Am. J. Physiol. Gastrointest. Liver Physiol. [JOURNAL]
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200 papers
Lactotransferrin reduction as a target mechanism of postnatal intestinal vulnerability in murine preeclampsia models.
Ohtani T, Ichinose M, Iriyama T … +10 more , Irie M, Ariyoshi Y, Yano E, Sayama S, Suzuki N, Hayakawa Y, Kumasawa K, Nagamatsu T, Harada M, Hirota Y
Am J Physiol Gastrointest Liver Physiol · 2026 Jun · PMID 42089809 · Publisher ↗
Fetal growth restriction (FGR) and preeclampsia (PE) are associated with placental insufficiency. Although FGR increases the risk of postnatal intestinal disorders, the mechanisms by which intrauterine stress causes thes...
Fetal growth restriction (FGR) and preeclampsia (PE) are associated with placental insufficiency. Although FGR increases the risk of postnatal intestinal disorders, the mechanisms by which intrauterine stress causes these disorders and the intestinal alterations underlying their pathogenesis remain unclear. In this study, we investigated the underlying molecular mechanisms and potential preventive strategies. Pregnant mice were administered angiotensin II or recombinant soluble fms-like tyrosine kinase-1 to induce PE with FGR. Offspring intestines were collected on for RNA sequencing and on (P) and for histological analyses. At P21, enteritis was induced using lipopolysaccharide and platelet-activating factors. Offspring from the PE model (PE offspring) exhibited shorter intestinal lengths and fewer secretory cells than the controls. RNA sequencing identified 226 differentially expressed genes, with lactotransferrin (), a protective secretory protein, downregulated in PE offspring. Immunohistochemistry demonstrated increased epithelial Ltf expression from P7 to P21, which was impaired in PE offspring. Following enteritis induction, the PE offspring showed increased severity, which was markedly mitigated by prophylactic LTF supplementation. These findings highlight the importance of risk-based preventive strategies for postnatal intestinal disorders in infants exposed to placental insufficiency-induced intrauterine stress. Children born to mothers with preeclampsia are at an increased risk of postnatal intestinal vulnerability, yet the mechanisms of such disorders remain unclear. In murine preeclampsia models with fetal growth restriction, offspring exhibited impaired intestinal epithelial differentiation and markedly reduced lactotransferrin expression from fetal to postnatal stages. Prophylactic oral lactotransferrin mitigated experimental enteritis, highlighting a risk-based preventive strategy for postnatal intestinal disorders in infants exposed to intrauterine stress.
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Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 42085704 · Publisher ↗
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Panaxynol mitigates chemotherapy-induced intestinal mucositis by improving the colonic microenvironment in murine models.
Bullard BM, VanderVeen BN, Cardaci TD … +9 more , McDonald SJ, Bastian AV, Willis NB, Xu M, Li J, Pierre JF, Hofseth LJ, Fan D, Murphy EA
Am J Physiol Gastrointest Liver Physiol · 2026 Jun · PMID 42065376 · Full text
Chemotherapy-induced mucositis (CIM) is a debilitating side effect impacting as many as 90% of patients with cancer undergoing treatment. Patients receiving 5-fluorouracil (5FU), a first-line chemotherapeutic in colorect...
Chemotherapy-induced mucositis (CIM) is a debilitating side effect impacting as many as 90% of patients with cancer undergoing treatment. Patients receiving 5-fluorouracil (5FU), a first-line chemotherapeutic in colorectal cancer, experience significant gastrointestinal distress that perpetuates poor patient quality of life and reduces treatment tolerance, efficacy, and survival. Natural compounds have shown promise in improving CIM through their pleiotropic actions, including immune and mucosal regulation. We examined whether panaxynol, a bioactive compound isolated from American ginseng, can alleviate murine CIM symptomology and severity. Intestinal mucositis was induced in C57BL/6J male and female mice by 5 consecutive intraperitoneal injections of 5FU (35 mg/kg/day); PBS was used as the control. Vehicle or panaxynol (2.5 mg/kg/day) was administered via oral gavage every other day, starting on , for a total of four treatments. Panaxynol significantly improved overall mucositis symptomology, attenuated 5FU-induced cytopenia and anemia, ameliorated the 5FU-induced loss of goblet cells per crypt, suppressed proinflammatory immune cells in the colonic lamina propria, and altered microbial diversity and taxonomy. Sex differences were observed, with panaxynol exerting a stronger effect in males, significantly reducing the relative percentage of colonic macrophages and neutrophils. Panaxynol treatment was associated with sex-dependent alterations in gut microbial community structure and modulation of specific taxa, including and , alongside male-specific increases in and ; abundance was primarily influenced by 5FU treatment. These preclinical findings support the potential of panaxynol as a therapeutic candidate for the treatment of CIM and highlight the importance of considering sex as a biological variable. This study identifies panaxynol, a bioactive compound from American ginseng, as a novel therapeutic candidate for chemotherapy-induced intestinal mucositis. In a murine 5-fluorouracil model, panaxynol attenuated mucosal injury, reduced cytopenia, suppressed proinflammatory immune cells, and altered gut microbial community structure. Importantly, panaxynol exhibited sex-dependent effects, with stronger immunological and microbial modulation in males. These findings highlight panaxynol's pleiotropic protective actions and underscore the importance of sex as a biological variable in mucositis therapeutics.
