, but the precise mechanisms underlying microbial contributions to esophageal pathophysiology remain speculative. This review explores the mechanisms by which the esophageal microbiome modulates mucosal immunity, epithelial barrier integrity, and inflammatory responses. We highlight key host receptors that mediate these interactions and microbial metabolites that influence the local immune environment and epithelial function. By synthesizing current knowledge on how the microbiome impacts esophageal health, we identify significant knowledge gaps and propose areas for future research.
Dietary 3-aminobenzoic acid enhances intestinal barrier integrity and attenuates experimental colitis.
Tanaka M, Toyonaga T, Nakagawa F … +11 more , Iwamoto T, Hasegawa Y, Komatsu A, Sumiyoshi N, Shibuya N, Minemura A, Ariyoshi T, Matsumoto A, Oka K, Shimoda M, Saruta M
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40338094 · Publisher ↗
Disruption of intestinal epithelial integrity and increased permeability is central to the pathogenesis of ulcerative colitis (UC). In this study, we identified 3-aminobenzoic acid (3-ABA), a dietary component abundant i...
Disruption of intestinal epithelial integrity and increased permeability is central to the pathogenesis of ulcerative colitis (UC). In this study, we identified 3-aminobenzoic acid (3-ABA), a dietary component abundant in azuki beans, soybeans, and chickpeas as a regulator of epithelial permeability and inflammation in the colon. Screening 119 gut microbial metabolites revealed the ability of 4-ABA, a structural isomer of 3-ABA, to enhance barrier function in Caco2 cells. Further analysis of structural isomers identified 3-ABA as the most effective, significantly increasing transepithelial electrical resistance and reducing epithelial permeability. Using liquid chromatography-mass spectrometry, 3-ABA was detected in dietary beans and human fecal samples. Fecal 3-ABA levels were significantly lower in patients with UC compared with healthy individuals. Metagenomic and functional prediction analyses revealed dysbiosis in patients with UC, characterized by an enrichment of bacterial genes involved in ABA degradation. Gene expression analysis of 3-ABA-stimulated Caco2 cells demonstrated upregulation of tight junction molecules, such as CLDN1 and TJP1, enhancing epithelial barrier integrity. In a dextran sodium sulfate-induced colitis mouse model, rectal 3-ABA administration ameliorated colitis by enhancing epithelial barrier function and reducing inflammation. These findings highlight 3-ABA's potential as a dietary therapeutic agent for UC, offering a novel strategy to enhance intestinal integrity and mitigate inflammation. Increased intestinal epithelial permeability is central to the pathogenesis of ulcerative colitis (UC). 3-Aminobenzoic acid (3-ABA), a dietary component abundant in beans, decreased epithelial permeability and attenuated colonic inflammation in a mouse experimental colitis model. Reduced fecal 3-ABA levels in patients with UC were associated with dysbiosis-driven accelerated degradation. These findings highlight the therapeutic potential of 3-ABA in UC by targeting colonic epithelium.
Hepatic and intestinal tissue-specific deficiency alters bile acid homeostasis in female mice.
Jiang J, Fan M, Yuan W … +7 more , Yue D, Wang Z, Yang L, Huang W, Jin L, Wang X, Ding L
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40338063 · Publisher ↗
Farnesoid X receptor (FXR), predominantly expressed in the liver and intestine, plays a crucial role in regulating bile acid (BA) metabolism. However, the specific contributions of FXR in different tissues to BA homeosta...
Farnesoid X receptor (FXR), predominantly expressed in the liver and intestine, plays a crucial role in regulating bile acid (BA) metabolism. However, the specific contributions of FXR in different tissues to BA homeostasis remain unclear. To elucidate the comprehensive roles of FXR, we developed a novel double tissue-specific knockout (KO) mouse model of in both liver and intestine (). Notably, mice exhibited significantly increased BA levels in the serum and liver, which were consistent with whole body KO mice (). However, mice only showed elevated hepatic BA concentration, whereas displayed remarkably increased BA concentration in feces. deletion increased the BA synthesis genes mRNA level, such as and , but reduced the expression of FXR downstream target genes and . These findings provide a valuable model to underscore the pivotal functions of tissue-specific FXR in maintaining BA homeostasis. Moreover, these insights facilitate the development of FXR-targeted therapeutic strategies for the BA dysregulation disease treatment. We successfully developed a double tissue-specific knockout (DKO) mouse model, which provides a novel tool for investigation of FXR functions in the liver and intestine. Unlike whole body KO, the DKO model excludes the FXR impact on other tissues. mice exhibited significantly increased BA levels in the serum and liver, which were consistent with mice. We established a powerful tool for therapeutic strategies for bile acid metabolism disorders associated with FXR.
