American Journal Of Physiology. Gastrointestinal And Liver Physiology[JOURNAL]
Sun
200 papers
sensitizes the intestinal epithelium to doxorubicin-induced apoptosis.
Janto NV, Gleizes AR, Sun SJ … +3 more , Ari G, Rao V, Gracz AD
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40243204 · Full text
Doxorubicin (DXR) is a widely used chemotherapy drug that can induce severe intestinal mucositis. Although the influence of gut bacteria on DXR-induced damage has been documented, the role of eukaryotic commensals remain...
Doxorubicin (DXR) is a widely used chemotherapy drug that can induce severe intestinal mucositis. Although the influence of gut bacteria on DXR-induced damage has been documented, the role of eukaryotic commensals remains unexplored. We discovered () in one of our mouse colonies exhibiting abnormal tuft cell hyperplasia, prompting an investigation into its impact on DXR-induced intestinal injury. Mice from -colonized and -excluded facilities were injected with DXR. Tissue morphology and gene expression were evaluated at acute injury (6 h) and regenerative (72 h and 120 h) phases. Changes to crypt and villus morphology were more subtle than previously reported and region-specific, with significantly shorter jejunal villi in mice at 72 h post-DXR compared with controls. Most notably, we observed elevated rates of DXR-induced apoptosis, measured by cleaved caspase 3 (CC3) staining, in intestinal crypts at 6 h post-DXR. mice also exhibited reduced expression of active intestinal stem cell (aISC) marker and facultative ISC (fISC) marker a at 6 h post-DXR compared with controls. , but not DXR, was associated with increased inflammation and expression of type 2 cytokines IL-5 and IL-13. mice also exhibited a decreased fecal abundance of , which promotes gut barrier integrity, and reduced claudin expression, indicating potential barrier dysfunction that could explain the increase in DXR-induced apoptosis. These findings highlight the significant influence of commensal microbiota, particularly eukaryotic organisms like , on intestinal biology and response to chemotherapy, underscoring the complexity of gut microbiota interactions in drug-induced mucositis. Our study found that the eukaryotic commensal () significantly increases DXR-induced intestinal apoptosis in mice. also reduces expression post-DXR injury and elevates inflammation and type 2 cytokine expression in the absence of injury. 16S sequencing identifies decreased abundance of protective in colonized mice, as well as decreased expression of barrier-forming claudins, which may explain increased apoptosis. These findings emphasize the complex role of microbiota in drug-induced intestinal damage.
Oryzanol ameliorates MCD-induced metabolic dysfunction-associated steatohepatitis in mice via gut microbiota reprogramming and TLR4/NF-κB signaling suppression.
Alam N, Ding X, Fu Y … +3 more , Jia L, Ali S, Liu E
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40243180 · Publisher ↗
Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major global health concern that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerge...
Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major global health concern that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as key mechanistic pathways in MASH development. Oryzanol (ORY), a rice bran bioactive compound, exhibits antioxidant, anti-inflammatory, hypolipidemic, and hypoglycemic properties. Here, we investigated the potential of ORY in alleviating MASH and its association with gut microbiota and MASH progression. Male C57BL/6J mice were fed normal chow diet or methionine-choline-deficient diet and received ORY supplementation at 300 mg/kg/day via gavage for 4 wk. Liver injury, inflammation, lipid accumulation, and TLR4/NF-κB signaling protein levels were assessed. In addition, changes in gut microbiota diversity and abundance across groups were evaluated using 16S rDNA sequencing. Our results demonstrated that ORY significantly reduced lipid accumulation and liver enzymes, ameliorated liver and ileum damage, and restored intestinal barrier function in MASH mice. Furthermore, ORY decreased plasma lipopolysaccharide levels, and inflammatory cytokines and downregulated TLR4, MyD88, and NF-κB protein levels in the liver. ORY enhanced tight junction protein level (ZO-1, occludin) in the gut. Microbial analysis revealed that ORY positively impacted Firmicutes and Bacteroidetes abundance, promoted beneficial bacteria like and , and inhibited harmful bacteria such as , , and . Notably, ORY increased abundance, potentially modulating metabolic and inflammatory pathways. ORY exerted restorative and reversible effects on the pathophysiological damage within the gut-liver axis in MASH mice. The therapeutic mechanism may be related to the modulation of the gut microbiota and TLR4/NF-κB signaling pathway. This study demonstrates that oryzanol (ORY), a bioactive rice bran compound, alleviates metabolic dysfunction-associated steatohepatitis (MASH) in mice by reducing lipid accumulation and inflammation. ORY beneficial effects are associated to the modulation of gut microbiota, enhancing gut barrier integrity, and lowering endotoxemia and TLR4/NF-κB signaling pathway. These findings suggest ORY potential in MASH prevention and treatment, highlighting its influence on gut-liver axis dynamics.