IP6K1 interacts with the syndecan SDC4 to support secretory granule biogenesis in gastric chief cells.
Sen J, Pore P, Bhandari R
Am J Physiol Gastrointest Liver Physiol · 2026 Jun · PMID 42053465 · Publisher ↗
Inositol hexakisphosphate kinases (IP6Ks) catalyze the synthesis of the inositol pyrophosphate 5-InsP, and regulate diverse physiological processes. mice display reduced body weight despite normal food intake, elevated...
Inositol hexakisphosphate kinases (IP6Ks) catalyze the synthesis of the inositol pyrophosphate 5-InsP, and regulate diverse physiological processes. mice display reduced body weight despite normal food intake, elevated fecal protein, and reduced skeletal muscle mass compared with mice, suggesting that IP6K1 may support protein digestion. IP6K1 is expressed throughout the mouse gastrointestinal tract, and is especially enriched in the cytoplasm of chief cells in the stomach, which are responsible for the storage and secretion of digestive enzymes. Pepsinogen C (PGC) containing granules were sparse, and gastric lipase F granules were completely absent in the gastric glands of mice, despite normal expression levels of these enzymes, implicating IP6K1 in digestive enzyme granule biogenesis. The level of the active protease pepsin C was decreased in the gastric lumen of mice compared with mice. CRISPR/Cas9-mediated deletion of IP6K1 in the gastric adenocarcinoma cell line AGS recapitulated the phenotype of reduced PGC granules seen in gastric chief cells of mice. PGC granule formation was restored in AGS cells by the reintroduction of catalytically active or inactive IP6K1, indicating that IP6K1 supports the formation of secretory granules independent of its enzymatic activity. The proteoglycan SDC4, identified as an interactor of IP6K1, was seen to colocalize and comigrate with PGC granules in but not in AGS cells. Our findings identify IP6K1 as a novel regulator of secretory granule biogenesis in gastric chief cells, to influence protein digestion in the mammalian stomach. Through detailed phenotypic analysis of mice and mechanistic studies, we identify IP6K1 as a key regulator of digestive enzyme granule biogenesis and secretion in gastric glands. IP6K1 is shown to act via its specific interactor, the proteoglycan syndecan-4 (SDC4), to mediate pepsinogen C granule biogenesis. By extending IP6K1's functional landscape into gastrointestinal biology, our study opens new avenues for understanding its impact on digestion and metabolic health.
The protease inhibitor darunavir prevents esophagitis and impairments in esophageal barrier function in a mouse model of GERD.
Sales TMAL, Daniel AML, Silva LMGD … +14 more , Franco AX, Costa Filho HBD, Monteiro CEDS, Ferreira ABA, Alicrim SAC, Lopes AS, Clementino MAF, Oliveira ACP, Nicolau LAD, Havt A, Soares PMG, Spechler SJ, Souza RF, Souza MHLP
Am J Physiol Gastrointest Liver Physiol · 2026 Jun · PMID 42013031 · Publisher ↗
Gastric reflux induces esophageal mucosal inflammation, partially mediated by the activation of hypoxia inducible factor 2α (HIF-2α). Pepsin, present in the refluxate, amplifies this inflammatory process and exacerbates...
Gastric reflux induces esophageal mucosal inflammation, partially mediated by the activation of hypoxia inducible factor 2α (HIF-2α). Pepsin, present in the refluxate, amplifies this inflammatory process and exacerbates tissue injury. Therefore, pepsin inhibition represents a promising strategy to reduce inflammation and preserve esophageal mucosal integrity. In this study, we evaluated the effects of darunavir, a protease inhibitor presently used to treat human immunodeficiency virus infection, in a gastroesophageal reflux disease (GERD) model in Swiss mice. Animals were anesthetized (ketamine and xylazine) and subjected to partial pyloric ligation and total ligation of the gastric fundus. Four experimental groups were established: sham (control), sham + darunavir, GERD, and GERD + darunavir. After 3 days, animals were euthanized, and the esophagus was collected to measure wet weight (edema), myeloperoxidase (MPO) activity, and keratinocyte-derived cytokines (KC). Western blot was performed for HIF-2α and tight junction proteins zonula occludens-1 (ZO-1) and occludin (OCLD). Histology with analysis of dilation of the intercellular space (DIS). Esophageal barrier function was assessed by transepithelial electrical resistance and fluorescein as an index of paracellular permeability. Darunavir's antipeptic activity was also demonstrated in vitro. GERD-induced inflammation, with significant increases in edema, MPO, KC, DIS, histological changes and HIF-2α, and disrupted barrier function, reducing ZO-1 and OCLD levels. All these alterations were significantly reversed in darunavir-treated animals. These findings demonstrate that darunavir, a clinically available drug with antipepsin properties, inhibits GERD-induced inflammation and HIF-2α activation, preserving tight junction proteins and mucosal integrity. Thus, darunavir could be repurposed as a novel therapeutic option for GERD. The gastroesophageal reflux of pepsin contributes importantly to esophageal damage in patients with GERD. We have found that darunavir, a drug presently used to treat HIV, inhibits pepsin activity and, in an animal model of GERD, darunavir reduces esophageal inflammation and HIF-2α levels while preserving levels of tight junction proteins and esophageal mucosal integrity. These findings suggest that darunavir might have a role as a novel treatment for GERD.
