American Journal Of Physiology. Gastrointestinal And Liver Physiology[JOURNAL]
Sun
200 papers
Investigating intestinal farnesoid X receptor functions at the intestinal mucosal barrier and in the intestinal microbiota in a biliary obstruction mouse model.
Cai Y, Chen X, Wang H … +5 more , Hou L, Zheng R, Wang Y, Jiang W, Tang W
Am J Physiol Gastrointest Liver Physiol · 2025 Aug · PMID 40623002 · Publisher ↗
Intestinal barrier dysfunction and dysbiosis are critical intestinal alterations in biliary obstructive diseases, for which farnesoid X receptor (FXR) is a potential intestinal therapeutic target, but its role and mechan...
Intestinal barrier dysfunction and dysbiosis are critical intestinal alterations in biliary obstructive diseases, for which farnesoid X receptor (FXR) is a potential intestinal therapeutic target, but its role and mechanism in the intestinal tract remain poorly defined. Using gut-specific knockout mice, we demonstrate that intestinal deficiency caused intestinal barrier function impairment and dysbiosis, and in a biliary obstruction model, obeticholic acid (OCA)-dependent intestinal activation protected against intestinal barrier injury and dysbiosis after bile duct ligation (BDL) surgery. Furthermore, from single-cell sequencing data, may directly regulate regenerating islet-derived protein 3γ () to influence intestinal functions. In conclusion, we elucidated FXR actions in the intestine under physiological and biliary obstruction conditions and suggest possible molecular targets that provide new insights for the intestinal treatment of biliary obstructive diseases. Intestinal barrier dysfunction and dysbiosis are critical in biliary obstructive diseases, making farnesoid X receptor (FXR) a potential therapeutic target. Our study shows that deficiency impairs barrier function and causes dysbiosis. In a biliary obstruction model, obeticholic acid (OCA) activation of protects against these effects. In addition, single-cell sequencing suggests that may regulate , influencing intestinal functions. This research reveals the role of FXR and offers new molecular targets for the treatment of biliary obstructive diseases.
Glia maturation factor-β in hepatocytes enhances liver regeneration and mitigates steatosis and ballooning in zebrafish.
Li HY, Zeng WL, Ye YW … +7 more , Chen X, Zhang MM, Chen YS, Liu CT, Zhong ZQ, Li J, Wang Y
Am J Physiol Gastrointest Liver Physiol · 2025 Aug · PMID 40602783 · Publisher ↗
Glia maturation factor-β (Gmfb), an actin filament debrancher, was initially identified in brain and recently linked to liver diseases. To investigate the role of hepatocyte Gmfb (hep-Gmfb) in liver reparative regenerati...
Glia maturation factor-β (Gmfb), an actin filament debrancher, was initially identified in brain and recently linked to liver diseases. To investigate the role of hepatocyte Gmfb (hep-Gmfb) in liver reparative regeneration, hepatocyte-specific knockout (HepGKO) and overexpression (HepGOE) zebrafish strains were constructed. Both transgenic and wild-type (WT) zebrafish underwent partial hepatectomy (PHX) or were fed high-fat, high-cholesterol diets to model metabolism-associated steatotic liver disease (MASLD). Under physiological conditions, the HepGKO, HepGOE, and WT fish displayed similar survival, gross appearance, and liver histology. Following PHX, WT liver gmfb levels positively correlated with cell proliferation and proinflammatory cytokine levels. HepGOE showed enhanced regeneration and reduced liver steatosis compared with WT, whereas HepGKO exhibited opposite effects. In MASLD, WT liver gmfb increased with disease progression. HepGKO experienced worsening liver enlargement, steatosis, ballooning, inflammation, and endoplasmic reticulum stress, whereas HepGOE showed improvements. HepGOE liver had the highest cell proliferation, but all three groups showed similar levels of cell apoptosis. Moreover, elevated proinflammatory cytokines were observed across MASLD groups, being the highest in HepGKO and lowest in HepGOE. However, signal transducer and activator of transcription 3 (stat3) activation was the lowest in HepGKO and highest in HepGOE, whereas jnk and mapk/extracellularly regulated kinase (erk) activation was consistent across the MASLD groups. In il6-treated primary hepatocytes, gmfb abundance influenced stat3 activation, and hep-gmfb abundance significantly affected actin filaments distribution in hepatocytes both in vivo and vitro. Hep-Gmfb boosts regenerative processes by enhancing hepatocyte proliferation, alleviating fatty liver histological abnormalities, and modulating the Il6/Stat3 signaling, potentially through remodeling of actin-filament network within hepatocytes. Glia maturation factor-β (Gmfb) has shown important implications in liver disease. Using transgenic zebrafish models, our research demonstrates that Gmfb in hepatocytes confers protective benefits for liver regeneration and repair. It promotes hepatocyte proliferation, alleviates steatosis and ballooning, and modulates Il6/Stat3 signaling in response to liver injuries, potentially through remodeling of actin-filament network. This submission represents the first in vivo observation of the phenotypic effects of Gmfb in hepatocytes during liver injury.