Saturated phosphatidic acids induce mTORC1-driven integrated stress response contributing to glucolipotoxicity in hepatocytes.
Guo R, Li Y, Jiang Y … +3 more , Khan MW, Layden BT, Song Z
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40241617 · Full text
Hepatic glucolipotoxicity, characterized by the synergistic detrimental effects of elevated glucose levels combined with excessive lipid accumulation in hepatocytes, plays a central role in the pathogenesis of various me...
Hepatic glucolipotoxicity, characterized by the synergistic detrimental effects of elevated glucose levels combined with excessive lipid accumulation in hepatocytes, plays a central role in the pathogenesis of various metabolic liver diseases. Despite recent advancements, the precise mechanisms underlying this process remain unclear. Using cultured AML12 and HepG2 cells exposed to excess palmitate, with and without high glucose, as an in vitro model, we aimed to elucidate the cellular and molecular mechanisms underlying hepatic glucolipotoxicity. Our data showed that palmitate exposure induced the integrated stress response (ISR) in hepatocytes, evidenced by increased eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation (serine 51) and upregulated activating transcription factor 4 (ATF4) expression. Moreover, we identified mammalian target of rapamycin complex 1 (mTORC1) as a novel upstream kinase responsible for palmitate-triggered ISR induction. Furthermore, we showed that either mTORC1 inhibitors, ISRIB (an ISR inhibitor), or ATF4 knockdown abolished palmitate-induced cell death, indicating that the mTORC1-eIF2α-ATF4 pathway activation plays a mechanistic role in mediating palmitate-induced hepatocyte cell death. Our continuous investigations revealed that glycerol-3-phosphate acyltransferase (GPAT4)-mediated metabolic flux of palmitate into the glycerolipid synthesis pathway is required for palmitate-induced mTORC1 activation and subsequent ISR induction. Specifically, we uncovered that saturated phosphatidic acid production contributes to palmitate-triggered mTORC1 activation. Our study provides the first evidence that high glucose enhances palmitate-induced activation of the mTORC1-eIF2α-ATF4 pathway, thereby exacerbating palmitate-induced hepatotoxicity. This effect is mediated by the increased availability of glycerol-3-phosphate, a substrate essential for phosphatidic acid synthesis. In conclusion, our study highlights that the activation of the mTORC1-eIF2α-ATF4 pathway, driven by saturated phosphatidic acid overproduction, plays a mechanistic role in hepatic glucolipotoxicity. Integrated stress response (ISR) activation contributes to palmitate-induced lipotoxicity in hepatocytes. mTORC1 acts as an upstream kinase essential for palmitate-mediated ISR activation and hepatocyte death. The formation of saturated phosphatidic acid mechanistically regulates hepatic mTORC1 activation induced by palmitate. Glucose-enhanced generation of saturated phosphatidic acid amplifies palmitate-induced hepatotoxicity, contributing to glucolipotoxicity.
Functional roles of interstitial cells of Cajal in the GI tract of rats.
Hwang SJ, Kwon JG, Beckett EAH … +4 more , Kim M, Herbert T, Sanders KM, Ward SM
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40235202 · Full text
Interstitial cells of Cajal (ICC) are distributed through the gastrointestinal (GI) tract, but the functional role of these cells comes primarily from studies of mice. Whether the functions of ICC are similar in larger a...
Interstitial cells of Cajal (ICC) are distributed through the gastrointestinal (GI) tract, but the functional role of these cells comes primarily from studies of mice. Whether the functions of ICC are similar in larger animals is largely speculative. We investigated whether the mutation in rats had consequences on ICC populations in the stomach, small intestine, and colon and whether loss of ICC resulted in functional defects similar to mutations in mice. Immunohistochemical labeling with c-KIT or ANO1 antibodies revealed loss of intramuscular ICC (ICC-IM) and reduced myenteric ICC (ICC-MY) in the stomachs of mutants. Disruption of ICC-MY networks but not ICC within the deep muscular plexus (ICC-DMP) was observed in the small intestine. ICC in the proximal colon was reduced, but no population was absent. ICC loss in the stomach caused loss of spontaneous transient depolarizations, reduced pacemaker activity, and reduced responses to cholinergic and nitrergic nerve stimulation. Loss of ICC-MY in the small intestine resulted in abnormal pacemaker activity, but neural responses appeared to be normal. In the proximal colon, tonic inhibition due to ongoing nitrergic neural inputs was reduced, spontaneous spike complexes were less rhythmic, and nitrergic neural responses were reduced. Apamin-sensitive inhibitory neural responses were retained throughout the GI tract. In summary, rats have lesions in ICC and functional deficits similar to, but not identical to, mutant mice. These larger animals with more robust GI muscles may be useful for investigations into the role of ICC in normal and abnormal GI motility. The physiological roles of interstitial cells of Cajal (ICC) throughout the gastrointestinal (GI) tract have been derived predominantly from studies of mice. We sought to determine whether reduction in ICC in the rat, a commonly used animal for studies of GI motor functions, leads to functional deficits. rats display reduced ICC leading to a disruption in pacemaker activity and neuroeffector responses. Our results provide additional evidence for the functions of ICC in the GI tract.