Site-specific bidirectional regulation of transcription in the mouse ileum.
Katafuchi T, Honda A, Makishima M
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41989861 · Publisher ↗
Fibroblast growth factor 15 (FGF15) plays a crucial role in the negative feedback loop of bile acid (BA) production by reducing mRNA levels of hepatic , a rate-limiting enzyme of BA synthesis. Here, we investigated the p...
Fibroblast growth factor 15 (FGF15) plays a crucial role in the negative feedback loop of bile acid (BA) production by reducing mRNA levels of hepatic , a rate-limiting enzyme of BA synthesis. Here, we investigated the postprandial regulation of mRNA levels in the ileum to unveil the physiological regulation of FGF15 production by feeding in mice. The postprandial mRNA level reached the minimum level in the distal ileum following starvation for 20 h and subsequent feeding for 3 h. In mice lacking tauro-β-muricholic acid, which is an endogenous antagonist for the farnesoid-X-receptor (FXR), the mRNA level in the distal ileum was still 3 h-postprandially reduced. We further explored the postprandial regulation of transcription in various sites of the ileum and found that the 3 h-postprandial levels were reduced in the distal ileum while elevated in the proximal ileum. Furthermore, the 3 h-postprandial plasma FGF15 level was reduced despite the elevated mRNA level in the proximal ileum. In mice lacking in the intestine, the relative amount of 3 h-postprandial mRNA level was still reduced in the distal ileum, whereas the 3 h-postprandial elevation was blunt in the proximal ileum. Oral administration of soybean oil, fatty acids, and PPARγ agonist pioglitazone reduced expression in the distal ileum, indicating that PPARγ signaling is involved in the negative regulation of mRNA level. Collectively, our data show the complicated regulation of plasma FGF15 concentration by bidirectional change in mRNA levels by food intake in different sites of the ileum. It is considered that feeding stimulates the release of bile acids, which ultimately bind to FXR to increase the transcription in the ileum. However, we found that mRNA levels were postprandially reduced, particularly in the distal ileum, and this reduction was mediated through fatty acid-PPARγ signaling. In the proximal ileum, however, we observed that mRNA levels were postprandially elevated through bile acid-FXR signaling, which was consistent with the current idea.
Therapeutic efficacy, biomarker signatures, and translatability of semaglutide in the liver biopsy-confirmed GAN DIO-MASH mouse model.
Kristensen JB, Nøhr-Meldgaard J, Pors SE … +13 more , Norlin J, Veidal SS, Bendtsen KM, Niss K, Andersen MW, Harder LM, Dalhoff MT, Madsen MR, Voldum-Clausen K, Latta M, Knudsen LB, Feigh M, Hansen HH
Am J Physiol Gastrointest Liver Physiol · 2026 Jun · PMID 41973550 · Publisher ↗
Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Importantly, semaglutide was recently approved as the first...
Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Importantly, semaglutide was recently approved as the first GLP-1-based treatment for people with MASH with moderate-to-severe fibrosis. Translational models that recapitulate human MASH are critical for guiding early-stage drug discovery, enabling rigorous efficacy evaluation, and facilitating the progression of drug candidates into clinical development. In this study, we investigated the efficacy of semaglutide across an extensive series of experiments in the liver biopsy-confirmed GAN diet-induced obese MASH (GAN DIO-MASH) mouse model, benchmarking outcomes against those from pivotal clinical trials of semaglutide in MASH. Treatment outcomes in the GAN DIO-MASH mouse closely mirrored clinical findings, particularly for hepatic steatosis and inflammation endpoints. Longer semaglutide treatment durations (≥16 wk) led to pronounced and consistent improvements in quantitative fibrosis histology across studies. In comparison, the response rate for fibrosis stage improvement with semaglutide was modest and largely independent of treatment duration. Notably, pooling data from long-term intervention studies revealed more favorable effects on fibrosis stage. Importantly, the GAN DIO-MASH mouse recapitulated many human MASH-associated changes in circulating proteins and semaglutide-responsive biomarkers. Collectively, these results support the therapeutic effects of semaglutide in MASH and underscore the reproducibility and clinical translatability of multiple disease-relevant features of the GAN DIO-MASH mouse model, highlighting its applicability as a robust platform for preclinical drug development. Translational preclinical models that faithfully recapitulate human MASH are essential for guiding early-stage drug discovery by enabling rigorous efficacy assessment. In this study, we demonstrate that the biopsy-confirmed GAN DIO-MASH mouse model replicates semaglutide treatment responses across metabolic, biochemical, and histological endpoints, as well as key biomarker signatures observed in pivotal clinical trials in people with MASH. These findings strongly support the model's clinical translatability to facilitate efficient progression of therapeutic candidates into clinical development.
Measuring autonomic influence on gastrointestinal contractility: development and preliminary validation of novel capsule-based indices.
Mehta M, Zhao Z, Erekat A … +6 more , Semler J, Neupane N, Mueller BR, Coyle K, Cedillo G, Robinson-Papp J
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41973547 · Full text
The migrating motor complex (MMC) is a key feature of fasting gastrointestinal (GI) motility, but its disruption in neuropathic conditions remains poorly characterized. Wireless motility capsules (WMCs) offer a noninvasi...