Adolescent binge drinking disrupts hepatic lipid homeostasis, leading to steatosis in rats: protective role of folic acid in cholesterol and fatty acid balance.
Gallego-López MDC, Nogales F, Romero-Herrera I … +3 more , Santana-Garrido Á, Carreras O, Ojeda ML
Am J Physiol Gastrointest Liver Physiol · 2025 Aug · PMID 40601868 · Publisher ↗
Alcohol liver damage (ALD) is increasing worldwide among adolescents, along with binge drinking (BD). BD is an acute alcohol consumption pattern, strongly pro-oxidant in the liver, and may be associated with steatosis, t...
Alcohol liver damage (ALD) is increasing worldwide among adolescents, along with binge drinking (BD). BD is an acute alcohol consumption pattern, strongly pro-oxidant in the liver, and may be associated with steatosis, the first step in ALD. Folic acid (FA), an antioxidant crucial for liver function, shows compromised hepatic stores after BD. Therefore, this study aims to analyze the hepatic lipid changes associated with BD-induced steatosis during adolescence in rats and to evaluate the efficacy of FA supplementation in preventing these alterations. Four groups of adolescent rats were used: control, BD (intraperitoneal alcohol exposure), control FA-supplemented, and BD-FA-supplemented. FA content was 2 ppm in control diets and 8 ppm in supplemented groups. BD impaired liver function by increasing transaminases and UGT-1 expression. BD also induced dyslipidemia and an anabolic liver lipid state by increasing hepatic cholesteryl esters depots through dysregulation of cholesterol modulators (HMGCR, SREBP1, LDLR, SR-B1, ACAT-2, and Ces1d) and enhancing FXR expression, which affected liver bile acid balance. Furthermore, BD promoted all sources of hepatic free fatty acids (de novo synthesis, dietary source, and adipose tissue uptake) and impaired their hepatic clearance, contributing to steatosis as confirmed by microvesicular lipid droplet accumulation. FA supplementation, mainly by improving hepatic cholesterol balance and stimulating free fatty acid mobilization, partially prevented these alterations, with beneficial effects on cardiovascular health. In conclusion, this study demonstrates for the first time that BD in adolescents disturbs hepatic lipid homeostasis, leading to steatosis, and that FA therapy could be used to mitigate these deleterious effects. Binge drinking (BD) in adolescent rats disrupts hepatic lipid homeostasis, inducing dyslipidemia and cholesteryl ester accumulation. BD alters hepatic cholesterol metabolism and bile acid homeostasis. In addition, it promotes free fatty acid (FFA) accumulation and steatosis. Folic acid supplementation improves cholesterol balance and enhances FFA mobilization, offering a protective role against BD-induced liver damage.
Integrating anorectal manometry, balloon expulsion, and defecography: insights into diagnosing pelvic floor dysfunction.
Zoabi N, Zelikovich D, Kanani F … +3 more , Ram E, Issa A, Carter D
Am J Physiol Gastrointest Liver Physiol · 2025 Aug · PMID 40569575 · Publisher ↗
Defecatory dysfunction (DD) is a common cause of chronic constipation resulting from functional abnormalities or structural pelvic pathologies. Accurate diagnosis requires combining anorectal manometry (ARM), balloon exp...
