American journal of physiology. Gastrointestinal and liver physiology最新文献

{"title":"Expression of Concern for Bhatia et al., volume 307, 2014, p. G533-G549.","authors":"","doi":"10.1152/ajpgi.00428.2013_EOC","DOIUrl":"10.1152/ajpgi.00428.2013_EOC","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"330 6","pages":"G703"},"PeriodicalIF":3.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IP6K1 interacts with the syndecan SDC4 to support secretory granule biogenesis in gastric chief cells.","authors":"Jayraj Sen, Pranjali Pore, Rashna Bhandari","doi":"10.1152/ajpgi.00342.2025","DOIUrl":"10.1152/ajpgi.00342.2025","url":null,"abstract":"<p><p>Inositol hexakisphosphate kinases (IP6Ks) catalyze the synthesis of the inositol pyrophosphate 5-InsP₇, and regulate diverse physiological processes. <i>Ip6k1^-</i>^/<i>^-</i> mice display reduced body weight despite normal food intake, elevated fecal protein, and reduced skeletal muscle mass compared with <i>Ip6k1</i>^+/+ 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 <i>Ip6k1^-</i>^/<i>^-</i> 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 <i>Ip6k1^-</i>^/<i>^-</i> mice compared with <i>Ip6k1</i>^+/+ 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 <i>Ip6k1^-</i>^/<i>^-</i> mice. PGC granule formation was restored in <i>IP6K1^-</i>^/<i>^-</i> 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 <i>IP6K1^+/+</i> but not in <i>IP6K1^-</i>^/<i>^-</i> 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.<b>NEW & NOTEWORTHY</b> Through detailed phenotypic analysis of <i>Ip6k1^-</i>^/<i>^-</i> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G684-G702"},"PeriodicalIF":3.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The protease inhibitor darunavir prevents esophagitis and impairments in esophageal barrier function in a mouse model of GERD.","authors":"Thiago Meneses Araújo Leite Sales, Ananda Moara Lima Daniel, Lara Mara Gomes da Silva, Alvaro Xavier Franco, Humberto Barbosa da Costa Filho, Carlos Eduardo da Silva Monteiro, Antonia Beatriz Alves Ferreira, Sarah Antonieli Carneiro Alicrim, Antonielle de Sousa Lopes, Marco Antonio de Freitas Clementino, Antonio Carlos Pereira de Oliveira, Lucas Antonio Duarte Nicolau, Alexandre Havt, Pedro Marcos Gomes Soares, Stuart Jon Spechler, Rhonda Frances Souza, Marcellus Henrique Loiola Ponte de Souza","doi":"10.1152/ajpgi.00058.2025","DOIUrl":"10.1152/ajpgi.00058.2025","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G718-G726"},"PeriodicalIF":3.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactotransferrin reduction as a target mechanism of postnatal intestinal vulnerability in murine preeclampsia models.","authors":"Tomohiro Ohtani, Mari Ichinose, Takayuki Iriyama, Miho Irie, Yu Ariyoshi, Eriko Yano, Seisuke Sayama, Nobumi Suzuki, Yoku Hayakawa, Keiichi Kumasawa, Takeshi Nagamatsu, Miyuki Harada, Yasushi Hirota","doi":"10.1152/ajpgi.00401.2025","DOIUrl":"10.1152/ajpgi.00401.2025","url":null,"abstract":"<p><p>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 <i>embryonic day 18.5</i> for RNA sequencing and on <i>postnatal days</i> (P) <i>7</i> and <i>21</i> 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 (<i>Ltf</i>), 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G704-G717"},"PeriodicalIF":3.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Panaxynol mitigates chemotherapy-induced intestinal mucositis by improving the colonic microenvironment in murine models.","authors":"Brooke M Bullard, Brandon N VanderVeen, Thomas D Cardaci, Sierra J McDonald, Arianna V Bastian, Nathaniel B Willis, Mingming Xu, Jie Li, Joseph F Pierre, Lorne J Hofseth, Daping Fan, E Angela Murphy","doi":"10.1152/ajpgi.00035.2026","DOIUrl":"10.1152/ajpgi.00035.2026","url":null,"abstract":"<p><p>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 <i>day -1</i>, 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 <i>Dubosiella</i> and <i>Bifidobacterium</i>, alongside male-specific increases in <i>Romboutsia</i> and <i>Alistipes</i>; <i>Akkermansia</i> 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G728-G748"},"PeriodicalIF":3.