The migrating motor complex (MMC) is a key feature of fasting gastrointestinal (GI) motility, but its disruption in neuropathic conditions remains poorly characterized. Wireless motility capsules (WMCs) offer a noninvasive means of collecting motility data, facilitating study of larger cohorts. We aimed to develop WMC-derived metrics to identify neuropathic dysmotility and its associations with autonomic nervous system (ANS) function. We analyzed WMC data from 98 controls and 71 people living with human immunodeficiency virus (HIV; PWH) in whom autonomic neuropathy (AN) and delayed small bowel transit time (dSBTT) are common. We studied nine contractility metrics, including established and novel metrics targeting rhythmic bursts of sustained contractile activity. Autonomic function, summarized as Modified Composite Autonomic Severity Score (MCASS), was used to draw associations with contractility measures. All contractility metrics were higher in PWH compared with controls ( ≤ 0.01 for all). Among PWH, those with AN showed the highest contractility, whereas those with dSBTT had the lowest. In controls, rhythmic bursts were more clustered, especially in the later portions of the small bowel recording, and had less variability in contraction amplitude and timing, potentially indicating greater organization. Overall, worse autonomic function was associated with higher contractility. WMC-derived metrics effectively capture fasting small bowel motility and may distinguish neuropathic patterns, which appear to progress from increased, disorganized contractility to decreased contractility as dSBTT develops. Future studies should validate these findings in other WMCs and populations to clarify their potential in advancing understanding of the pathophysiology of gut-brain-axis disorders. This study introduces novel WMC-derived contractility indices to quantify gastrointestinal motility, enabling noninvasive characterization of neuropathic dysmotility. In PWH, hypercontractility and disorganized rhythmic bursts were observed despite autonomic neuropathy and delayed transit, suggesting a spectrum in which inefficient high-amplitude contractions initially may preserve transit before progressive delay ensues. Leveraging raw pressure data from WMC technology, these indices are linkable to extrinsic autonomic biomarkers and may advance understanding of gut-brain axis disorder pathophysiology.
Fibroblast-specific deletion exacerbates IBD via lipid peroxidation.
Zhang Y, Ying Y, Huang W … +7 more , Rosenfeld ZA, El-Derany MO, Lee ZH, Castillo C, Oh TG, Greenson JK, Shah YM
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41955120 · Full text
Broad antioxidant strategies in inflammatory bowel disease (IBD) have had limited success, likely because they indiscriminately quench both harmful and physiological reactive oxygen species. In our recent work, we demons...
Broad antioxidant strategies in inflammatory bowel disease (IBD) have had limited success, likely because they indiscriminately quench both harmful and physiological reactive oxygen species. In our recent work, we demonstrated that fibroblast-specific overexpression of acyl-CoA synthetase long-chain family member 4 reprogrammed lipid metabolism and sensitized adjacent epithelial cells to ferroptosis in IBD models, pointing to heterocellular lipid cross talk as a driver of epithelial injury. Building on that insight, here we test the hypothesis that fibroblast glutathione peroxidase 4 (GPX4), a key enzyme detoxifying lipid hydroperoxides, is critical in restraining fibroblast-mediated lipid peroxidation and consequent epithelial ferroptosis during colitis. We generated tamoxifen-inducible fibroblast-specific GPX4 knockout mice and subjected them to acute dextran sulfate sodium (DSS) colitis. Fibroblast-specific GPX4 deletion did not alter basal colon morphology but significantly aggravated DSS-induced injury. It increased histological scores and led to greater weight loss and colon shortening compared with littermate control mice. In vitro, GPX4-deficient fibroblasts exhibited elevated lipid peroxidation in response to ferroptosis inducers, reversible by liproxstatin-1. Critically, liproxstatin-1 treatment rescued colitis severity in fibroblast-GPX4-deficient animals, restoring colon length, weight loss, and histologic injury. Together, these findings identify fibroblast GPX4 as a gatekeeper that limits stromal lipid peroxidation and suppresses epithelial ferroptosis under inflammatory stress. Targeting fibroblast-mediated lipid peroxidation may offer a refined therapeutic axis in IBD. Fibroblast-specific GPX4 deletion promotes IBD progression. Lipid peroxidation could be a potential therapeutic target of IBD.
Fecal DPP4 concentration reflects colonic injury in the TNBS-induced rat model of colitis.
Gomes SF, Ferreira-Duarte M, Dias-Pereira P … +4 more , Couto J, Duarte-Araújo M, Morato M, Magro F
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41954993 · Publisher ↗
Dipeptidyl peptidase 4 (DPP4) is involved in intestinal homeostasis and immune regulation. However, its distribution across biological matrices during intestinal inflammation remains poorly characterized. This study inve...