Defecatory dysfunction (DD) is a common cause of chronic constipation resulting from functional abnormalities or structural pelvic pathologies. Accurate diagnosis requires combining anorectal manometry (ARM), balloon expulsion test (BET), and defecography. This study evaluates the diagnostic utility of these modalities and explores uncertainties in their performance and interpretation. This retrospective study included 325 adult patients assessed for DD between 2020 and 2023. All patients went through ARM, BET in the left lateral position, and defecography. Statistical associations between test outcomes were analyzed to assess diagnostic concordance and significance. A strong correlation was observed between ARM and defecography, with 65% of patients with normal anal relaxation on ARM achieving normal rectal evacuation on defecography ( < 0.0001). Conversely, patients with paradoxical contraction during ARM demonstrated a higher likelihood of evacuation failure. BET demonstrated high specificity but limited sensitivity in association with relaxation on ARM and evacuation on defecography. BET failure did not demonstrate a significant association with the presence of pelvic floor pathologies. Combining ARM, BET, and defecography provides a comprehensive framework for diagnosing DD, addressing its functional and structural components. This integrated approach facilitates targeted interventions, ultimately improving clinical outcomes. This study demonstrates that anal relaxation on anorectal manometry significantly correlates with rectal evacuation on defecography, supporting its physiological relevance. Balloon expulsion in the left lateral position shows high specificity but low sensitivity for defecatory dysfunction. Notably, balloon expulsion test (BET) failure was not associated with anatomical abnormalities. An integrated diagnostic approach using anorectal manometry (ARM), BET, and defecography enhances accuracy in distinguishing functional from structural causes of pelvic floor dysfunction.
Farnesoid X receptor inhibits proinflammatory cytokine-induced epithelial necroptosis in vitro: implications for preservation of intestinal barrier function.
Curley CE, Lajczak-McGinley NK, Adorini L … +2 more , Ní Chonghaile T, Keely SJ
Am J Physiol Gastrointest Liver Physiol · 2025 Aug · PMID 40569574 · Publisher ↗
Epithelial cell death and compromised barrier function are key features of inflammatory bowel disease pathogenesis. Previous studies suggest that the nuclear bile acid receptor, farnesoid X receptor (FXR), promotes intes...
Epithelial cell death and compromised barrier function are key features of inflammatory bowel disease pathogenesis. Previous studies suggest that the nuclear bile acid receptor, farnesoid X receptor (FXR), promotes intestinal barrier function and protects against inflammation. Here, we investigated potential mechanisms involved. T cell monolayers were treated with a combination of IFNγ and TNFα to model cytokine-induced barrier dysfunction in vitro. Apoptosis and necroptosis were assessed by measuring caspase 3/PARP cleavage and RIP3 phosphorylation, respectively. Epithelial permeability was determined by measuring 4-kDa fluorescein isothiocyanate-dextran (FD4) flux. Effects of FXR on barrier function in dextran sulfate sodium (DSS)-treated mice were assessed by measuring plasma levels of orally administered FD4. Treatment with IFNγ and TNFα enhanced FD4 flux and increased apoptosis in T monolayers, as evidenced by increased cleaved PARP and caspase 3 levels. Pretreatment with the FXR agonist, GW4064, significantly inhibited cytokine-induced FD4 flux, but not apoptosis. Treatment with IFNγ and TNFα in the presence of the apoptosis inhibitor, Q-VD-OPh, induced necroptosis, as evidenced by increased RIP3 phosphorylation and enhanced FD4 flux, whereas a necroptosis inhibitor, necrostatin, inhibited these effects. GW4064 also inhibited cytokine-induced RIP3 phosphorylation and FD4 flux in the presence of Q-VD-OPh. In mice, treatment with the FXR agonist, obeticholic acid, attenuated DSS-induced disease activity and mucosal FD4 flux, but not levels of cleaved caspase 3 or phospho-RIP3. FXR activation inhibits cytokine-induced barrier dysfunction by inhibiting epithelial necroptosis rather than apoptosis in vitro. How such effects contribute to the protective actions of FXR in vivo requires further elucidation. These studies demonstrate for the first time that FXR activation inhibits cytokine-induced necroptosis in vitro, an effect that may underlie protection against dysregulated barrier function in the setting of intestinal inflammation. These data support the potential for targeting FXR to promote epithelial barrier function in treatment of IBD.
Inhibition of SREBP-1c rescues hepatic CYP7B1 expression and bile acid synthesis in malnourished mice.
Wan X, Soni KG, Choi JM … +3 more , Jung SY, Conner ME, Preidis GA
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40560816 · Full text
Malnutrition decreases intestinal bile acids, resulting in inefficient nutrient absorption and impaired catch-up growth. Mechanisms by which bile acid depletion occurs in malnutrition are unknown. Using a mouse model of...