Spontaneous ileitis and postsurgical murine models of enteric hyperoxaluria.
Jaber K, Zaidan N, Ho M … +7 more , Xiong X, Mishra R, Nair A, Mishra A, Chu Y, Mokadem M, Nazzal L
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40235154 · Full text
Enteric hyperoxaluria, a risk factor for kidney stone disease, often arises from malabsorptive bariatric surgeries or inflammatory bowel diseases. Current murine models for studying this condition are limited, necessitat...
Enteric hyperoxaluria, a risk factor for kidney stone disease, often arises from malabsorptive bariatric surgeries or inflammatory bowel diseases. Current murine models for studying this condition are limited, necessitating new approaches. This study aims to establish two novel and distinct mouse models to investigate enteric hyperoxaluria: one simulating Roux-en-Y gastric bypass surgery and the other Crohn's ileitis. In the first model, diet-induced obese C57BL/6J male mice underwent either sham or bypass surgery, followed by 3 wk on a high-fat, oxalate-enriched diet. In the second model, SAMP1/YitFc and AKR mice were gradually introduced to high-fat diets, later supplemented with oxalate while reducing fat content. Samples of urine, blood, and feces were collected to assess oxalate, creatinine, and fecal lipid profiles. Results showed hyperoxaluria and increased stool fat content, indicating fat malabsorption, in both SAMP1 and bypass mice compared with controls. Kidney injury was also observed. These findings confirm the successful establishment of enteric hyperoxaluria in both models, highlighting the role of dietary oxalate, intestinal inflammation, and fat malabsorption in disease progression. These models provide valuable tools for exploring cellular and molecular mechanisms in enteric hyperoxaluria and may inform future therapeutic strategies. This study is among the first to establish an enteric hyperoxaluria (EH) phenotype in two different and novel mouse models secondary to Roux-en-Y gastric bypass and ileitis. It also elucidates key factors affecting EH using the SAMP1 mice, revealing the significant roles of GI tract inflammation, fat malabsorption, and dietary fat in developing hyperoxaluria.
Dimethyl fumarate attenuates bile acid retention and liver fibrosis in a mouse model of cholestasis.
Lastuvkova H, Dohnalkova E, Manna DF … +15 more , Cermanova J, Mokry J, Pejchal J, Hirsova P, Nachtigal P, Pavkova I, Bajnokova M, Smutna L, Stefela A, Kamaraj R, Jandova L, Uher M, Pavek P, Micuda S, Hroch M
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40210415 · Publisher ↗
Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved anti-inflammatory drug that d...
Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved anti-inflammatory drug that demonstrated protective effects in several experimental models of liver injury. Still, its effect on BA homeostasis and liver fibrosis has not been thoroughly studied. Herein, we hypothesized that DMF could improve BA homeostasis and mitigate the progression of cholestasis-induced liver fibrosis. The DMF was administered to mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholestasis for 4 wk. The content of individual BAs in the plasma, liver, bile, intestine, and feces was measured using the LC-MS method alongside the analysis of liver phenotype and related executive and regulatory pathways. The DMF slowed down the progression of DDC-induced liver fibrosis by suppressing hepatic stellate cell and macrophage activation and by reducing c-Jun N-terminal kinase phosphorylation. Notably, DMF reduced BA cumulation in the plasma and liver of cholestatic mice by increasing BA fecal excretion via their reduced phyla-mediated deconjugation in the intestine. In addition, DMF was identified as the antagonist of the mouse farnesoid X receptor in enterocytes. In conclusion, DMF alleviates DDC-induced cholestatic liver injury through pleiotropic action leading to significant anti-inflammatory and antifibrotic activity of the agent. In addition, DMF mitigates BA retention in the liver and plasma by increasing their fecal excretion in cholestatic mice. These findings suggest that DMF warrants further investigation as a potential therapeutic agent for human chronic fibrosing cholestatic liver disorders. Chronic cholestatic cholangiopathies present a therapeutic challenge due to their complex pathophysiology, where the accumulation of bile acids plays a crucial role. In this study, we found that dimethyl fumarate attenuated cholestatic liver damage in a murine model through its significant anti-inflammatory and antifibrotic activity supported by reduced bile acid accumulation in the plasma and liver via their increased fecal excretion.
