Am. J. Physiol. Gastrointest. Liver Physiol. [JOURNAL]
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200 papers
Low-dose galactose rebalances HBP-mTORC1-SREBP-1c signaling to suppress hepatic lipogenesis and protect against early-stage alcohol-related liver disease.
Li Y, Guo R, Qian Y … +4 more , Hawro I, Cordoba-Chacon J, Jiang Y, Song Z
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41528029 · Full text
Overactivation of hepatic de novo lipogenesis (DNL) contributes to fatty liver disease. Although glucose and fructose strongly promote DNL, diary-rich galactose is only weakly lipogenic. However, whether and how it regul...
Overactivation of hepatic de novo lipogenesis (DNL) contributes to fatty liver disease. Although glucose and fructose strongly promote DNL, diary-rich galactose is only weakly lipogenic. However, whether and how it regulates hepatic DNL remains unclear. In this study, we investigated whether low-dose galactose supplementation attenuates glucose- or fructose-induced DNL activation and protects against fatty liver diseases driven by DNL overactivation, such as alcohol-associated liver disease (ALD). In this study, we used integrated hepatocyte and mouse models to assess hepatic DNL and related signaling under high-glucose or high-fructose conditions, with or without low-dose galactose. Pharmacological and genetic interventions targeting the Leloir and hexosamine biosynthetic pathways (HBP) defined underlying mechanisms. For in vivo validation, male C57BL/6 mice were fed an isocaloric control or ethanol-containing diet for 4 wk. We found that glucose engages the HBP-mTORC1-SREBP-1c axis to stimulate hepatic DNL, whereas fructose acts predominantly through carbohydrate-responsive element-binding protein (ChREBP). Low-dose galactose selectively suppressed glucose-induced hepatic fat accumulation, concomitant with the inhibition of the HBP-mTORC1-SERBP-1c pathway. These effects required an intact Leloir pathway for galactose metabolism and were not observed with fructose. In alcohol-fed mice, hepatic HBP-mTORC1-SREBP-1c signaling was markedly upregulated, contributing to steatosis and liver injury. Replacing even a small fraction of dietary glucose with galactose normalized these alterations, attenuating hepatic lipid accumulation and injury without altering systemic glucose levels. In conclusion, glucose-induced hepatic lipogenesis involves the HBP-mTORC1-SREBP-1c pathway, which is also activated during chronic alcohol exposure. Low-dose galactose, obtainable from dairy sources, attenuates this pathway, thereby limiting excessive lipogenesis and protecting against early-stage ALD. This study demonstrates that low-dose galactose, a dairy-derived monosaccharide, regulates hepatic de novo lipogenesis (DNL) by selectively inhibiting glucose-induced DNL activation. Mechanistically, low-dose galactose suppresses hexosamine biosynthetic pathway (HBP) flux, protein O-GlcNAcylation, and mTORC1 signaling, thereby inhibiting SREBP-1c activation in a Leloir pathway-dependent manner. Notably, galactose supplementation prevented early-stage alcohol-related liver disease by attenuating hepatic HBP-O-GlcNAcylation-SREBP-1c signaling.
Role of serine/threonine phosphatases 1 and 2A in pancreatic acinar fluid and electrolyte secretion.
Ramos-Álvarez I, Mantey SA, Jensen RT
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41525767 · Full text
Serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A) play important roles in mediating cellular signaling in different tissues to different stimuli, including in protein synthesis, growth, cell cycle regulation...
Serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A) play important roles in mediating cellular signaling in different tissues to different stimuli, including in protein synthesis, growth, cell cycle regulation, and secretion. However, their roles in various pancreatic exocrine functions, such as pancreatic acinar fluid/electrolyte secretion, is still unclear. Therefore, in the present study, we examined the ability of vasoactive intestinal peptide (VIP) and secretin, which stimulate cAMP generation in pancreatic acini, to activate serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A), the signaling cascades involved, and their possible role in activating sodium-potassium adenosine triphosphatase (Na-K-ATPase). Our results demonstrate that VIP and secretin activate PP1 and PP2A. However, they differ in their signaling cascades. Both VIP and secretin stimulate PP1 through cAMP-stimulated activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC). However, VIP stimulates PP2A through the activation of cAMP-mediated EPAC, whereas secretin does it through activation of PKA. Despite these differences, in cAMP effect on activation, both VIP and secretin activate PP2A through a p21-activated kinase 4 (PAK4)-mediated mechanism, without involvement of PAK2. Furthermore, PP1 and PP2A activation is needed for Na-K-ATPase activation, which mediates pancreatic acinar fluid and electrolyte secretion. These results support the conclusion that PP1 and PP2A play an important role in pancreatic acinar fluid and electrolyte secretion, mediated by a PAK4-dependent mechanism, which when combined with their recently described roles in pancreatic enzyme secretion, pancreatitis, and pancreatic acinar growth and cancer, demonstrate the important roles they play in both physiological and pathological responses in the exocrine pancreas, similar to their previously established roles in the endocrine pancreas. The roles of the serine/threonine phosphatase 1/2A in mediating fluid/electrolyte secretion by pancreatic acinar cells remains unclear. This study demonstrates that PP1/PP2A are activated vasoactive intestinal peptide (VIP)/secretin in pancreatic acini. VIP/secretin both activate PP1/PP2A but differed for their ability to activate exchange protein directly activated by cAMP (EPAC) and protein kinase A (PKA). VIP/secretin require PAK4, not PAK2, activation to stimulate PP2A, not PP1; however, PP1/PP2A activation stimulate sodium-potassium adenosine triphosphatase (Na-K-ATPase) activity. This study shows that PP1/PP2A play important roles in VIP-secretin-stimulated pancreatic acinar fluid/electrolyte secretion.