Malnutrition decreases intestinal bile acids, resulting in inefficient nutrient absorption and impaired catch-up growth. Mechanisms by which bile acid depletion occurs in malnutrition are unknown. Using a mouse model of early-life malnutrition, we explored bile acid homeostasis, focusing on transcriptional repression of oxysterol 7α-hydroxylase (CYP7B1), a rate-limiting enzyme in the alternative pathway of bile acid biosynthesis, by sterol regulatory element-binding protein-1c (SREBP-1c), a master regulator of lipid metabolism. Mice were maintained on a low-protein, low-fat, or isocaloric control chow until 8 wk of age, when livers were harvested for proteome profiling, western blot, reverse transcription quantitative real-time PCR, and chromatin immunoprecipitation. Cultured hepatocytes and mice were treated with the SREBP-1c inhibitors fatostatin and betulin to determine whether this therapeutic strategy rescues CYP7B1 expression and bile acid synthesis in malnutrition. Malnutrition decreased the bile acid pool size and altered the expression of multiple hepatic cytochrome P450 enzymes, with profound depletion of CYP7B1, in males but not females. Malnutrition activated SREBP-1c and led to its enrichment at a gene regulatory region that featured loss of binding by the basal transcriptional activator specificity protein 1 (SP1). Treatment of cultured hepatocytes or malnourished mice with the SREBP-1c inhibitors fatostatin or betulin increased CYP7B1 expression. Both drugs rescued the bile acid pool size in malnourished mice. These results suggest that malnutrition impairs bile acid synthesis via transcriptional repression of by SREBP-1c. SREBP-1c inhibitors restore hepatic CYP7B1 expression and bile acid synthesis. We applied liver proteomics to a unique mouse model of early-life malnutrition to reveal a novel mechanism of suppression of bile acid synthesis. Malnutrition activates the nuclear protein SREBP-1c, which displaces the transcriptional activator SP1 from the promoter of the gene. Two different SREBP-1c inhibitors rescue CYP7B1 expression in vitro and rescue the bile acid pool in malnourished mice. This discovery might facilitate novel adjunct therapies to enhance nutritional rehabilitation in malnourished children.
Retraction for Mancinelli et al., volume 297, 2009, G11-G26.
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40539932 · Publisher ↗
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Retraction for Marzioni et al., volume 284, 2003, G837-G852.
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40539931 · Publisher ↗
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Retraction for Gaudio et al., volume 291, 2006, G307-G317.
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40539930 · Publisher ↗
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strengthens the intestinal barrier: involvement of the endocannabinoidome.
Allam-Ndoul B, Pulido-Mateos EC, Bégin F … +10 more , St-Arnaud G, Tinoco Mar BA, Mayer T, Dumais E, Flamand N, Raymond F, Roy D, Desjardins Y, Di Marzo V, Veilleux A
Am J Physiol Gastrointest Liver Physiol · 2025 Aug · PMID 40522902 · Publisher ↗
Probiotics have been suggested to ameliorate intestinal epithelial homeostasis and barrier function. They also modulate several mediators and receptors of the expanded endocannabinoid system, or endocannabinoidome (eCBom...
Probiotics have been suggested to ameliorate intestinal epithelial homeostasis and barrier function. They also modulate several mediators and receptors of the expanded endocannabinoid system, or endocannabinoidome (eCBome), potentially explaining their beneficial effects on intestinal function. We aimed to study the effects of probiotic strains on gut barrier functions and the possible involvement of the eCBome in these effects. We cocultured three strains of with murine small intestine epithelial organoids and explored the involvement of eCBome signaling and inflammation in mediating the beneficial effects of the probiotics on the epithelial barrier function. All three strains reduced the transepithelial permeability of organoids and increased mRNA expression of several tight junction proteins (, , , , and ) and intestinal barrier proteins (, , , and ). Concomitantly, the three strains increased the expression of genes encoding eCBome receptors while decreasing the expression of two catabolic enzymes ( and ), and increasing one anabolic enzyme (). Altogether, these changes led to an overall increase in levels of eCBome mediators, namely -acyl-ethanolamines (NAEs) and, particularly, 2-monoacylglycerols (2-MAGs), as measured by LC-MS/MS. URB 597 and JZL 184, two selective inhibitors of NAE and 2-MAG catabolism, reduced the transepithelial permeability of organoids, as observed with strains. Interestingly, both inhibitors also reversed inflammation-induced transepithelial permeability in organoids. Elevated endogenous levels of NAEs or 2-MAGs promote improvement in small intestine transepithelial permeability, and strains may exploit this mechanism to exert this same beneficial effect. strains improve transepithelial permeability and concomitantly increase the levels of eCBome mediators in murine small intestine epithelial organoids. Pharmacological elevation of NAE or 2-MAG levels enhances the expression of intestinal epithelial barrier genes and reduces the transepithelial permeability of murine small intestine epithelial organoids, suggesting that may exploit eCBome signaling to exert its beneficial effects.