Corrigendum for Öhnstedt et al., volume 327, 2024, p. G140-G153.
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 40202492 · Publisher ↗
Abstract loading — click title to view on PubMed.
Dynamic functional luminal imaging probe analysis of the anal sphincter opening function during straining in healthy volunteers.
Desprez C, Leroi AM, Gourcerol G … +2 more , Zifan A, Duflot T
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40197109 · Publisher ↗
The objective of the present study was to introduce a novel method of assessing anal canal opening in healthy volunteers (HV) using the EndoFLIP system. By analyzing dynamic loops during push maneuvers, the study aimed t...
The objective of the present study was to introduce a novel method of assessing anal canal opening in healthy volunteers (HV) using the EndoFLIP system. By analyzing dynamic loops during push maneuvers, the study aimed to identify the most reliable markers of anal canal opening function during this maneuver. Forty HV women were recruited and underwent anal canal assessments with the EndoFLIP system, both at rest and during push maneuvers. Cross-sectional area (CSA)-pressure loops were constructed for each HV at distension volumes of 40 mL and 50 mL. Key parameters (pressure and CSA) derived from these loops were identified as potential markers of anal function to reduce dimensionality. Anal opening function during push maneuver was quantified in both percentage (relative variation) and absolute (absolute variation) values for pressure and CSA. The direction of the CSA-pressure loops during the push maneuver at 40 mL and 50 mL of distension was upward and to the right, indicating an increase in both pressure and CSA during straining. None of the demographic data were significant predictors of any characteristics of the CSA-pressure loops at 40 mL and 50 mL of distension. The mean relative variation in pressure and CSA at 50 mL of distension and, to a lesser extent, the maximal relative variation pressure and CSA, were identified as markers with the lowest variability. This pilot study points to potential markers for assessing anal opening function during push maneuvers. Further confirmatory studies are necessary to establish the clinical utility of these markers. In the present study, we generated a bioinformatics pipeline for analyzing anal EndoFLIP data in healthy volunteers using automated data reprocessing to identify potential markers of anal opening function during the push maneuver. Mean relative variations in pressure and CSA at 50 mL of distension were identified as the most indicative parameters. Given that this was a pilot study, our findings warrant further confirmatory research to establish the clinical relevance of these markers.
Optogenetic activation of the gut-brain axis in freely moving mice using a fully implantable wireless battery-free device.
Hibberd TJ, Efimov A, Wang Y … +13 more , Wu M, Travis L, Ting K, Lee MK, Kim J, Kang J, Riahi M, Kyloh M, Zagorodnyuk V, Hu H, Rogers JA, Spencer NJ, Vázquez-Guardado A
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40193274 · Publisher ↗
Considerable evidence suggests that the gut-brain axis can influence behavior. However, there has been a conspicuous lack of technology to provide targeted wireless activation of the gut-brain axis in conscious freely mo...
Considerable evidence suggests that the gut-brain axis can influence behavior. However, there has been a conspicuous lack of technology to provide targeted wireless activation of the gut-brain axis in conscious freely moving animals. We utilized a miniature fully implantable battery-free device to apply highly controlled optogenetic stimuli to the terminal region of gastrointestinal tract, in conscious freely moving mice. The optical stimulator was implanted and secured on the serosal surface of the distal colon and rectum to characterize the behavioral responses evoked by optogenetic stimulation of axons expressing channelrhodopsin (ChR2) driven by the Trpv1 promoter (Trpv1ChR2 mice). In freely moving Trpv1ChR2 mice, trains of blue light pulses to the distal colon and rectum induced increased abdominal grooming and reduced movement. In contrast to stimulation of the gut, trains of stimuli applied to the peritoneal cavity evoked writhing and abdominal contraction. Anterograde labeling from nodose ganglia revealed sparse vagal afferent axons and endings in the proximal and mid colon, with no labeled axons caudal of the mid colon (within 30 mm of the anus). The distal colon and rectum were densely innervated by spinal afferents. The findings demonstrate that wireless optogenetic stimulation of the gut-brain axis can induce specific behavioral patterns in conscious freely moving rodents, using fully implantable battery-free technology. The findings demonstrate that distinct behavioral changes can be induced by wireless activation of the terminal region of the large intestine (distal colon and rectum) in freely moving rodents, using fully implantable battery-free devices.
Ion transport and epithelial barrier dysfunction in experimental models of ulcerative colitis.
Sandle GI, Rajendran VM
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40184259 · Full text
The global prevalence of ulcerative colitis (UC) and Crohn's disease (CD) is increasing, placing greater burdens on national health systems. The pathophysiology of diarrhea, the commonest debilitating symptom in patients...