Loss of histone deacetylase 4 in hepatocytes perturbs lipid metabolism and insulin signaling in mice with diet-induced obesity.
Jang H, Bae M, Lee Y … +11 more , Kang H, Kim MB, Hu S, Corvino O, Lee J, Woo H, Kostour V, Odell W, Kim A, Park YK, Lee JY
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41512278 · Publisher ↗
Epigenetic regulations link environmental factors to the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). We determined the role of hepatocyte histone deacetylase 4 (HDAC4) in...
Epigenetic regulations link environmental factors to the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). We determined the role of hepatocyte histone deacetylase 4 (HDAC4) in the pathogenesis of MASLD. Male and female hepatocyte-specific knockout () mice and control floxed () mice were fed a high-fat, high-sucrose, high-cholesterol diet for 16 wk to induce obesity and MASLD. The loss of hepatic increased serum alanine transaminase activity and exacerbated hepatic steatosis with higher liver weights and triglyceride levels than mice in males. Hepatic expression of lipogenic genes was significantly higher in male and female mice than in controls. Moreover, primary hepatocytes and the liver of mice exhibited perturbed insulin signaling, characterized by reduced phosphorylated AKT2. Interestingly, hepatocyte loss increased inflammatory and fibrogenic genes in gonadal white adipose tissue (gWAT). Serum cytokine array and proteomic analysis demonstrated alterations in several serum factors, which may contribute to crosstalk between the liver and WAT in , leading to obesity-induced metabolic dysfunction in gWAT. In conclusion, hepatocyte loss exacerbates hepatic steatosis, accompanied by disturbed insulin signaling and WAT inflammation and fibrosis in obese mice, underscoring its crucial role in liver-WAT crosstalk. We examined the role of hepatocyte histone deacetylase 4 (HDAC4) in the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) using -deficient mice with hepatocyte-specific deletion. We found that deleting in hepatocytes worsens hepatic steatosis and disrupts insulin signaling in the liver. In addition, this deletion caused inflammation and fibrosis in the white adipose tissue of obese mice, highlighting the role of HDAC4 in the liver-adipose axis.
Disruption of gastrointestinal PDGFRα cells leads to loss of postjunctional inhibitory motor responses.
Hwang SJ, Sanders KM, Ward SM
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41474471 · Full text
Fibroblast-like cells (FLCs) exist in the smooth muscle layers of visceral organs, yet in many instances their functional role(s) have not been identified. FLCs express platelet-derived growth factor receptor (PDGFR) α a...
Fibroblast-like cells (FLCs) exist in the smooth muscle layers of visceral organs, yet in many instances their functional role(s) have not been identified. FLCs express platelet-derived growth factor receptor (PDGFR) α and are a novel class of excitable cells recently described in visceral organs. Crenolanib is a benzamidine quinolone derivative originally developed as an inhibitor of PDGFR to treat certain solid tumors with PDGFRα overexpression mutations. In the present study, we used crenolanib to disrupt PDGFRα expression and signaling in the gastrointestinal (GI) tracts of mice. Intraperitoneal injections of crenolanib (100 µg/g body wt) or DMSO control vehicle were given to littermates from postpartum P1 through P15. Crenolanib-injected mice were smaller in size and weight. The gastrointestinal tracts were also shorter and appeared partially distended. qPCR revealed downregulation of key gene transcripts involved in PDGFRα cell signaling including , , and . Confocal immunofluorescence demonstrated significant decreases in PDGFRα and SK3 protein expression. c-Kit expression was slightly inhibited, but gastric, intestinal, and colonic pacemaker activity was not affected by crenolanib. Purinergic inhibitory postjunctional motor responses were greatly attenuated in the GI tracts of crenolanib-treated animals compared with vehicle-treated controls in response to electric field-evoked nerve stimulation. These data provide evidence for a functional role of PDGFRα cells in inhibitory neuroeffector motor responses throughout the gastrointestinal tract. The physiological roles of newly described PDGFRα interstitial cells in neurotransmission within the gastrointestinal (GI) tract have predominantly come from studies on isolated cells. Here we used an inhibitor of PDGFRα, crenolanib, to examine the effects of PDGFRα cells in enteric inhibitory neurotransmission. Crenolanib caused loss of PDGFRα cells and neurally evoked fast inhibitory junction potentials associated with purine neurotransmission, providing evidence for the function of PDGFRα cells within intact tissues of the GI tract.