Polyamines regulate mitochondrial metabolism essential for intestinal epithelial renewal and wound healing.
Cairns CA, Chen T, Han N … +4 more , Chen H, Chung HK, Xiao L, Wang JY
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40471931 · Full text
Homeostasis of the mammalian intestinal epithelium is tightly regulated by multiple factors, including cellular polyamines, but the exact mechanism underlying polyamines in this process remains largely unknown. Mitochond...
Homeostasis of the mammalian intestinal epithelium is tightly regulated by multiple factors, including cellular polyamines, but the exact mechanism underlying polyamines in this process remains largely unknown. Mitochondria are the powerhouse of cells and can also function as signaling organelles by releasing metabolic by-products. Here, we determined whether polyamines regulate intestinal epithelial renewal and wound healing by altering mitochondrial activity. Depletion of cellular polyamines by inhibiting ornithine decarboxylase with α-difluoromethylornithine (DFMO) resulted in mitochondrial dysfunction as evidenced by decreases in basal and maximal respiration levels, ATP production, and spare respiration capacity. Polyamine depletion by DFMO also decreased the levels of mitochondria-associated proteins prohibitin 1 and COX-IV. Mitochondrial dysfunction induced by DFMO was associated with an inhibition of intestinal organoid growth and epithelial repair after wounding, and this inhibition was ameliorated by administration of the mitochondrial activator Mito-Tempo or exogenous polyamine putrescine. These results indicate that polyamines are necessary for mitochondrial metabolism, in turn, controlling constant intestinal mucosal growth and epithelial repair after acute injury. Our results indicate that polyamines are required for maintaining mitochondrial integrity in intestinal epithelial cells. Polyamine depletion led to mitochondrial dysfunction, along with an inhibition of intestinal epithelial renewal and delayed wound healing. Reinforcing mitochondrial activity by Mito-Tempo ameliorated reduced epithelial renewal and delayed healing in polyamine-deficient cells, demonstrating the importance of mitochondrial metabolism in polyamine-regulated mucosal growth and repair after injury.
Corrigendum for Yang et al., volume 328, 2025, p. G243-G251.
Am J Physiol Gastrointest Liver Physiol · 2025 Jun · PMID 40471095 · Publisher ↗
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Mouse models of eosinophilic esophagitis: molecular and translational insights.
Jackson JL, Staub AJ, Fuller AD … +9 more , Crespo JM, Bordner TH, Worrell C, Shanas N, Waheed D, Karakasheva TA, Ruffner M, Muir AB, Whelan KA
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40459956 · Full text
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease of the esophagus that exerts a significant clinical and financial burden in developed countries. Despite an emerging interest in this disease, the...
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease of the esophagus that exerts a significant clinical and financial burden in developed countries. Despite an emerging interest in this disease, the cellular and molecular mechanisms driving EoE pathogenesis remain elusive. Addressing this knowledge gap is critical to guide the development of novel approaches for diagnosis, monitoring, and therapy in patients with EoE. As EoE is an allergic inflammatory disorder that results in esophageal inflammation and tissue remodeling, in vivo studies are critical to develop a better understanding of this disease. Here, we provide a review of murine models of EoE, highlighting the mechanistic and translational insights into EoE pathogenesis and therapeutic approaches that studies using these models have uncovered. We further discuss the strengths and limitations of EoE mouse models, as well as opportunities for future in vivo approaches to study EoE. Overall, this article reviews the progress, challenges, unmet needs, and opportunities in murine modeling of EoE.
Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in KO mice.
Hasan MN, Wang H, Luo W … +2 more , Du Y, Li T
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40418643 · Full text
Cholestasis results from impaired bile flow that causes accumulation of hepatic bile acid and injury. Alleviating bile acid hepatobiliary toxicity is a major therapeutic goal in cholestasis. Our recent study revealed a p...