The global prevalence of ulcerative colitis (UC) and Crohn's disease (CD) is increasing, placing greater burdens on national health systems. The pathophysiology of diarrhea, the commonest debilitating symptom in patients with UC and CD, has been studied more extensively in UC, where it reflects defective colonic Na absorption combined with changes in colonic Cl and K transport, which significantly reduce colonic water absorption. Dysfunctional ion transport in patients with UC is accompanied by abnormalities in tight junctional protein distribution and function, which cause the inflamed colonic epithelium to become "leakier." Progress in understanding how abnormal colonic ion transport in UC might be influenced pharmacologically has been hampered by the low availability of clinical material. To counter this, various animal models of acute colitis have been developed, but differ in the way mucosal inflammation is induced. Identifying models that closely mimic human UC in terms of pathology and ion transport abnormalities remains challenging. However, the introduction of human colonic epithelial organoids (colonoids) has added a new and exciting dimension to research in this area. Here, we review current knowledge about abnormal colonic ion transport and barrier function in experimental and human colitis as well as the use and potential of human colonoids to better understand the pathophysiology of UC, which may ultimately lead to novel approaches to the treatment of diarrhea in this disease.
Metabolic balance of human livers during long-term normothermic machine perfusion.
Lascaris B, Woltjes LC, Bodewes SB … +3 more , Porte RJ, de Meijer VE, Nijsten MWN
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40179046 · Publisher ↗
Normothermic machine perfusion (NMP) is used to preserve and assess the viability of (extended criteria) high-risk donor livers. Long-term NMP (LT-NMP; ≥24 h) is emerging as a method to improve or repair livers initially...
Normothermic machine perfusion (NMP) is used to preserve and assess the viability of (extended criteria) high-risk donor livers. Long-term NMP (LT-NMP; ≥24 h) is emerging as a method to improve or repair livers initially deemed unsuitable for transplantation. This study investigated metabolism during LT-NMP, focusing on hepatic energy consumption and nitrogen and electrolyte balances to better understand long-term perfusion requirements. In this study, we measured oxygen consumption (V̇o) and carbon dioxide production (V̇co) to determine the energy expenditure of 14 human livers during LT-NMP for 7 days. In addition, hepatic balances of glucose and lactate as well as of nitrogen and electrolytes were determined. Initial high metabolic rates during the first day of LT-NMP decreased and stabilized at nearly 50% on , suggesting a quiescent state until . Most energy was derived from glucose (75%-88%). Continuous amino acid supplementation was essential to maintain an anabolic state, whereas livers without supplementation became catabolic. Although net electrolyte balances were close to zero, significant uptake and release of electrolytes occurred throughout LT-NMP. During LT-NMP, livers reached a metabolically quiescent state after 3 days with decreased energy consumption. Tailoring perfusate composition and supplementation protocols to the specific needs of the liver could enhance organ preservation and potentially expand the pool of viable donor livers after LT-NMP. A long-term normothermic machine perfusion platform is being developed for repairing and regenerating damaged livers to make them suitable for transplantation. The energy expenditure and the metabolic needs of 14 human donor livers were observed during NMP for up to a week. We noticed that livers become metabolically quiescent after 3 days and that a change in our nutrimental support protocol might be necessary to provide a better environment for the livers during NMP.
Deletion of H-ferritin in macrophages mitigates the development of steatohepatitis and hepatocellular carcinoma in mice.
Ikeda Y, Funamoto M, Itami H … +4 more , Yamamoto M, Ly-Nguyen HD, Imanishi M, Tsuchiya K
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40179009 · Publisher ↗
Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern. Approximately one quarter of patients have nonalcoholic steatohepatitis (NASH), which leads to the development of hepatocellular carcinoma....
Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern. Approximately one quarter of patients have nonalcoholic steatohepatitis (NASH), which leads to the development of hepatocellular carcinoma. Several studies have shown the involvement of iron in NASH, but it remains unclear which cell of iron is at issue. This study aims to explore the role of iron in macrophages in NASH development. Conditional macrophage-specific H-ferritin knockout (LysM-Cre KO) mice were divided into four groups: wild-type (WT) and LysM-Cre KO mice fed a normal diet, and WT and LysM-Cre KO mice with NASH model induced by diet and chemical. Histological analysis revealed that the NAFLD activity score and hepatic fibrosis were alleviated in the livers of LysM-Cre KO mice with NASH compared with WT mice with NASH. The expression and signaling of inflammatory cytokines and fibrosis-related genes were increased in the livers of WT mice with NASH, but not elevated in the livers of LysM-Cre KO mice with NASH. Similarly, macrophage infiltration and oxidative stress were augmented in the livers of WT mice with NASH but were inhibited in the livers of LysM-Cre KO mice with NASH. In addition, hepatocellular carcinoma development was observed in 90% of WT mice and 62% of LysM-Cre KO mice 30 wk after NASH induction, with tumor number and size being lower in LysM-Cre KO mice. Deletion of macrophage H-ferritin alleviated NASH development by reducing inflammation, fibrosis, and oxidative stress. The findings of this study highlight macrophage iron levels as a potential therapeutic target in NASH. NASH is a type of NAFLD with severe damage such as inflammation and fibrosis, which causes hepatocellular carcinoma. This study explores macrophage-specific iron involvement in NASH using LysM-Cre KO mice. Results show that knocking out H-ferritin in macrophages reduces NASH-related inflammation, fibrosis, and oxidative stress compared with wild-type mice. Tumor occurrence was lower in LysM-Cre KO mice. These findings suggest that macrophage iron modulation may be a therapeutic target for NASH treatment.