Dipeptidyl peptidase 4 (DPP4) is involved in intestinal homeostasis and immune regulation. However, its distribution across biological matrices during intestinal inflammation remains poorly characterized. This study investigated DPP4 concentrations in feces, colonic tissue, and serum in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced rat model of colitis and assessed host and/or microbiota contribution to fecal DPP4 in knockout and germ-free mice. Colitis was induced in male Wistar rats by intrarectal administration of an ethanolic solution of TNBS. Disease severity was assessed using clinical evaluation, macroscopic scoring, and histopathological indices. DPP4 concentrations were quantified by ELISA in serum, proximal and distal colonic tissue, luminal content, and cage-collected feces. Colonic DPP4 location was assessed by immunohistochemistry. To explore host and microbiota contributions, fecal DPP4 concentration was also measured in DPP4 knockout and germ-free mice. TNBS-induced colitis resulted in regionally heterogeneous inflammation, predominantly affecting the distal colon. In healthy rats, colonic DPP4 showed a proximal-to-distal gradient that was lost during inflammation. Fecal DPP4 concentrations were significantly increased in TNBS-treated animals, exhibited a proximal-to-distal increase, and reached highest levels in cage fecal pellets. Fecal DPP4 correlated with macro- and microscopic scores and with distal colonic DPP4 levels, whereas serum DPP4 did not differ between groups. Fecal DPP4 levels were reduced in DPP4 knockout and germ-free mice, suggesting a modulation of fecal DPP4 by a host-microbiota cross talk. DPP4 distribution is context- and matrix-dependent. Fecal DPP4 reflects regional and histological features of experimental colitis, by integrating local intestinal injury with luminal shedding. This study broadens current views of DPP4 in intestinal inflammation by showing that its regulation extends beyond tissue and circulation into the intestinal lumen. By mapping DPP4 across colonic regions and biological compartments in experimental colitis, we highlight feces as a window into spatial features of mucosal injury and into host-microbiota influences on enzyme regulation during intestinal inflammation.
Correction for Berndt et al., volume 303, 2011, p. G1384-G1392.
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41931647 · Publisher ↗
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TNF-α alters dedifferentiation of enterochromaffin cells, redirecting toward neuroendocrine tumors.
Sei Y, Feng J, Zhao X … +1 more , Wank SA
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41903127 · Publisher ↗
Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting, well-differentiated neuroendocrine tumors of enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood....
Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting, well-differentiated neuroendocrine tumors of enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Prior studies using TPH1 Cre-ERT2-driven RPM mice [EC cell-targeted RB1 (R) and Trp53 (P) loss and Myc (M) gain] showed nonendocrine adenocarcinomas in the small intestine through dedifferentiation of EC cells to intestinal stem cells, which are prone to transformation. However, these studies were limited by early death from tumors at other sites, leaving the potential for SI-NET development unclear over longer periods. To circumvent this time-limited off-target effect, the present study used intestinal enteroids from RPM mice to examine the effect of RB1 and Trp53 loss with or without gain of Myc function on EC cell-derived tumors. Initial results confirmed the previous in vivo induction of nonendocrine adenoma/adenocarcinoma. However, the addition of TNF-α to the enteroid media induced EC cell clusters in multiple crypts and well-differentiated neuroendocrine tumor versus carcinoma in the absence and presence of gain of Myc function, respectively. These findings suggest that TNF-α blocked EC cell dedifferentiation to intestinal stem cells, promoting their survival and expansion and shifting their fate from intestinal adenoma/carcinoma to a differentiated neuroendocrine tumor type. The present study thus highlights the crucial role of the microenvironment in influencing EC cell-derived tumorigenesis and provides insights into SI-NET development. Small intestinal neuroendocrine tumors are of putative enterochromaffin (EC) cell origin and are the most common malignancy in the small intestine. However, the tumorigenesis of these specified tumor types remains poorly understood. The present organoid studies show that the addition of TNF-α to the microenvironment maintains the specificity of EC cells during their transformation to neuroendocrine tumors while blocking their dedifferentiation to ISC-derived adenomas.
Fecal microbiota transplantation mitigates cardiac remodeling and functional impairment in mice with chronic colitis.
Zhong XS, Lopez KM, Liu M … +6 more , Xiao Y, Ou R, Kochkarian T, Powell DW, Fujise K, Li Q
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41902828 · Publisher ↗
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestines accompanied by profound extraintestinal manifestations. Although IBD shows a clear clinical association with cardiovascular derangemen...
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestines accompanied by profound extraintestinal manifestations. Although IBD shows a clear clinical association with cardiovascular derangements, whether and how chronic colitis impairs heart function remains unclear. To address this gap, we investigated the impact of chronic colitis on cardiac performance and the cardiac transcriptome using two mouse models: dextran sodium sulfate (DSS)-treated and mice. Heart function was assessed by echocardiography and molecular characterization was performed using RNA-sequencing (RNA-Seq), reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and Western blot. Both models exhibited significant functional cardiac impairment, characterized by reduced ejection fraction and fractional shortening along with histologically evident increase in collagen deposition, inflammation, and myofibril reorganization. Molecular analyses revealed a profibrotic cardiac environment. RNA sequencing unveiled a shared upregulation of eicosanoid-associated and inflammatory genes (, , , and ) across both models, alongside model-specific alterations in pathways governing cAMP and cGMP signaling, arachidonic and linoleic acid metabolism, and immune cell responses. DSS colitis caused differential regulation of 232 cardiac genes, whereas colitis yielded 105 dysregulated genes. Notably, reconstitution of a healthy balance of gut microbiota by therapeutic fecal microbiota transplantation (FMT), validated using quantitative polymerase chain reaction (qPCR), successfully rescued heart function and mitigated fibrosis in both models. However, mice demonstrated relatively less cardiac recovery following FMT, highlighting interleukin-10 (IL-10)'s cardioprotective and anti-inflammatory contribution. Collectively, these findings provide evidence that chronic colitis impairs heart function, offer novel insights into colitis-induced cardiac remodeling, and suggest that FMT mitigates cardiac dysfunction by correcting gut dysbiosis, attenuating systemic inflammation, and reestablishing homeostasis along the gut-heart axis. Inflammatory bowel disease (IBD) extends beyond the gut, as chronic inflammation and microbiota dysbiosis contribute to serious extraintestinal complications. This study demonstrates that chronic colitis induces cardiac remodeling and dysfunction in two mouse models, marked by reduced cardiac performance, fibrosis, and upregulated fibrotic and inflammatory genes. Importantly, fecal microbiota transplantation (FMT) alleviated cardiac injury, highlighting its therapeutic potential. These findings reveal FMT as a promising therapy against chronic inflammation contributing to cardiovascular complications in IBD.