Glucose metabolism through the hexosamine biosynthetic pathway drives hepatic de novo lipogenesis via promoting -linked protein glycosylation.
Li Y, Song Q, Guo R … +3 more , Qian Y, Jiang Y, Song Z
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40331866 · Publisher ↗
De novo lipogenesis (DNL) converts excess glucose into lipids, whereas the hexosamine biosynthetic pathway (HBP), a glycolytic branch, generates UDP--acetylglucosamine for protein glycosylation, including -GlcNAcylation...
De novo lipogenesis (DNL) converts excess glucose into lipids, whereas the hexosamine biosynthetic pathway (HBP), a glycolytic branch, generates UDP--acetylglucosamine for protein glycosylation, including -GlcNAcylation and -linked glycosylation. Both pathways are active in hepatocytes and integral to glucose metabolism; however, their functional interplay remains unclear. Here, we investigated the role of HBP in hepatic DNL activation using both in vitro and in vivo models. AML12 hepatocytes were cultured in low- and high-glucose media with or without HBP blockade, both pharmacologically and genetically. For in vivo studies, male C57BL/6J mice were subjected to a fasting-refeeding regimen with or without intraperitoneal administration of azaserine, a competitive inhibitor of glutamine-fructose-6-phosphate transaminase 1 (GFPT1), the rate-limiting enzyme of the HBP. Our results demonstrated that, in AML12 cells, glucose exposure activated both DNL and HBP, leading to triacylglycerol (TAG) accumulation, whereas HBP inhibition ameliorated DNL and TAG accumulation. In mice, refeeding after a 24-h fasting induced hepatic DNL, which was abolished by HBP inhibition, indicating its mechanistic involvement in glucose-driven lipogenesis. Mechanistically, we identified ATF4 as a key regulator of GFPT1 upregulation under high-glucose conditions. As expected, both glucose-treated hepatocytes and livers from fasting-refed mice exhibited increased protein glycosylation. Notably, blocking -linked glycosylation, but not -GlcNAcylation, abolished glucose-induced DNL activation, indicating that HBP is essential for glucose-induced DNL pathway activation via promoting -linked glycosylation, independent of -GlcNAcylation. In conclusion, our findings establish that an intact HBP is required for glucose-induced hepatic DNL activation, primarily through promoting protein -linked glycosylation. High-glucose exposure activates both hepatic HBP and DNL pathways. The glucose metabolism into HBP is essential for the activation of the DNL pathway. ATF4 activation plays a mechanistic role in high glucose-induced HBP activation. HBP drives high glucose-induced hepatic DNL activation via promoting -linked protein glycosylation.
Contribution of neuroligin and neurexin alternative splicing to the establishment of enteric neuronal synaptic specificity.
D'Autréaux F, Chalazonitis A, Arumugam D … +2 more , Gershon T, Gershon MD
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40327378 · Full text
The enteric nervous system (ENS) is unique among components of the peripheral nervous system due to its complexity in structure and neurotransmitter phenotype diversity. In this complexity, the ENS resembles the central...
The enteric nervous system (ENS) is unique among components of the peripheral nervous system due to its complexity in structure and neurotransmitter phenotype diversity. In this complexity, the ENS resembles the central nervous system (CNS). Although the ENS is derived from the neural crest rather than the neural tube, similar mechanisms may generate complex connectivity in both the ENS and the CNS. Neuroligins and neurexins are cell adhesion molecules that participate in regulating CNS synaptogenesis. We investigated whether these molecules also play a role in establishing enteric synapses. We found that neuroligins and neurexins were expressed in mouse, rat, and human gut. Transcripts of both types of molecule were extensively spliced in the bowel during fetal and adult life. When transfected into non-neuronal cells, neuroligins and neurexins were sufficient to recruit, respectively, presynaptic and postsynaptic elements. Engineered soluble neurexin, which interferes with endogenous neurexin-neuroligin binding, inhibited enteric synapse formation/stabilization and recruitment of neurotransmitter receptors. Finally, we demonstrated that alternative splicing of neuroligin and neurexin contributes to ENS synaptic specificity. Some isoforms preferentially induced cholinergic synapses, whereas others promoted serotonergic synaptogenesis. We found that neuroligins and neurexins play roles in establishing ENS synapses. Both are extensively spliced in the fetal and adult gut. When expressed in non-neuronal cells, both neuroligins and neurexins are sufficient to recruit, respectively, presynaptic and postsynaptic elements. Soluble neurexin inhibits enteric synapse formation and recruitment of neurotransmitter receptors by interfering with endogenous neurexin/neuroligin binding. The neurexin/neuroligin splice code contributes physiologically to ENS synaptic specificity, promoting for example, cholinergic or serotonergic synaptogenesis.