Effects of potassium on laryngeal-induced swallowing rate in rats.
Kawada S, Chotirungsan T, Pan CR … +5 more , Tsutsui Y, Okamoto K, Magara J, Tsujimura T, Inoue M
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40178944 · Publisher ↗
The swallowing reflex can be induced by peripheral stimulation of the larynx. Although previous studies have suggested that potassium ions exert facilitatory effects on the initiation of swallowing, little information is...
The swallowing reflex can be induced by peripheral stimulation of the larynx. Although previous studies have suggested that potassium ions exert facilitatory effects on the initiation of swallowing, little information is available on the mechanism underlying the potassium ion-evoked swallowing reflex. In this study, we evaluated the effects of potassium ions on peripheral afferent responses and the initiation of swallowing in conscious and anesthetized rats. Furthermore, the possible receptors involved were explored. The topical application of potassium chloride (KCl) significantly facilitated the swallowing reflex; these facilitatory effects were more prominent than those of distilled water (DW) or sodium chloride (NaCl). This phenomenon depended not on the concentrations of anions but on those of potassium ions. The potassium ion-induced response in the superior laryngeal nerve was most prominent after treatment with KCl, especially at the early stage. In chronic rats, without differences in licking behavior between DW, NaCl, and KCl, the intervals between swallows were the smallest during KCl-associated licking. Inward rectifier potassium channel (Kir)3.1- and Kir6.2-positive cells were detected in the nodose ganglion and vocal folds. The rate of expression of these molecules in immunoreactive cells was relatively high at 74.1% for Kir3.1 and 75.3% for Kir6.2. Kir3.1 and Kir6.2 blockers significantly decreased the number of KCl-induced swallows. Possible mechanisms underlying potassium ion-induced swallowing are discussed. Our findings suggest that Kir3.1 and Kir6.2 are involved in K ion-induced swallowing in rats. Potassium ion-containing solutions readily induce responses in the superior laryngeal nerve and swallowing reflexes, particularly at an early stage. Inward rectifier potassium channel (Kir)3.1 and Kir6.2 channel-positive cells were detected in the nodose ganglion and vocal folds. Kir3.1 and Kir6.2 blockers significantly decreased the number of KCl-induced swallows. Kir3.1 and Kir6.2 are involved in potassium ion-induced swallowing in rats.
The effect of corticotropin-release hormone on duodenal permeability and immune activation in healthy volunteers in a double-blind placebo-controlled study.
Schol J, Huang IH, Balsiger L … +7 more , Tóth J, Van den Houte K, Verheyden A, Raymenants K, Broeders B, Vanuytsel T, Tack J
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40167262 · Publisher ↗
In functional dyspepsia, increased gut permeability, low-grade inflammation, and altered sensorimotor function have been reported. Both stress and corticotropin-release hormone (CRH) have been shown to increase small bow...
In functional dyspepsia, increased gut permeability, low-grade inflammation, and altered sensorimotor function have been reported. Both stress and corticotropin-release hormone (CRH) have been shown to increase small bowel permeability in a mast-cell-dependent manner. Moreover, eosinophil-derived CRH has been implicated in mast cell activation. The aim of this study was to evaluate whether CRH administration alters duodenal permeability and immune activation in healthy volunteers (HVs). An intravenous bolus of 100-µg CRH or placebo was administered in HVs in a crossover, double-blind, randomized manner. Two hours later, a gastroscopy was performed to measure permeability in Ussing chambers and to count mast cells and eosinophils on duodenal biopsies. Supernatant was assessed for eosinophil-derived neurotoxin (EDN), tryptase, and chymase. In addition, CRH was administrated ex vivo to baseline biopsies pretreated with or without lodoxamide. Results are described as means ± SD. values < 0.05 were considered significant. Twenty HVs completed the study. Mast cell or eosinophil counts were not significantly altered after CRH versus Placebo (respectively = 0.31 and = 0.069). Tryptase, but not chymase, significantly decreased after CRH (respectively = 0.037 and = 0.44) with a trend for a decrease in EDN ( = 0.053). Permeability was unaltered comparing both conditions. Ex vivo, transepithelial electrical resistance significantly decreased after CRH exposure compared with baseline ( = 0.010), which was not prevented by pretreatment with lodoxamide. In vivo CRH administration reduced tryptase levels in the supernatant of duodenal biopsies without affecting permeability, whereas ex vivo duodenal permeability increased regardless of mast cell stabilization. These results suggest the involvement of mast cells in regulating gut permeability in HVs in response to CRH, possibly influenced by in vivo compensatory mechanisms. Our investigation breaks new ground by directly examining the effects of corticotropin-release hormone (CRH) on duodenal alterations, including permeability and immune activation, in healthy subjects. Intriguingly, our findings highlight disparities between ex vivo and in vivo pathways affecting duodenal permeability, offering novel insights into the potential pathophysiology of CRH on the duodenum.