Interregulation of gut transport and motility: the way forward.
de Loubens C, Capuano E, Loverdo C … +2 more , de Jonge CS, El Aidy S
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41455102 · Publisher ↗
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HNF4A intestinal ablation positively influences the fate of ileal goblet cells during infection.
Gómez DP, Nicolás VR, Marrero GC … +6 more , De Castro AC, Jones C, Leon Chirino LM, Perreault N, Menendez A, Boudreau F
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41452599 · Publisher ↗
Hepatocyte nuclear factor 4 A (HNF4A) is a transcription factor that regulates a diverse range of intestinal epithelial genes involved in tissue renewal, differentiation, and metabolism, among other functions. The HNF4A...
Hepatocyte nuclear factor 4 A (HNF4A) is a transcription factor that regulates a diverse range of intestinal epithelial genes involved in tissue renewal, differentiation, and metabolism, among other functions. The HNF4A locus is associated with inflammatory bowel disease (IBD) susceptibility, and its deletion in the mouse intestine causes long-term chronic inflammation of the colon. However, it remains unclear whether HNF4A is part of the regulatory mechanisms involved in the inflammatory processes of the small intestine. Using a tamoxifen-inducible mouse intestinal knockout of , we observed a spontaneous increase in mucosal barrier permeability in the absence of HNF4A. However, when these mice were infected with the invasive-deficient SB103, this increase in permeability did not result in an increase in liver and spleen bacterial colonization compared with undeleted mice. Interestingly, ileal secretory cell lineage differentiation was favored when HNF4A was depleted during the early stages of infection. This resulted in increased production of ileal goblet cells and the expression of , as well as the expression of specific antimicrobial peptides such as . We conclude that epithelial HNF4A is sensitive to in the ileum and that its reduction in expression during the early phase of infection may contribute to rapidly reinforcing the chemical barrier response to elicit mucosal threat from pathogens. HNF4A is associated with inflammatory bowel disease susceptibility and protects against chronic colon inflammation. Whether HNF4A acts similarly in the small intestine remains speculative. Although its deletion led to an increase in paracellular permeability, exposure to an attenuated strain did not cause systemic infection. Ileal goblet cell lineage commitment was stimulated with increased expression of antimicrobial peptide genes. HNF4A reduction of expression may contribute to early mucosal protection against luminal pathogen burdens.
The secondary bile acid, lithocholic acid, inhibits cystic fibrosis transmembrane conductance regulator expression and activity in colonic epithelial cells.
Curley CE, Mobbs CL, Mroz MS … +2 more , McLean MH, Keely SJ
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41452581 · Publisher ↗
Classically known for their roles in facilitating lipid digestion and absorption, bile acids are now also appreciated as enterocrine hormones that modulate many aspects of intestinal physiology. We have previously shown...
Classically known for their roles in facilitating lipid digestion and absorption, bile acids are now also appreciated as enterocrine hormones that modulate many aspects of intestinal physiology. We have previously shown lithocholic acid (LCA), a secondary bile acid, to be protective against colonic inflammation. Here, we investigated whether LCA also regulates colonic epithelial fluid and electrolyte transport. T cell monolayers were mounted in Ussing chambers for measurements of transepithelial Cl secretion. CFTR mRNA and protein expression were analyzed by qRT-PCR and Western blotting in T cells and human-derived colonic organoids. CFTR promoter activity was assessed using a luciferase promoter/reporter assay in HEK293 cells. Pretreatment of T cells with LCA inhibited Cl secretory responses to the cAMP-dependent agonist, forskolin (FSK), with maximal effects occurring at a concentration of 10 µM after 24 h of treatment. Under these conditions, LCA also inhibited responses to the Ca-dependent secretagogues, thapsigargin, and histamine. In nystatin-permeabilized T monolayers, LCA reduced FSK-stimulated apical Cl conductances, an effect that correlated with reduced CFTR Cl channel expression. Although LCA activated both farnesoid X receptor (FXR) and vitamin D receptor (VDR), its effects on CFTR expression and Cl conductances were mimicked only by an FXR agonist, GW4064, and not by a VDR agonist, calcitriol. Finally, LCA inhibited CFTR promoter activity in HEK3 cells, but only when FXR was expressed. LCA, at physiologically relevant concentrations, chronically inhibits colonic epithelial Cl secretion, likely via FXR-induced downregulation of CFTR. These data broaden our knowledge of the regulatory roles of LCA in the colon and highlight its potential as a therapeutic target for intestinal disorders. This study reveals a previously unrecognized role for lithocholic acid (LCA) in chronically suppressing colonic epithelial chloride secretion. We demonstrate a genomic mechanism of action for LCA that is likely mediated by FXR-induced downregulation of CFTR expression and function. These findings highlight LCA as a key modulator of intestinal fluid and electrolyte transport and underline the therapeutic potential of targeting bile acids and their receptors for the treatment of diarrheal diseases.
Pathologically relevant trypsinogen activation in pancreatitis.
Geisz-Fremy A
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41412572 · Full text
Pancreatitis is an inflammatory disorder of the pancreas that occurs in acute, recurrent acute, and chronic forms, often leading to severe complications and long-term functional impairment. The disease develops through m...