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13270280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblast-specific <i>Gpx4</i> deletion exacerbates IBD via lipid peroxidation.","authors":"Yuezhong Zhang, Yinzhi Ying, Wesley Huang, Zoe A Rosenfeld, Marwa O El-Derany, Zheng Hong Lee, Cristina Castillo, Tae Gyu Oh, Joel K Greenson, Yatrik M Shah","doi":"10.1152/ajpgi.00387.2025","DOIUrl":"10.1152/ajpgi.00387.2025","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> Fibroblast-specific GPX4 deletion promotes IBD progression. Lipid peroxidation could be a potential therapeutic target of IBD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G591-G600"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13264965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fecal DPP4 concentration reflects colonic injury in the TNBS-induced rat model of colitis.","authors":"Sandra F Gomes, Mariana Ferreira-Duarte, Patrícia Dias-Pereira, Joana Couto, Margarida Duarte-Araújo, Manuela Morato, Fernando Magro","doi":"10.1152/ajpgi.00030.2026","DOIUrl":"10.1152/ajpgi.00030.2026","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G645-G656"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomics reveals that air-liquid interface culture promotes goblet cell differentiation and inhibits glycolysis in organoid cell monolayers.","authors":"Tania Malonga, Emeline Lhuillier, Christelle Marrauld, Deborah Fourmy, Elodie Riant, Cedric Cabau, Nathalie Vialaneix, Martin Beaumont","doi":"10.1152/ajpgi.00251.2025","DOIUrl":"10.1152/ajpgi.00251.2025","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G513-G531"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147455262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improvement of glucose homeostasis during leptin treatment does not alter the intestinal microbiome in male diabetic UC Davis type-2 diabetes mellitus rats.","authors":"Manuel Martínez-Ruiz, Leslie Tabor-Simecka, James L Graham, Christopher Randolph, Renee Fox, Renny Lan, Lindsay Pack, Tanya LeRoith, Kimber L Stanhope, Laxmi Yeruva, Peter J Havel, Brian D Piccolo","doi":"10.1152/ajpgi.00412.2025","DOIUrl":"10.1152/ajpgi.00412.2025","url":null,"abstract":"<p><p>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; <i>n</i> = 12) or recombinant leptin (0.5 mg/kg; <i>n</i> = 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 <i>Pparg</i> and <i>Ldha</i> 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G549-G564"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13104595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T cells are induced by gut microbiota through differentially regulating costimulatory molecules of enteric glial cells.","authors":"Jiahui Yang, Qishan Zeng, Min Zou, Jiao Nie, Huatian Gan","doi":"10.1152/ajpgi.00032.2025","DOIUrl":"10.1152/ajpgi.00032.2025","url":null,"abstract":"<p><p>Probiotics have been proven to be effective in inducing and maintaining remission of inflammatory bowel disease (IBD). However, their precise mechanisms remain unclear. Interactions between the gut microbiota and enteric glial cells (EGCs) have gained increasing attention. We aimed to investigate whether and how <i>Bifidobacterium longum</i> (B.l), as a typical probiotic, exerts anti-inflammatory effects by acting on EGCs. Herein, we demonstrate that EGCs possess bacterial phagocytosis and antigen-presenting functions, and their costimulatory molecule expression is differentially regulated by bacteria. Specifically, B.l significantly upregulates EGC expression of programmed death-ligand 1 (PD-L1), while enterohemorrhagic <i>Escherichia coli</i> (EHEC) markedly increases CD86 expression. B.l ameliorates dextran sulfate sodium (DSS)-induced experimental colitis by activating the p38 MAPK signaling pathway, upregulating PD-L1 expression in EGCs, and inducing the conversion of CD4⁺ cells into regulatory T (Treg) cells through the PD-L1/PD-1 pathway. This process promotes Treg cell expansion, inhibits pathogenic T-helper type 17 (Th17) cells, increasing IL-10 production, and reduces TNF-α and IL-1β production. Notably, ablation of EGCs significantly diminishes the efficacy of B.l in alleviating experimental colitis. In conclusion, our findings suggest that B.l induces the conversion of CD4⁺ cells into Treg cells by acting on EGCs and alleviating intestinal inflammation. These findings support the notion that EGCs are not only neural cells but also potential immune cells, which exert immune regulatory functions depending on the type of bacteria and which signaling molecules are being expressed. This study provides new data for elucidating the mechanisms of probiotics in the treatment of IBD.<b>NEW & NOTEWORTHY</b> The interactions between gut microbiota and enteric glial cells (EGCs) are increasingly recognized. This study reveals that EGCs possess bacterial phagocytosis and antigen-presentation functions, which are modulated differently by various bacteria. Specifically, <i>Bifidobacterium longum</i> (B.l) relieves DSS-induced colitis by enhancing PD-L1 expression on EGCs and promoting Treg cell differentiation through EGC-mediated immune regulation. Understanding the dual role of EGCs as both neural and immune cells expands our comprehension of gut microbiota-neural-immune interaction in intestinal health.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G532-G548"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}