Hope for the gut: new evidence suggests Western diet damage can be undone.
Bhagavatula G, Cartwright IM
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40139253 · Full text
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Hypobaric hypoxia exposure impairs colonic goblet cell subpopulation via the HIF-1α signaling pathway.
Zhang S, Jiang X, Zhang W … +8 more , Meng F, Gao J, Cheng X, Hu Y, Liu J, Zhao T, Zhu L, Wang G
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40132123 · Publisher ↗
Exposure to hypobaric hypoxia during rapid ascent to high altitudes significantly impacts intestinal barrier function. Goblet cells, as one of the primary cell types in the intestinal mucosa, play a crucial role in maint...
Exposure to hypobaric hypoxia during rapid ascent to high altitudes significantly impacts intestinal barrier function. Goblet cells, as one of the primary cell types in the intestinal mucosa, play a crucial role in maintaining this barrier. However, the effects of hypobaric hypoxia on goblet cell function and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of hypobaric hypoxia exposure (simulating an altitude of 6,000 m) and studied its effects on colonic goblet cells by transcriptomic analysis. In addition, the hypoxia-treated (1% O) goblet cell line Ls174t was used to investigate potential mechanisms underlying hypoxia-induced changes in goblet cells. In the present study, we discovered that hypobaric hypoxia exposure not only reduced the number of colonic goblet cells in mice by 27.6% but also impaired their mucus secretion. Transcriptome sequencing analysis of sorted goblet cells from the mice colon revealed significant changes in gene expression profiles, particularly in the expression of canonical goblet cell markers such as calcium-activated chloride channel regulator 1 () and Fcγ-binding protein (). We confirmed the effects of hypobaric hypoxia/hypoxia exposure on CLCA1 and FCGBP expression at both mRNA and protein levels in mouse colonic tissues and in Ls174t cells. The expression of these canonical goblet cell marker genes was dependent upon hypoxia-inducible factor-1α (HIF-1α) activity; their expression decreased upon hypoxia-induced activation of HIF-1α and increased when HIF-1α was knocked down using siRNA. Thus, hypobaric hypoxia exposure regulates the distribution and function of colonic goblet cell subsets through the HIF-1α signaling pathway. We investigated the role of hypoxia-inducible factor-1α (HIF-1α) in colonic goblet cell injury under hypobaric hypoxia exposure. Our results indicate that the elevation of HIF-1α caused by hypobaric hypoxia exposure can significantly reduce canonical goblet cells and disrupt intestinal mucosal barrier function. It provides a potential intervention strategy for restoring goblet cell function under hypobaric hypoxic conditions.
subspecies targets M cells in enteroid-derived monolayers through interactions with β1 integrins.
Baruta G, Flannigan KL, Alston L … +5 more , Thorne A, Zhang H, De Buck J, Colarusso P, Hirota SA
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40112014 · Publisher ↗
Paratuberculosis is an infectious disease caused by the bacterium, subspecies (MAP). MAP infection of ruminants triggers progressive wasting disease characterized by granulomatous lymphadenitis, enteritis, and severe i...