Pancreatitis is an inflammatory disorder of the pancreas that occurs in acute, recurrent acute, and chronic forms, often leading to severe complications and long-term functional impairment. The disease develops through multiple pathological mechanisms, including the premature activation of the digestive proenzyme trypsinogen within the pancreas. Conversion of trypsinogen to its active form trypsin may be catalyzed by the lysosomal protease cathepsin B or may occur through autoactivation, a self-amplifying reaction in which trypsin activates trypsinogen. Accumulating evidence from genetic, biochemical, and animal model studies on trypsinogen mutations associated with human pancreatitis strongly supports autoactivation as a key driver of disease pathogenesis, whereas cathepsin B-mediated activation may play a context-dependent, lesser role. This review explores the biochemical pathways of intrapancreatic trypsinogen activation and discusses their respective contributions to the multifactorial pathogenesis of pancreatitis.
Neurometabolic adaptations to intestinal inflammation in a mouse model of colitis.
D'Alessio A, Liguori FM, Wenzel MA … +4 more , Cristiano C, Russo R, Hunter J, Aviello G
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41407315 · Publisher ↗
The inflammatory process is a conserved and adaptive biological response to infection or tissue damage. Despite its substantial energy demands, inflammation triggers centrally regulated changes in behavior, commonly refe...
The inflammatory process is a conserved and adaptive biological response to infection or tissue damage. Despite its substantial energy demands, inflammation triggers centrally regulated changes in behavior, commonly referred to as sickness behavior, which includes anorexia and consequent negative energy balance. Although these responses have been extensively modeled through infection or cytokine administration, they remain less explored in a more dynamic spectrum of clinical conditions, such as inflammatory bowel disease (IBD). In this study, we used the dextran sodium sulfate (DSS) model of colitis, which mimics key features of human IBD. We assessed food and water intake, locomotor activity, and body composition over the disease progression. We further assessed neuronal activation and transcriptional changes in metabolic-sensing brain regions at key disease stages. Acute DSS-induced disease progression was associated with metabolic alterations, including anorexia, energy conservation, reduced physical activity, and changes in body mass composition. A positive correlation between disease severity and neuronal activation in the hypothalamus and the caudal brainstem was also found. Transcriptomic analysis revealed changes in hypothalamic gene expression associated with the immune response. Furthermore, targeted colocalization studies identified the activation of hypothalamic hunger-promoting AgRP/NPY-expressing neurons as a neuronal population recruited during colitis, suggesting a role for these neurons in coordinating allostatic metabolic adaptations to intestinal inflammation. This study provides evidence that the DSS model is a clinically relevant, dynamic, and tractable tool for studying the progression of sickness-like behavior in IBD, as well as the underlying neurometabolic adaptations that extend beyond the gut. By showing that experimental colitis induced by DSS in mice triggers metabolic adaptations and activation of brain regions regulating energy balance, this study expands the model's relevance beyond intestinal inflammation. These findings provide a framework to investigate gut-brain interactions and the neurometabolic components of sickness-like behavior in inflammatory bowel disease.
Enteric glia, neuropeptides, and Parkinson's: impacts of calcitonin gene-related peptide on gut alpha synuclein.
Templeton HN, Lanser TB, Tobet SA … +1 more , Schwerdtfeger LA
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41401974 · Full text
Parkinson's disease is a neurodegenerative disorder pathologically characterized by accumulation of misfolded α-synuclein in the central and peripheral nervous systems, influencing symptomology at both sites. Calcitonin...
Parkinson's disease is a neurodegenerative disorder pathologically characterized by accumulation of misfolded α-synuclein in the central and peripheral nervous systems, influencing symptomology at both sites. Calcitonin gene-related peptide (CGRP), a neuropeptide produced in the brain and intestine, has been linked with altered α-synuclein aggregation. This study examines the role of calcitonin gene-related peptide in modulating enteric α-synuclein accumulation and enteric glial cell reactivity using an ex vivo slice culture model from A53T human α-synuclein mutant mice. In slices treated with calcitonin gene-related peptide, α-synuclein immunoreactivity was elevated in myenteric neurons within 24 h. A stark elevation in gut mucosal calcitonin gene-related peptide immunoreactivity was revealed to be predominantly S100β+ enteric glia cells rather than neuronal fibers, pointing toward a reactive enteric glial cell phenotype. In addition, CGRP treatment increased enteric glial cell count in the mucosa in wildtype colon slices without evidence of incorporation of the DNA synthesis marker 5-ethynyl-2'-deoxyuridine indicating a lack of cell proliferation. Mucosal increases in enteric glial cell counts were accompanied by a decrease in these cells in the submucosa. This supports the idea that an inflamed gut environment may shift enteric glial cells to a reactive phenotype, inducing alterations in their number and anatomic localization. These data implicate calcitonin gene-related peptide in the accumulation of enteric α-synuclein, an effect potentially driven by an inflammatory environment that we hypothesize is due in part to enteric glial cell activation. Gastrointestinal symptoms of Parkinson's disease (PD) are an emerging area of investigation with implications for disease etiology. Utilizing intestinal ex vivo slices from a PD mouse model, Templeton et al., identify calcitonin gene-related peptide (CGRP) as a key modulator of enteric α-synuclein accumulation and enteric glial reactivity. These findings suggest that targeting peripheral CGRP signaling pathways in the enteric nervous system may represent a novel therapeutic approach for early intervention in PD.