Liver bypass in the development of pathogen-associated pulmonary vascular disease: contribution of mesocaval and portosystemic shunts.
Silva CLM, Puthanveetil PN, Oliveira SD
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40323787 · Full text
Portosystemic and mesocaval shunts are aberrant vascular connections that bypass hepatic detoxification process, directly linking the portal to the systemic circulation. These shunts, whether congenital or acquired, migh...
Portosystemic and mesocaval shunts are aberrant vascular connections that bypass hepatic detoxification process, directly linking the portal to the systemic circulation. These shunts, whether congenital or acquired, might play a pivotal role in the pathogenesis of systemic inflammatory diseases, such as schistosomiasis-associated pulmonary hypertension (Sch-PH) by facilitating the dissemination of pathogen-derived eggs and antigens from the gut and mesentery into the lungs. Beyond the translocation of eggs, emerging evidence implicates that gut-lung microbiome dysbiosis contributes to the development of pulmonary hypertension (PH) in the preclinical animal model of Sch-PH. Sch-PH emerges as a chronic complication of schistosomiasis and evolves silently, progressively increasing the mean pulmonary arterial pressure and vascular resistance, leading to right heart hypertrophy, failure, and significant morbidity and mortality. Chronic schistosomiasis is often linked to the development of portal hypertension, which significantly contributes to the formation of the porto/mesocaval shunt as a compensatory response that can have far-reaching implications on pulmonary vascular physiology. In addition, portal hypertension compromises the integrity of the intestinal barrier, exacerbating peritoneal and mesenteric inflammation, potentially facilitating microbial and metabolite entrance into the systemic circulation. This article briefly discusses the mechanisms by which porto/mesocaval shunts contribute to PH, especially Group I PH, focusing on the interplay between portosystemic shunting, microbial translocation, and systemic dissemination of proinflammatory metabolites.
Gut microbiota dysbiosis in a novel mouse model of colitis potentially increases the risk of colorectal cancer.
Pramana AAC, Xu GB, Liang S … +6 more , Garcia Vazquez EO, Allen JM, Loman BR, Mei W, Pan YX, Chen H
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40323196 · Publisher ↗
This research investigates the gut microbiota profile in a novel mouse model of colitis with a specific knockout (KO) of the gene in intestinal epithelial cells. This KO mouse model is characterized by activation of the...
This research investigates the gut microbiota profile in a novel mouse model of colitis with a specific knockout (KO) of the gene in intestinal epithelial cells. This KO mouse model is characterized by activation of the NF-κB pathway and early-onset colitis. Although the influence of gut microbiota on colitis pathophysiology is well established, its role in KO mice remains unexplored. To address this, we used 16S rRNA gene amplicon sequencing to compare the gut microbiota between KO and wild-type (WT) mice at baseline and following a dextran sodium sulfate (DSS) challenge. Untargeted metabolomics was also used to profile bacterial metabolites identified in the 16S rRNA analysis. Fecal DNA was extracted and analyzed to determine gut microbiota composition. Body weight and the disease activity index (DAI) were measured, while organ samples, including liver, spleen, and colon, were collected during necropsy for analysis. Representative bacteria identified from 16S-rRNA gene sequencing were cultured in designated media to further characterize their metabolite profiles. Initial findings on 16S-rRNA gene analysis revealed significant disparities in the gut microbiota between KO and WT mice. Notably, KO mice exhibited lower levels of sp. but higher levels of and compared with WT mice. The DSS challenge exacerbated colitis in KO mice and led to further alterations in gut microbiota diversity and composition. After DSS treatment, significant shifts were observed in five bacterial species. Specifically, sp. remained consistently low, whereas persisted at high levels in DSS-treated KO mice. In addition, elevated levels of and were detected in KO mice, whereas was significantly higher in WT mice. The metabolomic analysis highlighted distinct bacterial metabolic profiles between and . were found to produce higher levels of glycocholate, urocanate, and deoxycholate, whereas predominantly produced N-formyltryptophan, indole-3-carboxaldehyde, and glycyl-l-norleucine. Importantly, an imbalance in the abundance of sp. and was observed in KO mice, suggesting a potential role in colitis pathogenesis. Comprehensive pathway analysis based on 16S rRNA gene sequences revealed disturbances in several pathways, including those related to human diseases such as cancer, which were notably increased in KO mice after the DSS challenge. These findings underscore the disrupted microbiome balance in KO mice, particularly the altered levels of sp., which may play a pivotal role in gut health and colitis development. Ablation of in intestinal epithelia modulates gut microbiota; causing dysbiosis. Increased ratio of fecal to sp. is a signature of inflammation in hnRNPI knockout mice. hnRNPI knockout exacerbated colitis from dextran sodium sulfate challenge in knockout mice. Bacterial metabolites produced by and could impact colon health in mice. gene ablation exacerbates chemically induced inflammation and colitis; potentially increasing cancer risk.