Improvement of glucose homeostasis during leptin treatment does not alter the intestinal microbiome in male diabetic UC Davis type-2 diabetes mellitus rats.
Martínez-Ruiz M, Tabor-Simecka L, Graham JL … +9 more , Randolph C, Fox R, Lan R, Pack L, LeRoith T, Stanhope KL, Yeruva L, Havel PJ, Piccolo BD
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41875058 · Full text
Gut dysbiosis contributes to type 2 diabetes mellitus (T2DM) progression according to the preclinical evidence. Alterations in gut microbiome, energy metabolism, and barrier function were observed in individuals with obe...
Gut dysbiosis contributes to type 2 diabetes mellitus (T2DM) progression according to the preclinical evidence. Alterations in gut microbiome, energy metabolism, and barrier function were observed in individuals with obesity and insulin resistance. However, it remains unclear whether therapeutic interventions can reverse these alterations. This study aimed to evaluate whether improvements of glucose homeostasis resulting from leptin administration can lead to changes in colonic epithelial metabolism and barrier function in male UC Davis type 2 diabetic mellitus (UCD-T2DM) rats. Male UCD-T2DM rats (age: 173 ± 41 days) with 6 wk postonset of diabetes were randomized to receive daily subcutaneous injections of either phosphate buffer solution (control; = 12) or recombinant leptin (0.5 mg/kg; = 12) for 4 wk. Metabolic and intestinal outcomes were assessed, including glucose tolerance, insulin sensitivity, glucagon-like protein 1 levels, gut permeability, microbiota composition, short-chain fatty acids content, colon epithelial hypoxia, intestinal morphology, and gene/protein expression. Leptin treatment significantly reduced food intake and improved glucose homeostasis and insulin sensitivity without affecting body weight. No changes were observed in microbiome composition, gut permeability, or colon epithelial hypoxic gradients. Ileal villus height was decreased, whereas colonic crypt depth was not different between leptin-treated rats and control rats. Butyric, isocaproic, and valeric acids levels were increased in colonic content, colonic gene expression of and was downregulated, whereas PHD2 and Occludin protein levels were upregulated in leptin-treated compared with control. Despite improvements of glucose homeostasis, chronic leptin treatment did not modify gut microbiota or barrier function markers and colonic metabolic gene expression showed no clear adaptive shift. Our data indicate that chronic administration of recombinant leptin in diabetic UCD-T2DM rats does not change the gut microbiome, despite improvements in food intake, glucose homeostasis, and insulin sensitivity.
Hyperoxia-induced fatty liver injury through the AKT-dependent and HIF-2α-independent pathways.
Song Y, Lee SR, Lee BW
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41849799 · Publisher ↗
Supplemental oxygen is widely used to treat hypoxemia, but prolonged exposure induces oxidative stress. We investigated whether hyperoxia-induced reactive oxygen species contribute to fatty liver injury and delineated th...
Supplemental oxygen is widely used to treat hypoxemia, but prolonged exposure induces oxidative stress. We investigated whether hyperoxia-induced reactive oxygen species contribute to fatty liver injury and delineated the underlying mechanism. To enhance translational relevance, mice were housed under normoxic (21% O) or hyperoxic (30% O) conditions for 10 days. We also used HO-treated HepG2 cells and human liver organoids. Western blotting, real-time PCR, and immunostaining were performed to assess molecular changes. Hyperoxia increased systemic oxidative stress, inflammatory markers, liver weights, and hepatic triglyceride (TG) accumulation. These changes were accompanied by repression of fatty acid β-oxidation (FAO) and mitochondrial biogenesis genes and activation of lipogenesis. Hyperoxia also increased glycolysis, as shown by increased glucose transporter 2 (GLUT2) and glucokinase () expression, and activated protein kinase B (AKT) signaling without altering hypoxia-inducible factor-2α (HIF-2α) expression. Consistently, HO-treated HepG2 cells and human liver organoids exhibited similar alterations, including TG accumulation, upregulation of glycolytic and lipogenic markers, downregulation of FAO genes, and increased fibrosis marker and inflammation. Notably, si failed to attenuate TG accumulation, confirming an HIF-2α-independent mechanism. Finally, inhibition of AKT signaling attenuated TG accumulation and fibrosis in vitro by preventing glycolysis (via downregulation of ) and de novo lipid synthesis, whereas improving mitochondrial function; however, GLUT2 expression remained unaffected. In summary, hyperoxia-induced oxidative stress promotes hepatic TG accumulation and fibrosis by impairing mitochondrial function and enhancing glycolysis and lipogenesis in an AKT-dependent, HIF-2α-independent manner. These findings highlight risks of oxygen therapy on hepatic metabolism and identify AKT signaling as a therapeutic target to mitigate hyperoxia-induced fatty liver injury. Hyperoxia-induced oxidative stress caused hepatic triglyceride accumulation and fibrosis through mitochondrial dysfunction, suppressed FAO, and enhanced glycolysis and lipogenesis. These effects were AKT-dependent but HIF-2α-independent, highlighting AKT signaling as a potential therapeutic target to mitigate oxygen-related fatty liver injury.