Antibiotics alter duodenal immune populations upon gluten exposure in mice: implications for non-coeliac gluten sensitivity.
Pryor JC, Hoedt EC, Soh WS … +12 more , Fowler S, Caban S, Minahan K, Sherwin S, Nieva C, McCarthy H, Horvat J, Hedley KE, Duncanson K, Burns GL, Talley NJ, Keely S
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41389008 · Publisher ↗
A growing proportion of the non-celiac population experiences adverse symptoms to gluten. The pathogenesis of non-celiac gluten sensitivity (NCGS) is unclear, but elevated duodenal eosinophils and altered mucosa-associat...
A growing proportion of the non-celiac population experiences adverse symptoms to gluten. The pathogenesis of non-celiac gluten sensitivity (NCGS) is unclear, but elevated duodenal eosinophils and altered mucosa-associated microbiota (MAM) populations have been reported. Given the microbiome's role in gluten digestion and its susceptibility to antibiotics, we hypothesized that altering the microbiome with antibiotics would modify immune responses to gluten in mice. BALB/C mice consuming gluten-free chow received amoxicillin/clavulanate (5 mg/kg) or PBS-vehicle daily for 5 days. Mice were then treated with a 3-mg wheat-gluten suspension, or vehicle, on and before euthanasia on . Duodenal immune cells were analyzed by histology and flow cytometry, whereas the duodenal MAM and fecal microbiome were characterized via 16S rRNA and shotgun metagenomic sequencing, respectively. Antibiotic treatment followed by gluten reintroduction significantly reduced in the duodenal MAM, enriched in feces, and resulted in altered microbial carbohydrate and lipid metabolism, compared with vehicle controls. Treatment with antibiotics and gluten also increased duodenal eosinophils, which positively correlated with the genus Flow cytometry revealed that sequential antibiotic and gluten treatment resulted in a greater proportion of active eosinophils and epithelial γδ T-cells, compared with vehicle control mice. This study demonstrated that modulating the microbiome with antibiotics was sufficient to alter the immune response to gluten in mice, suggesting that the microbiome may determine the capacity for gluten to induce immune responses. These findings contribute valuable insights into possible microbial mechanisms underlying NCGS, such as altered gluten metabolism or production of immunomodulatory metabolites. A mouse model examined how microbial modulation affects immune responses to gluten. Antibiotic treatment followed by gluten reintroduction reduced duodenal and altered microbial carbohydrate and lipid metabolism pathways in the fecal microbiome. Antibiotics and gluten treatment resulted in increased abundance and activation of duodenal eosinophils and elevated γδ T-cells in the duodenal epithelium. These findings highlight the role the microbiome plays in gluten-induced immune responses, providing insights into mechanisms behind non-celiac gluten sensitivity.
Corrigendum for Okamura et al., volume 318, 2020, p. G989-G999.
Am J Physiol Gastrointest Liver Physiol · 2025 Dec · PMID 41364817 · Publisher ↗
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Intestinal adaptations increase basolateral intestinal glucose uptake and glycolysis in a mouse model of cystic fibrosis.
Lesser AF, Perez A, Wu C … +10 more , Hao S, Erokwu B, Host D, Jafri A, Barbato E, Yeh L, Eastman J, Sankararaman S, Flask CA, Drumm ML
Am J Physiol Gastrointest Liver Physiol · 2026 Jan · PMID 41364542 · Full text
The gastrointestinal manifestations of cystic fibrosis (CF) are a continued source of morbidity and mechanistic uncertainty despite recent advances in CF care. We sought to characterize intestinal glucose demand in a mou...
The gastrointestinal manifestations of cystic fibrosis (CF) are a continued source of morbidity and mechanistic uncertainty despite recent advances in CF care. We sought to characterize intestinal glucose demand in a mouse model of CF to better understand CF intestinal disease. We assessed in vivo systemic glucose uptake from circulation, including intestinal glucose demand, using F-fluorodeoxyglucose positron emission tomography (PET) imaging studies in wild-type (WT) and CF mice. RNA-sequencing studies with complementary assessments of protein expression and functional metabolism were performed to identify the responsible glucose transporter and relevant metabolic pathways. Finally, morphologic and histologic differences between the CF and WT small intestine were investigated. Increased glucose uptake from circulation to CF intestine was detected with the most prominent increases seen in CF jejunum and ileum. Increased mRNA and protein expression of GLUT1 was evident in whole intestinal tissue and isolated crypts, suggesting that GLUT1 is responsible for mediating the increased glucose uptake from the blood supply. We found transcriptional and functional enrichment of glycolysis in the CF jejunum and ileum. Proliferative intestinal adaptations, including increased intestinal length and weight, in addition to increased villi length and crypt depth, were observed in CF mice. The increased intestinal glucose uptake from circulation and increased glycolysis, in combination with the morphologic and histologic changes in the CF intestine, are suggestive of a proliferative adaptive response and increased intestinal glucose demand in CF. This work may yield novel markers of CF disease status and new therapeutic approaches. We found transcriptional, protein level, and functional evidence of increased intestinal glucose uptake from circulation and increased glycolysis in a cystic fibrosis mouse model. These findings in the context of hyperplastic morphologic and histologic changes in the cystic fibrosis intestine are indicative of an adaptive response. Our work elucidates new mechanisms of intestinal disease in cystic fibrosis and identifies altered intestinal glucose uptake and glycolysis as potential markers of disease status and gastrointestinal cancer risk.