The multifaceted role of sirtuins in inflammatory bowel diseases.
Samant SA, Hyoju SK, Alverdy JC … +1 more , Gupta MP
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40298096 · Full text
Inflammatory bowel diseases (IBDs), mainly involving the disease states of ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic, relapsing inflammation of the gastrointestinal tract. IBD has an...
Inflammatory bowel diseases (IBDs), mainly involving the disease states of ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic, relapsing inflammation of the gastrointestinal tract. IBD has an unclear etiology and likely develops from a complex interaction between the host's genetic predisposition, the gut microbiota, the immune system, and elements within the environment. In the United States alone, the estimated health care cost for IBD, according to a recent study, exceeds $25 billion. More than 200 genetic loci have been identified to be associated with IBD, highlighting its complex pathophysiology. Although existing treatments for IBD are generally supportive, they are not curative, underscoring the need to identify the causative agents that drive disease pathogenesis. Several studies have reported metabolic alterations in the pathogenesis of IBD. In all living cells, the central action of nicotinamide adenine dinucleotide (NAD) plays a pivotal role in the regulation of energy metabolism and cell signaling. Dysregulated NAD metabolism is reported in patients with IBD. Sirtuins, a protein family of posttranslational modifiers, need NAD as a cofactor to perform enzymatic reactions such as deacylation and ADP-ribosylation of not only histones, but also of various other key cellular proteins. Therefore, sirtuins play a vital and central role as stress-responsive metabolic sensors in cells. In this review, we address novel mechanisms by which sirtuins play a role in IBD pathogenesis, thus exposing a potential therapeutic role of this group of enzymes that might be useful in curtailing IBD and several other debilitating gastrointestinal inflammatory disorders.
Fructooligosaccharides slow colonic motility and activate myenteric neurons via calcium sensing and 5-HT receptors in the proximal colon.
Wongkrasant P, Wallace LE, MacNaughton WK … +1 more , Sharkey KA
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40279204 · Publisher ↗
Calcium-sensing receptors (CaSR) regulate a variety of functions in the gastrointestinal tract. Recently, prebiotic-independent effects of fructooligosaccharides (FOS) on epithelial barrier function were found to be medi...
Calcium-sensing receptors (CaSR) regulate a variety of functions in the gastrointestinal tract. Recently, prebiotic-independent effects of fructooligosaccharides (FOS) on epithelial barrier function were found to be mediated by CaSR. Here, we tested the hypothesis that FOS acts via the CaSR to regulate colonic motility and neuronal activity in the enteric nervous system. Using immunohistochemistry, we determined that CaSR were localized on the colonic epithelium of the mouse proximal colon and that a small proportion of enterochromaffin cells coexpress CaSR. We demonstrated that intraluminal administration of FOS slows colonic motility in vivo in male and female mice, an effect that is mediated by both CaSR and 5-HT receptors. We assessed neuronal activity in response to luminally perfused FOS in intact segments of the proximal colon from male and female mice expressing a genetically encoded fluorescent calcium reporter in intrinsic primary afferent neurons (Calb1-GCaMP6 mice) or in all enteric neurons (Wnt1-GCaMP6 mice) using live cell confocal imaging. In both Calb1-GCaMP6 mice and Wnt1-GCaMP6 mice, intraluminal FOS perfusion induced a sustained elevation of intracellular Ca in neurons of the myenteric plexus. This effect was sensitive to tetrodotoxin and mediated by CaSR and 5-HT receptors. Serosal application of FOS was without effect. Our results demonstrate that FOS acts acutely to slow colonic motility in vivo and activates the enteric nervous system via CaSR and 5-HT receptors. Calcium-sensing receptors regulate a variety of functions in the gastrointestinal tract. Here, we demonstrate a novel action of fructooligosaccharides to regulate colonic motility in vivo and activate the enteric nervous system. These effects are mediated by calcium-sensing and 5-HT receptors.