Cholestasis results from impaired bile flow that causes accumulation of hepatic bile acid and injury. Alleviating bile acid hepatobiliary toxicity is a major therapeutic goal in cholestasis. Our recent study revealed a potent anticholestasis effect of glycine-conjugated β-muricholic acid (Gly-βMCA) in knockout (KO) mice with humanized hydrophobic bile acid composition. To better understand the mechanisms and human relevance of the therapeutic benefits of Gly-βMCA, we investigated the effects of Gly-βMCA on bile acid metabolism and biliary injury in KO mice, a cholestasis model with a hydrophilic murine bile acid composition. Gly-βMCA significantly reduced serum alkaline phosphatase (ALP), ductular reaction, and liver cytokine expression in female mice but offered little benefits in male mice. Consistently, Gly-βMCA reduced hepatic bile acids and total bile acid pool size in female but not male mice, due to its ability to promote fecal bile acid excretion. However, the endogenous taurine-conjugated muricholic acid (T-MCA) limited the ability of Gly-βMCA to further enrich the bile acid pool with Gly-βMCA-derived T-βMCA to reduce bile acid hydrophobicity. Overall, Gly-βMCA showed diminished therapeutic efficacy in KO mice than KO mice, which may be due to differences in bile acid hydrophobicity and disease etiology in the two cholestasis models. These findings suggest that the benefits of Gly-βMCA are mediated by its unique pharmacokinetics, which allows for simultaneous reduction of bile acid pool size and hydrophobicity. Gly-βMCA may be a promising therapy for treating human cholestasis, despite its reduced efficacy in improving the toxicity profile of murine bile acid pool. Gly-βMCA decreases liver injury in female but not male KO mice. Gly-βMCA blocks bile acid absorption to reduce bile acid pool in female KO mice. Gly-βMCA reduces bile acid hydrophobicity by causing T-βMCA enrichment in bile, but this therapeutic benefit was partially masked by a murine bile acid composition due to abundantly synthesized T-MCA in KO mice. Gly-βMCA alleviates bile acid hepatobiliary toxicity by reducing both bile acid pool size and hydrophobicity.
-driven remodeling of arginine metabolism mitigates gut barrier dysfunction.
Antonio JM, Liu Y, Suntornsaratoon P … +12 more , Jones A, Ambat J, Bala A, Kanattu JJ, Flores J, Bandyopadhyay S, Upadhyay R, Bhupana JN, Su X, Li WV, Gao N, Ferraris RP
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40418622 · Full text
Inflammatory bowel diseases (IBDs) and gut barrier impairment are associated with changes in dietary tryptophan and arginine metabolism, but mechanisms of barrier perturbation and restoration are unclear. We show here th...
Inflammatory bowel diseases (IBDs) and gut barrier impairment are associated with changes in dietary tryptophan and arginine metabolism, but mechanisms of barrier perturbation and restoration are unclear. We show here that the widely consumed probiotic GG (LGG) enhances gut barrier functions in part through stimulating the intestinal arginine metabolic pathway, and this mechanism depends on the sufficiency of dietary tryptophan in the host. Specifically, LGG markedly upregulates argininosuccinate lyase (ASL), the enzyme that breaks down argininosuccinate into arginine. ASL expression is markedly reduced during experimental colitis with an accumulation of serum argininosuccinate. LGG colonization in mice reduces serum argininosuccinate, a metabolite that inversely correlates with tight junction gene expression, impairs barrier function, and exacerbates dextran sodium sulfate colitis. We show that LGG-derived indoles as well as arginine metabolites enhanced argininosuccinate lyase (ASL) and nitric oxide synthase (NOS2) expression, linking microbial metabolism to nitric oxide production and epithelial homeostasis. Patients with IBD have increased ASS1 and decreased ASL expression, suggesting a metabolic bottleneck driving ASA accumulation. We propose that signaling pathways underlying LGG and tryptophan-mediated ASL upregulation can be useful therapeutic targets to normalize arginine metabolism in select patients with IBD. This study identifies a novel probiotic-driven mechanism linking dietary tryptophan and host arginine metabolism. GG, in synergy with tryptophan, enhances gut barrier integrity by upregulating argininosuccinate lyase (ASL), a critical enzyme in arginine biosynthesis. Furthermore, we uncover ASL downregulation and serum argininosuccinate elevation in experimental colitis in mice, suggesting a target to guide precision probiotics.
Gut-heart axis: cardiac remodeling and heart failure in the context of inflammatory bowel disease and dysbiosis.
Kochkarian T, Nagy HI, Li Q
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40387516 · Full text
Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are debilitating and complex chronic gastrointestinal disorders that affect not only the gut but also extraintestinal organs, includin...
Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are debilitating and complex chronic gastrointestinal disorders that affect not only the gut but also extraintestinal organs, including the heart. The gut-heart cross talk has garnered increasing attention in recent years; however, the molecular mechanisms underlying this complex interplay remain poorly understood. This review explores the gut-heart axis, focusing on how IBD disrupts gut microbiota homeostasis and promotes cardiac remodeling through systemic inflammation and various mediators, ultimately contributing to the onset or progression of heart failure. IBD compromises the integrity of the intestinal barrier, allowing microbial metabolites such as trimethylamine N-oxide and phenylacetylglutamine, along with inflammatory cytokines and microRNAs (miRNAs) (e.g., miR-155, miR-21, and let-7a), to enter the circulation and contribute to cardiac remodeling and heart failure. We identify dysfunction of nucleotide-binding oligomerization domain-containing protein 2 as a critical link between gut immunity and cardiovascular pathology. In addition, we discuss emerging microbiome-based therapeutic strategies, including fecal microbiota transplantation and IL-23 inhibitors, aimed at restoring gut homeostasis and mitigating cardiovascular risk. By integrating molecular mechanisms, clinical evidence, and therapeutic approaches, this review underscores the pivotal role of gut dysbiosis in cardiac dysfunction and offers new perspectives for managing cardiac dysfunction in patients with IBD.
Biomarkers of intestinal permeability are linked to incident cardiovascular diseases and cardiovascular events: a review of prospective studies.
Quirk AR, Schifferer JK, Maki KA … +2 more , Robinson AT, Keirns BH
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40386879 · Publisher ↗
Intestinal hyperpermeability, which refers to translocation of microbial factors into the bloodstream, is associated with many chronic diseases. Increased intestinal permeability may contribute to the pathophysiology of...
Intestinal hyperpermeability, which refers to translocation of microbial factors into the bloodstream, is associated with many chronic diseases. Increased intestinal permeability may contribute to the pathophysiology of these diseases by promoting systemic inflammation. Although early work on the health implications of increased intestinal permeability focused on diseases of the gastrointestinal tract, subsequent preclinical and cross-sectional data identified that various types of cardiometabolic and cardiovascular diseases (CVDs) are linked to gut barrier dysfunction. More recently, a body of epidemiological studies has emerged, indicating that elevated biomarkers of intestinal permeability are prospectively linked to incident CVD and CVD events, such as myocardial infarction and stroke, even after controlling for traditional CVD risk factors. In this brief review, we discuss gut barrier function in health and disease, highlight methodologies used to assess intestinal permeability, and review the emerging literature demonstrating that measures of intestinal permeability predict future CVD across several populations.
Microbiota encroachment and a gut-adipose-liver axis in metabolic dysfunction-associated steatotic liver disease.
Igudesman D, Yu G, Dauriat C … +5 more , Roman T, Kashi MR, Blakley E, Chassaing B, Corbin KD
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40380373 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects ∼40% of adults, but causal mechanisms remain elusive. Preclinical models implicate the gut microbiota in MASLD pathogenesis, yet translation to hum...
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects ∼40% of adults, but causal mechanisms remain elusive. Preclinical models implicate the gut microbiota in MASLD pathogenesis, yet translation to humans is hampered by variability in microbial composition. We addressed this gap by investigating whether stable, quantitative gut phenotypes, including microbiota encroachment, are pathological features of MASLD. Sigmoid colon biopsies were collected from participants with and without imaging-defined MASLD. Mucus immunostaining was paired with fluorescent in situ hybridization to image and quantify the distance separating bacteria from the colonic epithelium (i.e., encroachment). Secondary outcomes included intestinal permeability, colon histopathology, and insulin resistance. RNA sequencing was combined with weighted gene network correlation analysis to explore correlations between colonic gene expression and clinical endpoints. Microbiota encroachment did not differentiate participants with MASLD ( = 13 with simple steatosis, = 13 with fibrosis stage <4) from controls ( = 12; = 0.20). Circulating lipopolysaccharide and flagellin-specific immunoglobulins (intestinal permeability), and colon histopathology were similar across cohorts ( = 0.23, = 0.11, and = 0.73, respectively). Microbiota encroachment and adipose tissue insulin resistance (Adipo-IR) were correlated with a colonic gene network regulating insulin and lipid metabolism (Pearson's = -0.33, = 0.04 and = 0.47, = 0.003, respectively). Pathway analysis of this network revealed genes involved in hepatic steatosis ( = 3.95E-06) and liver cell proliferation ( = 0.0003), suggesting a gut-adipose-liver cross talk. Microbiota encroachment and related gut phenotypes do not correlate with MASLD severity. However, colonic expression of genes related to insulin signaling and lipid metabolism links microbiota encroachment to Adipo-IR and MASLD. Future research should investigate how colonic gene products interact with microbiota-focused MASLD mechanisms. In a first-in-human study, we observed that colonic expression of insulin and lipid-related genes may bridge the pathophysiology of colonic microbiota encroachment with adipose tissue insulin resistance and metabolic dysfunction-associated steatotic liver disease.