FAM134B controls collagen I dynamics in hepatic stellate cell-driven fibrosis.
Misra J, Hanquier Z, Baxter R … +3 more , Barupala N, Jackson A, Maiers JL
Am J Physiol Gastrointest Liver Physiol · 2026 Feb · PMID 41348592 · Full text
Liver fibrosis is driven by the accumulation of scar tissue in response to injury. Activated hepatic stellate cells (HSCs) secrete fibrogenic proteins that deposit into the extracellular matrix, leading to fibrosis. Incr...
Liver fibrosis is driven by the accumulation of scar tissue in response to injury. Activated hepatic stellate cells (HSCs) secrete fibrogenic proteins that deposit into the extracellular matrix, leading to fibrosis. Increased production of fibrogenic proteins by HSCs leads to endoplasmic reticulum (ER) stress, triggering the unfolded protein response (UPR). The UPR is important in regulating HSC activation and fibrogenesis, but mechanisms driving this regulation are unclear. A key process regulated by the UPR is degradation of misfolded proteins through various pathways, including ER-to-lysosome-associated degradation (ERLAD). ERLAD targets proteins for lysosomal degradation and can involve autophagosomes engulfing portions of the ER, termed ER-phagy. ER-phagy is implicated in degradation of misfolded fibrillar collagen, but its role in fibrogenesis is unknown. We show that collagen I levels are posttranslationally regulated by autophagy, and this correlates with ER-phagy receptor expression. Furthermore, activation of HSCs induces ER-phagy flux and expression of ER-phagy receptors, including FAM134B, in a process dependent on UPR transducer ATF6α. Loss of FAM134B decreases intracellular collagen I without affecting COL1A1 mRNA. Moreover, FAM134B deletion blocks transforming growth factor β-induced collagen I deposition despite increased secretion. Together, we show that ER-phagy receptor FAM134B is pivotal for collagen I deposition during fibrogenesis. We show for the first time that TGFβ-mediated activation of HSCs induces selective autophagy of the endoplasmic reticulum (ER-phagy), through upregulation of ER-phagy receptors and ER-phagic flux. We further show that the unfolded protein response is critical for this effect. Finally, we identify the ER-phagy receptor FAM134B as a critical regulator of collagen I dynamics and fibrogenesis, with loss of FAM134B dysregulating collagen I secretion and deposition.
Association between gastric rhythm and gastroesophageal reflux defined by simultaneous body surface gastric mapping and 24-h pH testing.
Xu W, Simmonds S, Foong D … +10 more , Bhat S, Varghese C, Andrews CN, Schamberg G, Gharibans A, Abell TL, Rowbotham D, Ho V, Calder S, O'Grady G
Am J Physiol Gastrointest Liver Physiol · 2026 Jan · PMID 41343192 · Publisher ↗
Gastroesophageal reflux disease (GERD) is common and often medically refractory. Abnormal gastric myoelectrical function may contribute to pathogenesis. This prospective observational study with matched controls assessed...
Gastroesophageal reflux disease (GERD) is common and often medically refractory. Abnormal gastric myoelectrical function may contribute to pathogenesis. This prospective observational study with matched controls assessed if myoelectrical abnormalities measured using body surface gastric mapping were correlated with reflux measured by 24-h pH testing and symptom severity. Gastric Alimetry was performed simultaneously on patients undergoing 24-h pH testing for investigation of reflux symptoms, with a standardized 4.5-h test and validated symptom logging. Data were segmented into 15-min epochs. Forty subjects were recruited (mean age 46.5 yr, 60% female): 20 undergoing pH testing (12 with GERD and 8 symptomatic patients without) and 20 controls. Patients with GERD displayed lower gastric rhythm stability measured by the Gastric Alimetry Rhythm Index (GA-RI) when compared with controls ( = 0.011), but not with patients without GERD ( = 0.605). Lower gastric rhythm stability measured by GA-RI was associated with increased esophageal acid exposure (DeMeester score; = -0.46, = 0.042). Periods of decreased gastric rhythm stability measured by GA-RI were not temporally correlated with reflux ( = 0.08, = 0.182) or heartburn severity ( = 0.04, = 0.309) but were correlated with nausea ( = -0.22, < 0.001) and excessive fullness ( = -0.28, < 0.001). We demonstrated that gastric rhythm instability is associated with increased symptom severity and overall acid exposure in patients with GERD. Although there was no temporal link between rhythm instability and heartburn, rhythm instability was temporally associated with increased nausea and fullness. GA-RI therefore offers an emerging biomarker of concurrent gastric neuromuscular dysfunction in patients with GERD. Gastroesophageal reflux disease (GERD) is common and often medically refractory. We assessed whether gastric myoelectrical function contributes to pathogenesis by simultaneously measuring myoelectrical activity with Gastric Alimetry and reflux events on 24-h pH testing in patients. We demonstrated that gastric rhythm instability is associated with increased symptom severity and acid exposure in patients with GERD. Although there was no temporal link between rhythm instability and heartburn found, rhythm instability was temporally associated with dyspepsia.