Gut neuropeptide involvement in Parkinson's disease.
Templeton HN, Tobet SA, Schwerdtfeger LA
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40279198 · Full text
Parkinson's disease (PD) is a neurodegenerative disorder affecting over 10 million people. A key pathological feature of PD is the accumulation of misfolded α-synuclein (aSyn) protein in the substantia nigra pars compact...
Parkinson's disease (PD) is a neurodegenerative disorder affecting over 10 million people. A key pathological feature of PD is the accumulation of misfolded α-synuclein (aSyn) protein in the substantia nigra pars compacta. Aggregation of aSyn can form Lewy bodies that contribute to dopaminergic neuron degeneration and motor symptoms, such as tremor, rigidity, and bradykinesia. Beyond the central nervous system, aSyn aggregates have been detected in the gastrointestinal (GI) tract, suggesting a link between peripheral aSyn and nonmotor PD symptoms. GI symptoms, often preceding motor symptoms by up to 20 years, highlight the bidirectional communication between the central nervous system and the enteric nervous system (gut-brain axis) in PD. Although microbiome alterations and intestinal inflammation have been associated with PD, functional impacts on gut-brain signaling or aSyn aggregation remain unclear. Intestinal neuropeptides are key modulators of gut-brain communication, alter immune response to pathogens and environmental toxins, and may contribute to the function of the luminal gut barrier. Dysregulation of gut neuropeptide signaling, including vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide, ghrelin, cholecystokinin, glucagon-like peptide 1, and substance P, have been associated with pathologic effects of PD in animal models. Despite their potential role in pathogenesis and disease modulation, gut neuropeptide roles in PD are underexplored. This article reviews current knowledge surrounding microbial metabolite and immune influences on gut neuropeptide signaling, aSyn aggregation in the enteric nervous system, and downstream neuroimmune pathway alterations within the context of PD and its mouse models.
A novel human hepatocyte cell line to study PNPLA3-associated steatotic liver disease.
Huang G, Wallace DF, Subramaniam VN
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40266007 · Publisher ↗
Patatin-like phospholipase domain-containing protein 3 () p.I148M is a well-established variant associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steato...
Patatin-like phospholipase domain-containing protein 3 () p.I148M is a well-established variant associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Conflicting in vitro and in vivo data about the impact of the variant suggest that the p.I148M variant could be gain- or loss-of-function, or neomorphic. Most in vitro models used to study MASLD are cancer-derived hepatoma cell lines such as HepG2 and Huh7, which already endogenously express the homozygous p.I148M variant. This highlights the need to develop models that better reflect disease and allow comparisons with wild-type cells. Clustered regularly interspaced short palindromic repeats (CRISPR) prime editing was used to introduce the p.I148M gene variant into a healthy-derived immortalized human hepatocyte (IHH) cell line to generate a new in vitro model of MASLD that would better reflect PNPLA3-associated MASLD/MASH. Heterozygous and homozygous p.I148M IHH cell lines were generated and validated with Sanger sequencing. Mutant cell lines exhibited lipid accumulation, increased cluster of differentiation 36 () gene expression and a decline in carnitine palmitoyltransferase 1 alpha () gene expression compared with the wild-type control, basally or in the presence of free fatty acid (FFA)-induced steatosis. The homozygous p.I148M IHH cell line also demonstrated reduced gene and protein expression compared with the wild-type control. We have developed a new human hepatocyte cell line and in vitro model to help understand PNPLA3-associated steatotic liver disease and provide a new resource for developing potential therapeutics. We have developed a novel in vitro model for studying the p.I148M variant in steatotic liver disease using a normal, healthy-derived hepatocyte cell line, which does not endogenously express the variant. We show that carrying the homozygous p.I148M variant results in reduced PNPLA3 gene and protein expression, more lipid accumulation, increased lipid uptake, and reduced mitochondrial lipid oxidation-associated gene expressions and altered expression of genes associated with lipid synthesis and transport.