Crural and costal diaphragm function during emesis.
Park JJ, Tagliabue G, Ji M … +2 more , Mittal RK, Easton PA
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40380351 · Publisher ↗
Together, the costal and crural diaphragm constitute the primary respiratory muscle in mammals, but functionally, they are distinct. The crural segment has additional gastrointestinal function, wrapped around the esophag...
Together, the costal and crural diaphragm constitute the primary respiratory muscle in mammals, but functionally, they are distinct. The crural segment has additional gastrointestinal function, wrapped around the esophagus at the esophagogastric junction, contributing to the esophageal sphincter. Emesis is an expulsive process that requires the coordinated action of multiple muscles to rapidly force out gastric contents. The simultaneous mechanical action and neural activation of the diaphragm segments during the process of emesis, especially expulsion, is uncertain. Detailed divergence of the crural diaphragm to sphincter function during emesis has not been studied. In six awake, spontaneously breathing canines, electrical activity and corresponding muscle shortening of the costal and crural diaphragm were measured at five phases of emesis (rest, early prodrome, mid prodrome, late prodrome, and expulsion) induced by apomorphine. Overall, baseline muscle length decreased and baseline EMG increased progressively from rest through prodrome for both costal and crural, but at expulsion, the crural segment diverged, lengthening abruptly. Shortening and EMG activity per breath for costal changed slightly throughout emesis; crural shortening and EMG activity increased abruptly at expulsion. The divergent action of crural during expulsion developed sequentially through each breath. Also, neuromechanical coupling of the segments reversed at expulsion, with contractility of the crural surpassing that of the costal. These measurements confirm a disparate action of crural diaphragm, compared with costal, to facilitate expulsion. During the process of emesis, although the costal persists as an obligatory respiratory muscle, the crural converts from respiratory muscle to opening sphincter. Although the diaphragm is known as a primary respiratory muscle, the two diaphragm sections, the costal and crural, have notably different functions. This study elucidates the essential role of the crural diaphragm during emesis, a gastrointestinal process. During emesis, the crural diaphragm abandons respiratory function and transmutes to act as an esophageal sphincter. Meanwhile, the costal diaphragm continues ventilatory function.
ASBT governs neonatal bile acid homeostasis early in life despite its strong ileal repression.
Morales Aparicio J, Hu Z, Peiper AM … +7 more , Phophi L, Wilt HM, Nair MS, Winton HB, Blessing K, Romero-Gonzalez GP, Karst SM
Am J Physiol Gastrointest Liver Physiol · 2025 Aug · PMID 40380125 · Full text
Neonatal bile acid metabolism is distinct from that of adults due to developmental regulation of key transporters and enzymes. The apical sodium-dependent bile acid transporter (ASBT) is transiently repressed in the inte...
Neonatal bile acid metabolism is distinct from that of adults due to developmental regulation of key transporters and enzymes. The apical sodium-dependent bile acid transporter (ASBT) is transiently repressed in the intestine after birth, yet its role in neonatal bile acid homeostasis remains unclear. Here, we demonstrate that ASBT plays a crucial role in limiting fecal bile acid loss and suppressing hepatic bile acid synthesis in neonates. ASBT-deficient pups exhibited a marked decrease in serum bile acids and concomitant increase in fecal bile acids, accompanied by upregulated hepatic bile acid synthesis genes, including CYP7A1, CYP7B1, and CYP27A1. We also illuminated a tissue-specific distinction in neonatal negative feedback regulation of bile acid synthesis, with intact hepatic regulation but impaired intestinal regulation. Our study identifies ASBT as a key regulator of neonatal bile acid homeostasis despite its strong repression early in life, highlighting its role in bile acid retention and synthesis regulation. Despite being repressed after birth, ASBT is essential for neonatal bile acid homeostasis. This study reveals that ASBT limits fecal bile acid loss and suppresses hepatic bile acid synthesis in neonates. ASBT-deficient pups showed reduced serum bile acids, increased fecal loss, and upregulation of bile acid synthesis genes. Notably, feedback regulation of bile acid synthesis was intact in the liver but impaired in the intestine, uncovering tissue-specific control mechanisms in early life.
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