Microbial dysbiosis alters serotonin signaling in a postinflammatory murine model of visceral pain.
Roth TD, Russo-Savage L, Bahojb Habibyan Y … +6 more , Keenan CM, Wallace LE, Nasser Y, Mawe GM, Lavoie B, Sharkey KA
Am J Physiol Gastrointest Liver Physiol · 2026 Jan · PMID 41343181 · Full text
Serotonin (5-HT) is a multifunctional signaling molecule in the gastrointestinal (GI) tract. 5-HT synthesis is regulated by the gut microbiota. Microbial dysbiosis has been implicated in visceral pain and persistent alte...
Serotonin (5-HT) is a multifunctional signaling molecule in the gastrointestinal (GI) tract. 5-HT synthesis is regulated by the gut microbiota. Microbial dysbiosis has been implicated in visceral pain and persistent alterations in gut function that occur following inflammation. Here, we tested the hypothesis that alterations in gut microbiota in a postinflammatory model of visceral pain contribute to dysregulated 5-HT signaling. We used mice treated with dextran sodium sulfate (DSS) 42 days earlier (postcolitis) or untreated mice as donors for fecal microbiota transplants (FMTs) into germ-free mice to explore changes in enterochromaffin (EC) cell populations, expression of 5-HT synthesis, transport, and degradation genes, levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and 5-HT release. Significant differences were observed in EC cells, , , and gene expression, 5-HT and 5-HIAA levels, and 5-HT release between germ-free mice and mice receiving an FMT from either control or postcolitis donor mice. We observed no differences in the total number of EC cells, , or gene expression of mice after FMT from postcolitis or control mice. However, there was a significant increase in gene expression in the terminal ileum, an increased 5-HIAA/5-HT ratio in the proximal colon, and reduced 5-HT release to mechanical and chemical stimulation in the proximal and distal colon after FMT from postcolitis mice. Collectively, these findings provide additional evidence that the gut microbiota regulates 5-HT signaling. Moreover, they reveal functional changes in EC cell sensitivity in the presence of an altered microbiota after recovery from inflammation. The gut microbiota regulates serotonin biosynthesis in enterochromaffin cells. Here, we show that a dysbiotic gut microbiota that occurs after recovery from inflammation alters serotonin signaling and produces functional changes in enterochromaffin cell sensitivity.
Neutrophil-T cell cross talk in noninfectious liver diseases.
Gromova B, Kupcova V, Longhi MS … +1 more , Gardlik R
Am J Physiol Gastrointest Liver Physiol · 2026 Jan · PMID 41324991 · Full text
Sterile inflammation, resulting from hepatocyte death and subsequent release of damage-associated molecular patterns (DAMPs), significantly contributes to liver disease pathogenesis. Neutrophils, as primary responders to...
Sterile inflammation, resulting from hepatocyte death and subsequent release of damage-associated molecular patterns (DAMPs), significantly contributes to liver disease pathogenesis. Neutrophils, as primary responders to liver injury, undergo NETosis-an immune response generating neutrophil extracellular traps (NETs), further amplifying inflammatory damage. Extracellular DNA (ecDNA), a major constituent of NETs and released cell fragments, potentiates inflammation through pattern recognition receptor activation. Mitochondrial DNA, released during hepatocyte damage, especially provokes robust immune responses due to its bacterial DNA-like structure and unmethylated CpG motifs. Concurrently, purinergic signaling-particularly via ATP release and its conversion into adenosine by ectonucleotidases CD39 and CD73-critically modulates immune homeostasis and inflammatory responses. Dysregulated expression of CD39/CD73, driven by altered aryl hydrocarbon receptor (AhR) signaling, exacerbates inflammatory states through disturbed regulatory T (Treg) and T helper (Th) 17 cell balance. Recent insights highlight that neutrophils and NETs not only drive innate inflammatory responses but significantly influence adaptive immunity by modulating T cell differentiation. NET components, such as cathelicidin and histones, actively promote Th17 differentiation while simultaneously impairing Treg functions, thereby sustaining inflammatory conditions. In addition, T cells reciprocally influence neutrophil activation and recruitment, predominantly through interleukin-17A (IL-17A) production. Detailed mechanisms underlying neutrophil-T cell cross talk in autoimmune hepatitis, acute liver failure, ischemia/reperfusion injury, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease underscore potential therapeutic targets. Future strategies targeting NET formation, ecDNA clearance via DNase therapy, purinergic receptor modulation, and restoring AhR signaling hold promise for effectively attenuating sterile inflammation and immune dysregulation in liver diseases.