Single-cell transcriptomics reveals that air-liquid interface culture promotes goblet cell differentiation and inhibits glycolysis in organoid cell monolayers.
Malonga T, Lhuillier E, Marrauld C … +5 more , Fourmy D, Riant E, Cabau C, Vialaneix N, Beaumont M
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41830459 · Publisher ↗
Faithfully recapitulating the cellular heterogeneity of the intestinal epithelium is essential when using organoid models. Air-liquid interface (ALI) culture has been shown to promote secretory cell differentiation, but...
Faithfully recapitulating the cellular heterogeneity of the intestinal epithelium is essential when using organoid models. Air-liquid interface (ALI) culture has been shown to promote secretory cell differentiation, but its impact on gene expression in each epithelial cell type remains unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the cellular heterogeneity of rabbit cecum-derived organoid monolayers grown under immerged or ALI conditions. We then compared these organoid cell type-specific gene expression profiles to a scRNA-seq atlas of the rabbit cecal epithelium in vivo. We selected the rabbit model notably because, unlike mice, it possesses BEST4 epithelial cells, a newly discovered subset of mature absorptive cells. Our analysis revealed a high degree of transcriptomic similarity between in vivo and organoid-derived stem and transit-amplifying cells. ALI culture markedly enhanced the differentiation of the secretory lineage, especially goblet cells, whose transcriptome closely resembled that of in vivo goblet cells. Furthermore, ALI was the only condition allowing the detection of enteroendocrine cells. BEST4 cells, however, were absent from organoids in immerged or ALI conditions despite their presence in vivo. In addition, ALI culture led to a consistent downregulation of hypoxia and glycolysis-associated genes across all cell types, which suggests a metabolic shift likely driven by increased oxygen availability in ALI conditions. Cell-cell communication analyses further indicated that ALI more closely mirrored in vivo patterns than immerged condition. Altogether, these results demonstrate that ALI culture allows for better recapitulation of the in vivo cellular heterogeneity and molecular signatures of the intestinal epithelium. Using single-cell RNA sequencing, this study shows that air-liquid interface (ALI) culture enhances secretory lineage differentiation of intestinal organoid cell monolayers and improves transcriptomic similarity to the native epithelium. ALI reduced hypoxia-associated gene expression and better recapitulates in vivo-like cell-cell interactions, supporting its value for modeling intestinal epithelial heterogeneity in organoids.
Plasma linoleic acid is related to lower hepatic steatosis index and higher linoleate-rich cardiolipin in adults with MAFLD.
Kalhori A, Cole RM, Zarich S … +5 more , Li N, Kolipaka A, Ni A, Sparagna GC, Belury MA
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41811730 · Full text
Linoleic acid (LA, C18:2n-6) is a required nutrient that supports mitochondrial function as a component of the inner mitochondrial membrane, cardiolipin (CL). Tetralinoleoyl CL (LACL) supports optimal fatty acid oxidatio...
Linoleic acid (LA, C18:2n-6) is a required nutrient that supports mitochondrial function as a component of the inner mitochondrial membrane, cardiolipin (CL). Tetralinoleoyl CL (LACL) supports optimal fatty acid oxidation, which is impaired in the liver in adults with metabolic dysfunction-associated fatty liver disease (MAFLD). Data were analyzed from 74 adults with MAFLD recruited from the Columbus region, Ohio, United States. Fatty acid content and CL species were measured in blood and peripheral blood mononuclear cells (PBMCs). Liver fat was assessed using magnetic resonance imaging-proton density fat fraction, and liver stiffness was assessed using magnetic resonance elastography. Although plasma LA was not significantly associated with liver fat or stiffness, there was a borderline inverse association with liver fat in females ( = 0.091). Plasma LA was negatively associated with hepatic steatosis index ( = 0.014) and homeostatic model assessment for insulin resistance (HOMA-IR) ( = 0.05). Plasma LA was positively correlated with LACL in PBMC expressed as a percentage of total cardiolipin ( = 0.501, < 0.001) and 72-C CL ( = 0.535, < 0.001). Borderline inverse relationships with liver fat were observed for LACL expressed as a percentage of 72-C CL ( = 0.074) and total CL ( = 0.063). LACL (% of 72-C CL) was positively associated with HOMA-IR in men ( = 0.006) but not women. Plasma LA was inversely associated with the presence of type 2 diabetes mellitus (odds ratio = 0.831, 95% confidence interval = 0.711, 0.955, = 0.013). Mediation analysis indicated that HOMA-IR accounted for ∼25.2% of this relationship. Remodeling of cardiolipin (CL) is altered in the peripheral blood mononuclear cells (PBMCs) of individuals with metabolic dysfunction-associated fatty liver disease (MAFLD), with reduced linoleic acid (LA). Whether specific CL species, such as LACL in PBMCs, or circulating LA levels relate to liver stiffness or hepatic fat is unknown. This study identifies both global- and sex-specific associations between plasma LA, PBMC-derived LACL, hepatic fat, liver stiffness, and type 2 diabetes mellitus in adults with MAFLD.