Lymphatic alterations in Crohn's disease: the villain or victim.
Hespe GE, Kataru RP
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40265954 · Full text
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Blame skewed neurogenesis for an inflamed askew gut.
Puttapaka SN, Kulkarni S
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40265924 · Publisher ↗
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Indole-3-propionic acid protects medium-diversity colitic mice via barrier enhancement preferentially over anti-inflammatory effects.
Nieves KM, Flannigan KL, Hughes E … +13 more , Stephens M, Thorne AJ, Delanne-Cuménal A, Strayer K, Kola-Ilesanmi D, Wickramasinghe S, Mirzadzar N, Baruta G, McDonald B, Cobo ER, Petri B, Mani S, Hirota SA
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40257386 · Publisher ↗
Metabolites generated from the intestinal microbiota regulate local and distant tissues. One important metabolite generated from l-tryptophan is indole-3-propionic acid (IPA), which has been shown previously to regulate...
Metabolites generated from the intestinal microbiota regulate local and distant tissues. One important metabolite generated from l-tryptophan is indole-3-propionic acid (IPA), which has been shown previously to regulate intestinal mucosal homeostasis in specific pathogen-free (SPF)-colonized animals through distinct receptor-mediated events. Interestingly, IPA levels are reduced in patients with inflammatory bowel disease (IBD). In the current study, we assessed whether IPA could improve colitis outcomes in the absence of its production by the microbiota. To do this, colitis was induced by dextran sulfate sodium (DSS) in gnotobiotic mice colonized with the 12-member stable defined moderately diverse microbiota mouse 2 (sDMDMm2) microbial consortium, which lacks the genes required for IPA generation. We found that these mice were exquisitely sensitive to DSS compared with SPF-colonized mice. However, IPA treatment significantly increased survival. Infiltrating immune cells in the colon were not altered by IPA treatment nor were there any remarkable changes in local and systemic inflammatory mediator levels. Nevertheless, IPA treatment changed the composition of the fecal microbiota and enhanced intestinal barrier function, demonstrated by a reduction in FITC-dextran flux and retainment of a bioluminescent within the lumen of colitic mice. Together, our data suggest that IPA treatment in the context of its systemic depletion enhances barrier function and enhances survival in the presence of established inflammation. These data support continued assessment of IPA as a potential treatment for IBD. Indole-3-propionic acid (IPA) is a metabolite produced by the intestinal microbiota that has been shown to elicit beneficial effects in the gastrointestinal (GI) tract that include regulating intestinal barrier function, reducing inflammation, and controlling immune responses that lead to fibrosis. In patients with inflammatory bowel disease (IBD), IPA levels are reduced. In the current study, we found that treating mice with IPA at the peak of intestinal inflammation improved clinical outcomes and disease.
Costimulation with high-fat diet and acidic bile salts may promote Warburg effect in gastric carcinogenesis around the squamocolumnar junction in Gan mice.
Sudo K, Uno K, Tamahara T … +8 more , Asano N, Kusano K, Tanabe M, Ogasawara K, Kanno T, Koike T, Shimizu R, Masamune A
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40246521 · Publisher ↗
Epidemiological studies demonstrated relationships between gastric cardia adenocarcinoma (GCA) and metabolic syndrome (MetS). We aimed to clarify the mechanism underlying their relationship. To investigate whether system...