Paratuberculosis is an infectious disease caused by the bacterium, subspecies (MAP). MAP infection of ruminants triggers progressive wasting disease characterized by granulomatous lymphadenitis, enteritis, and severe intestinal pathology that often requires early culling of the animal. The resulting economic burden is significant, and MAP exposure in the workplace constitutes a significant zoonotic risk. Although it has been established that the MAP propagates within resident immune cells, less is known about how it traverses the epithelium. It is currently thought that MAP infects the small intestinal epithelium by targeting both enterocytes and M cells, with a potential tropism for the latter. In the current study, we developed and validated an enteroid-based in vitro assay containing functional M cells to identify the target cells for MAP's entry. Upon exposure to MAP, the bacteria were detected within both enterocytes and M cells; however, quantitative image analysis revealed significant tropism for the latter. Complementary studies using the Caco-2/Raji-B coculture system provided similar results. Since other mycobacteria have been shown to initiate cell attachment and entry by using a fibronectin-bridging process, we tested whether these interactions were involved in MAP's targeting of M cells. We found that MAP's M cell tropism was enhanced by fibronectin and that this effect was abolished when monolayers were pretreated with an integrin-blocking peptide. Our data demonstrate that MAP preferentially targets M cells and that this involves a fibronectin-bridging process. Furthermore, our study supports the utility of M cell-containing enteroids to study host-pathogen interaction at the intestinal epithelium. We developed and validated a novel enteroid-based in vitro infection model with functional M cells and incorporated leading-edge imaging approaches to determine how MAP interacts with the intestinal epithelium. Using this model, we found that MAP preferentially enters M cells and that this process is enhanced by fibronectin opsonization and interactions with M cell-associated b1 integrins-the so-called fibronectin bridging mechanism that is used by other Mycobacterium to mediate cell attachment and entry.
Unique properties of proximal and distal colon reflect distinct motor functions.
Morales-Soto W, Smith-Edwards KM
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 40095602 · Full text
The gastrointestinal tract is made up of specialized organs that work in tandem to facilitate digestion. The colon regulates the final steps in this process where complex motor patterns in proximal regions facilitate the...
The gastrointestinal tract is made up of specialized organs that work in tandem to facilitate digestion. The colon regulates the final steps in this process where complex motor patterns in proximal regions facilitate the formation of fecal pellets that are propelled along the distal colon via self-sustaining neural peristalsis and temporarily stored before defecation. Historically, our understanding of colonic motility has focused primarily on distal regions, and the intrinsic reflex circuits of the enteric nervous system involved in neural peristalsis have been defined, but we do not yet have a clear grasp on the mechanisms orchestrating motor function in proximal regions. New approaches have brought to the forefront the unique structural, neurochemical, and functional characteristics that exist in distinct regions of the mouse and human colon. In this mini-review, we highlight key differences along the proximal-distal colonic axis and discuss how these differences relate to region-specific motor function.
Key mechanisms in alcohol-associated liver disease: hepatic ADH deficiency, dysregulated hepatic lipid metabolism, and nonoxidative ethanol metabolites.
Park SH, Seo W
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 40063038 · Publisher ↗
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Cinnabarinic acid protects against metabolic dysfunction-associated steatohepatitis by activating aryl hydrocarbon receptor-dependent AMPK signaling.
Patil NY, Rus I, Ampadu F … +8 more , Abu Shukair HM, Bonvicino S, Brush RS, Eaton E, Agbaga MP, Oh TG, Friedman JE, Joshi AD
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 40062565 · Full text
Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by the accumulation of fats in the liver, chronic inflammation...
Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by the accumulation of fats in the liver, chronic inflammation, hepatocytic ballooning, and fibrosis. This study investigates the significance of hepatic aryl hydrocarbon receptor (AhR) signaling in cinnabarinic acid (CA)-mediated protection against MASH. Here, we report that livers of high-fat, high-fructose, high-cholesterol diet-fed hepatocyte-specific aryl hydrocarbon receptor knockout mice (AhR-hKO) exhibited aggravated steatosis, inflammation, and fibrosis compared with control AhR-floxed livers. Moreover, treatment with a tryptophan catabolite, CA, reduced body weight gain and significantly attenuated hepatic steatosis, inflammation, ballooning, fibrosis, and liver injury only in AhR-floxed but not in AhR-hKO mice, strongly indicating that the CA-mediated protection against steatohepatitis is AhR-dependent. Furthermore, protection against lipotoxicity by CA-activated AhR signaling was confirmed by utilizing an in vitro human hepatocyte model of MASLD. Mechanistically, CA-induced AhR-dependent signaling augmented AMP-activated protein kinase (AMPK), leading to the upregulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1α) and attenuation of sterol regulatory element-binding protein-1 (SREBP1) to regulate hepatic lipid metabolism. Collectively, our findings indicate that CA-mediated protection against MASH is dependent on hepatic AhR signaling, and selective endogenous AhR agonists that regulate lipogenesis can serve as promising future therapeutics against MASLD. The study showed that the absence of AhR in hepatocytes results in exacerbated metabolic dysfunction-associated steatohepatitis (MASH) in mice subjected to a Western-style high-fat, high-fructose, high-cholesterol diet. Moreover, treatment with a tryptophan catabolite, cinnabarinic acid (CA), mitigated hallmarks of MASH in an AhR-dependent manner. In conclusion, the study delineates the significance of hepatic AhR-dependent AMPK signaling in CA-mediated protection against MASH.
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