Inhibiting VTCN1 overcomes immunosuppression in colorectal cancer to activate T cells via galectin-3.
Wu Z, Zhong J, Xu C … +6 more , Zhao C, Yang Q, Zhao L, Lin C, Zhang S, Zhong J
Am J Physiol Gastrointest Liver Physiol · 2026 May · PMID 41778365 · Publisher ↗
Colorectal cancer (CRC) continues to be a major cause of cancer-related death globally, largely due to mechanisms of immune evasion that drive treatment resistance. Although multidisciplinary care has improved outcomes,...
Colorectal cancer (CRC) continues to be a major cause of cancer-related death globally, largely due to mechanisms of immune evasion that drive treatment resistance. Although multidisciplinary care has improved outcomes, how immune checkpoint molecules, particularly V-set domain-containing T-cell activation inhibitor 1 (VTCN1) and galectin-3, drive immunosuppression in CRC remains incompletely defined. In this study, we used an integrated multi-omics framework combining single-cell sequencing, transcriptomics, and proteomics to delineate the VTCN1-galectin-3 axis in CRC. We then validated its functional relevance using the VTCN1 inhibitor SGN-B7H4 in vitro and in vivo by assessing T cell function and tumor progression. Our results show that inhibiting VTCN1 markedly downregulates galectin-3 expression in T cells ( < 0.01), promoting T cell activation, as reflected by a 42% increase in CD25+CD69+ populations. Consequently, CRC cell proliferation was reduced by 58%, migration by 72% in scratch assays, and invasion by 65% in Transwell assays. In mouse models, SGN-B7H4 administration suppressed tumor growth by 63% relative to controls. These outcomes identify the VTCN1-galectin-3 axis as a pivotal mediator of immune suppression in CRC and highlight the therapeutic promise of targeting this pathway. Our work underscores the potential of VTCN1 inhibitors as part of combined treatment modalities, especially for immunotherapy-resistant CRC. This study identifies the V-set domain-containing T-cell activation inhibitor 1 (VTCN1)-galectin-3 axis as a key immunosuppressive pathway in colorectal cancer (CRC). We show that inhibiting VTCN1 downregulates galectin-3 in T cells, reversing their dysfunction and reactivating antitumor immunity. Therapeutically, the VTCN1 inhibitor SGN-B7H4 restricted tumor progression by enhancing T-cell activity and impairing cancer cell proliferation, migration, and invasion. These findings reveal a novel immune checkpoint mechanism and establish VTCN1 as a promising target to overcome immunotherapy resistance in CRC.
Expression of Concern for Garneau et al., volume 293, 2007, p. G758-G772.
Am J Physiol Gastrointest Liver Physiol · 2026 Mar · PMID 41774096 · Publisher ↗
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The gut microbiota metabolite isovalerate enhances the epithelial barrier function in cell monolayers derived from porcine ileum organoids.
Beaumont M, Vicente CM, Plata-Calzado C … +4 more , Lencina C, Jones E, Lecuelle S, Chalvon-Demersay T
Am J Physiol Gastrointest Liver Physiol · 2026 Apr · PMID 41740169 · Publisher ↗
The gut microbiota produces numerous metabolites that influence the epithelial barrier function. Bacterial catabolism of amino acids produces a wide variety of metabolites whose effects on the intestinal epithelium remai...
The gut microbiota produces numerous metabolites that influence the epithelial barrier function. Bacterial catabolism of amino acids produces a wide variety of metabolites whose effects on the intestinal epithelium remain to be identified. In this study, we investigated the effects of amino acid-derived metabolites (isovalerate, isobutyrate, 2-methylbutyrate, 5-aminovalerate, cadaverine, putrescine, and tryptamine) in cell monolayers derived from porcine ileum organoids. Our results show that the branched-chain fatty acid (BCFA) isovalerate improved the epithelial barrier function, as assessed by transepithelial electrical resistance measurement and paracellular permeability assay. Isovalerate upregulated the expression of genes involved in innate immunity, markers of absorptive and enteroendocrine cells, while reducing the expression of stem cells and mucus-related genes. Most of the effects of isovalerate on epithelial cells were also observed with butyrate, an inhibitor of the epigenetic enzymes histone deacetylases (HDAC). We found that isovalerate also inhibited HDAC, although to a lesser extent than butyrate. Furthermore, the structurally unrelated HDAC inhibitor trichostatin A improved epithelial barrier function and upregulated SLPI and IL10RA gene expression, as observed with isovalerate and butyrate. Interestingly, the other two BCFAs, isobutyrate and 2-methylbutyrate, did not replicate the effects of isovalerate. Overall, our in vitro results suggest that targeting the bacterial production of isovalerate may be useful to promote gut health. In this perspective, we performed an in silico analysis that identified species belonging to dominant gut microbiota genera, such as and , as potential producers of BCFAs through the POR enzymatic pathway. The microbiota degrades branched-chain amino acids to produce branched-chain fatty acids, the effects of which on the intestinal epithelial barrier remain poorly described. In this study, we demonstrate that the leucine-derived metabolite isovalerate enhances epithelial barrier function in cell monolayers derived from porcine ileum organoids. We also identified gut microbiota species potentially able to produce branched-chain fatty acids that could be targeted to promote gut health.
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