Epidemiological studies demonstrated relationships between gastric cardia adenocarcinoma (GCA) and metabolic syndrome (MetS). We aimed to clarify the mechanism underlying their relationship. To investigate whether systemic inflammation against high-fat diet (HFD)-related dysbiosis promotes the Warburg effect in tumors at the squamocolumnar junction (SCJ), we applied K19-Wnt1/C2mE (Gan) mice, fed either HFD or control diet ± acidic bile salts (ABS) with/without clodronate liposomes (CLs), and in vitro studies using MKN7 cells with/without THP1-derived macrophages. Then, we assessed the involvement of oxidative stress (OS) in the Warburg effect by comparing nuclear factor-erythroid 2-related factor 2 (Nrf2) knockout Gan mice with Gan mice. Tumors with macrophage infiltration in the HFD + ABS group were larger than in the control group. Gene Set Enrichment Analysis revealed enhancement of the OS signaling in tumor of the HFD + ABS group. The HFD + ABS group mice demonstrated induction of OS, Nqo1, tumor necrosis factor alpha (TNFα), and the Warburg effect in tumors and mucosal barrier dysfunction of dysbiotic gut. All of them were abolished with diminishing macrophage infiltration by additional CL treatment. Stimulation with TNFα, but not ABS nor lipopolysaccharide, on MKN7 cells activated the Warburg effect. In MKN7 cells cocultured with the macrophages whose TNFα expression was induced by the lipopolysaccharide pretreatment, the Warburg effect was enhanced in TNFα concentration-dependent manners. In Nrf2 knockout Gan mice, tumors shrank with reducing OS, TNFα, and Warburg effect, along with decreasing macrophage infiltration. Accordingly, MetS may develop GCA through the Nrf2-related Warburg effect under the TNFα stimulation from the macrophages activated by both local ABS exposure and systemic lipopolysaccharide exposure from leaky gut with HFD-related dysbiosis. In K19-Wnt1/C2mE (Gan) mice, a high-fat diet accompanied by orally taking acidic bile salts (ABS) promoted inflammation-associated carcinogenesis at the squamocolumnar junction (SCJ), maybe due to transudates from dysbiotic gut into systemic circulation. Systemic lipopolysaccharide exposure and local ABS exposure at the SCJ activate macrophages to induce the expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) and TNFα, which might promote Warburg effect in cancer cells. These phenomena were abolished in the Nrf2-knockout Gan mice.
Chronic intermittent hypoxia alleviates alcohol-related liver injury via downregulation of hepatic hypoxia-inducible factor-2α.
Chen Y, Zhang D, Wu Y … +7 more , Jiang W, Guo L, Pan D, He Q, Yin Z, Sun L, Wang S
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40243734 · Publisher ↗
Alcohol-related liver disease (ALD) is one of the leading causes of alcohol-related morbidity and mortality worldwide. Unfortunately, limited therapeutic options are currently available, due to the complex risk factors i...
Alcohol-related liver disease (ALD) is one of the leading causes of alcohol-related morbidity and mortality worldwide. Unfortunately, limited therapeutic options are currently available, due to the complex risk factors involved as well as the lack of information on the molecular mechanisms driving its progression. Interestingly, chronic, excessive alcohol intake has been reported to exacerbate the severity of obstructive sleep apnea (OSA), a respiratory disorder typically characterized by chronic intermittent hypoxia (CIH). However, this relationship between alcohol-enhanced OSA and ALD development/progression remains to be elucidated. As an approach to investigate this relationship, in vivo Gao-binge ALD and CIH mouse models were established. Alcohol-related liver injury, hepatic steatosis, inflammation, and oxidative stress were then assessed in these models. In addition, lipopolysaccharide (LPS) and ethanol-cotreated mouse normal hepatocyte cell line AML12 served as an in vitro model to investigate the mechanisms through which CIH affects ethanol-induced liver injury. CIH intervention ameliorated alcohol-related liver injury, reduced hepatic lipid accumulation and oxidative stress, and alleviated liver inflammation. Mechanistically, in the liver of these Gao-binge mice, CIH intervention inhibited alcohol-induced upregulation and activation of hypoxia-inducible factor 2α (HIF-2α), a protein which plays a key role in hepatic lipid metabolism and liver injury. Similar to these effects observed in response to CIH intervention, treatment of Gao-binge mice with the selective inhibitor of HIF-2α, PT2385, alleviated alcohol-related liver injury and steatosis while inhibiting oxidative stress and inflammation. Additional findings from our in vitro model revealed that CIH downregulated HIF-2α by promoting calpains protein expression, thereby reducing the accumulation of lipid droplets and decreasing reactiveoxygenspecies (ROS) production in AML12 cells co-challenged with LPS and ethanol. The above results provide important, new evidence that reconceptualizes the role of alcohol-enhanced OSA in ALD progression. Moreover, these findings can serve as the foundation for the development of HIF-2α inhibitors for use in the prevention and treatment of ALD. Chronic intermittent hypoxia (CIH) intervention mitigated hepatic lipid accumulation and reduced hepatic injury, inflammation, and oxidative stress in alcohol-related liver disease (ALD) mice. CIH alleviates ALD and is likely linked to the downregulation of hypoxia-inducible factor 2α (HIF-2α) expression mediated by calpains. This study presents a new possibility for ALD treatment and lays a theoretical foundation for the clinical treatment of ALD.
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