Impaired intestinal cell proliferation parallels increased senescence after burn injury in aged mice.
Walrath TM, Evans MR, Meza Monge K … +5 more , Najarro KM, Orlicky DJ, Idrovo JP, McMahan RH, Kovacs EJ
Am J Physiol Gastrointest Liver Physiol · 2026 Jan · PMID 41309057 · Full text
The global population is aging, with one in six people projected to be 65 yr or older by 2050. Since people aged 65 and older experience higher rates of morbidity and mortality after burn injury, there is an increased ne...
The global population is aging, with one in six people projected to be 65 yr or older by 2050. Since people aged 65 and older experience higher rates of morbidity and mortality after burn injury, there is an increased need to develop effective burn treatments in this age group. Heightened morbidity and risk of mortality may stem from increased gut leakiness and death of intestinal epithelial cells of aged individuals. Herein, we used our clinically relevant model of scald burn injury in young and aged mice to ascertain whether the colon, isolated colonic epithelium, and organoids grown from the colon have deficiencies in cell growth, senescence, and apoptosis pathways. Aged, burn-injured mice displayed increased senescence marker in the colon and isolated epithelium, and displayed a reduction in proliferation marker in the colon when compared with young mice. Changes in senescence and proliferation coincided with a reduction in stem cell marker in the colon and colonic epithelium, suggesting a burn-related reduction in the stemness of the epithelial crypt. Although we failed to see histological changes in the colonic epithelium, we observed an increase in proapoptotic cleaved caspase 3 and 9 within the colons of aged, burn-injured mice. Finally, there was a decrease in the expression of antimicrobial peptide , and not in the colons of aged, burn-injured mice. Taken together, these data suggest that in the colon, disruption of proliferation and apoptosis in aged burn-injured mice occurs primarily in the nonepithelial compartment. Aged mice have more senescent cells in their colons and burn injury in aged mice leads to suppression of proliferation markers in the colon, but not in epithelial cells or cultured organoids. Colonic expression of stem cell marker is reduced in colon from aged, burn-injured mice, and a proapoptotic caspase cascade was seen in this cohort. Finally, antimicrobial peptide expression is decreased in colons from both aged and aged, burn-injured mice.
Ubiquitin-proteasome pathway activation in the diaphragm of humans with reflux esophagitis.
Paula SM, Alves MNM, Simões DTCDS … +6 more , Coutinho TAA, Andrade MC, Sales LAS, Siqueira Pinheiro FA, Santos AA, Souza MÂN
Am J Physiol Gastrointest Liver Physiol · 2025 Dec · PMID 41273780 · Publisher ↗
Some forms of gastroesophageal reflux disease (GERD) are associated with crural diaphragm (CD) dysfunction, suggesting that GERD may be influenced by skeletal muscle deficiencies. Skeletal muscle atrophy has been strongl...
Some forms of gastroesophageal reflux disease (GERD) are associated with crural diaphragm (CD) dysfunction, suggesting that GERD may be influenced by skeletal muscle deficiencies. Skeletal muscle atrophy has been strongly linked to alterations in the ubiquitin-proteasome system, the primary pathway for protein degradation. This study aimed to assess the expression of muscle atrophy-related proteins in the CD of patients with reflux esophagitis compared with those without esophagitis. In addition, we examined the correlation between these proteins, esophagitis severity, and esophageal acid exposure. CD biopsies were obtained from 15 volunteers (8 males, 7 females; mean age 43 yr) during antireflux laparoscopic Nissen fundoplication (GERD group) or gallbladder surgery (control group). The GERD group was further classified based on the Los Angeles classification into ( = 5), ( = 7), and ( = 3). We analyzed key signaling pathways involved in muscle atrophy, including AKT, phosphorylated AKT (pAKT), muscle-specific RING finger 1 protein (MuRF-1), and muscle atrophy F-box (MAFbx/atrogin-1), normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). No significant differences were observed in MuRF-1, pAKT/AKT ratio, or MAFbx/atrogin-1 expression between the control and GERD groups. However, MuRF-1 expression was significantly elevated in the GERD C group compared with GERD B group. The control group showed no differences from GERD A or B. Notably, MuRF-1 expression correlated with esophageal total reflux time in the supine position. These findings suggest that increased MuRF-1 expression may contribute to CD fiber atrophy and weakness in patients with GERD, potentially impairing gastroesophageal junction function and influencing disease progression. This study demonstrated, for the first time, an increased activation of the ubiquitin-proteasome pathway and elevated MuRF-1 expression in the crural diaphragm of humans with moderate reflux esophagitis. It showed a positive correlation between the supine reflux time and MuRF-1 expression, suggesting a molecular mechanism associated with diaphragm fiber atrophy and weakness. These findings highlight a potential link between diaphragm degradation and reflux esophagitis, which may modulate gastroesophageal reflux and symptoms.
Mechanisms of liver regeneration and their relevance to steatotic liver disease.
Huang G, Subramaniam VN
Am J Physiol Gastrointest Liver Physiol · 2025 Dec · PMID 41259120 · Publisher ↗
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