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

{"title":"Glucose metabolism through the hexosamine biosynthetic pathway drives hepatic de novo lipogenesis via promoting <i>N</i>-linked protein glycosylation.","authors":"Yanhui Li, Qing Song, Rui Guo, Yanyu Qian, Yuwei Jiang, Zhenyuan Song","doi":"10.1152/ajpgi.00056.2025","DOIUrl":"10.1152/ajpgi.00056.2025","url":null,"abstract":"<p><p>De novo lipogenesis (DNL) converts excess glucose into lipids, whereas the hexosamine biosynthetic pathway (HBP), a glycolytic branch, generates UDP-<i>N</i>-acetylglucosamine for protein glycosylation, including <i>O</i>-GlcNAcylation and <i>N</i>-linked glycosylation. Both pathways are active in hepatocytes and integral to glucose metabolism; however, their functional interplay remains unclear. Here, we investigated the role of HBP in hepatic DNL activation using both in vitro and in vivo models. AML12 hepatocytes were cultured in low- and high-glucose media with or without HBP blockade, both pharmacologically and genetically. For in vivo studies, male C57BL/6J mice were subjected to a fasting-refeeding regimen with or without intraperitoneal administration of azaserine, a competitive inhibitor of glutamine-fructose-6-phosphate transaminase 1 (GFPT1), the rate-limiting enzyme of the HBP. Our results demonstrated that, in AML12 cells, glucose exposure activated both DNL and HBP, leading to triacylglycerol (TAG) accumulation, whereas HBP inhibition ameliorated DNL and TAG accumulation. In mice, refeeding after a 24-h fasting induced hepatic DNL, which was abolished by HBP inhibition, indicating its mechanistic involvement in glucose-driven lipogenesis. Mechanistically, we identified ATF4 as a key regulator of GFPT1 upregulation under high-glucose conditions. As expected, both glucose-treated hepatocytes and livers from fasting-refed mice exhibited increased protein glycosylation. Notably, blocking <i>N</i>-linked glycosylation, but not <i>O</i>-GlcNAcylation, abolished glucose-induced DNL activation, indicating that HBP is essential for glucose-induced DNL pathway activation via promoting <i>N</i>-linked glycosylation, independent of <i>O</i>-GlcNAcylation. In conclusion, our findings establish that an intact HBP is required for glucose-induced hepatic DNL activation, primarily through promoting protein <i>N</i>-linked glycosylation.<b>NEW & NOTEWORTHY</b> High-glucose exposure activates both hepatic HBP and DNL pathways. The glucose metabolism into HBP is essential for the activation of the DNL pathway. ATF4 activation plays a mechanistic role in high glucose-induced HBP activation. HBP drives high glucose-induced hepatic DNL activation via promoting <i>N</i>-linked protein glycosylation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G746-G759"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962803","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":"Indole-3-propionic acid protects medium-diversity colitic mice via barrier enhancement preferentially over anti-inflammatory effects.","authors":"Kristoff M Nieves, Kyle L Flannigan, Elizabeth Hughes, Matthew Stephens, Andrew J Thorne, Ameline Delanne-Cuménal, Kathryn Strayer, Darasimi Kola-Ilesanmi, Senya Wickramasinghe, Niloofar Mirzadzar, Grace Baruta, Braedon McDonald, Eduardo R Cobo, Björn Petri, Sridhar Mani, Simon A Hirota","doi":"10.1152/ajpgi.00256.2024","DOIUrl":"10.1152/ajpgi.00256.2024","url":null,"abstract":"<p><p>Metabolites generated from the intestinal microbiota regulate local and distant tissues. One important metabolite generated from l-tryptophan is indole-3-propionic acid (IPA), which has been shown previously to regulate intestinal mucosal homeostasis in specific pathogen-free (SPF)-colonized animals through distinct receptor-mediated events. Interestingly, IPA levels are reduced in patients with inflammatory bowel disease (IBD). In the current study, we assessed whether IPA could improve colitis outcomes in the absence of its production by the microbiota. To do this, colitis was induced by dextran sulfate sodium (DSS) in gnotobiotic mice colonized with the 12-member stable defined moderately diverse microbiota mouse 2 (sDMDMm2) microbial consortium, which lacks the genes required for IPA generation. We found that these mice were exquisitely sensitive to DSS compared with SPF-colonized mice. However, IPA treatment significantly increased survival. Infiltrating immune cells in the colon were not altered by IPA treatment nor were there any remarkable changes in local and systemic inflammatory mediator levels. Nevertheless, IPA treatment changed the composition of the fecal microbiota and enhanced intestinal barrier function, demonstrated by a reduction in FITC-dextran flux and retainment of a bioluminescent <i>Escherichia coli</i> within the lumen of colitic mice. Together, our data suggest that IPA treatment in the context of its systemic depletion enhances barrier function and enhances survival in the presence of established inflammation. These data support continued assessment of IPA as a potential treatment for IBD.<b>NEW & NOTEWORTHY</b> Indole-3-propionic acid (IPA) is a metabolite produced by the intestinal microbiota that has been shown to elicit beneficial effects in the gastrointestinal (GI) tract that include regulating intestinal barrier function, reducing inflammation, and controlling immune responses that lead to fibrosis. In patients with inflammatory bowel disease (IBD), IPA levels are reduced. In the current study, we found that treating mice with IPA at the peak of intestinal inflammation improved clinical outcomes and disease.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G696-G715"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955608","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":"Saturated phosphatidic acids induce mTORC1-driven integrated stress response contributing to glucolipotoxicity in hepatocytes.","authors":"Rui Guo, Yanhui Li, Yuwei Jiang, Md Wasim Khan, Brian T Layden, Zhenyuan Song","doi":"10.1152/ajpgi.00027.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00027.2025","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 6","pages":"G663-G676"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963869","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":"Functional roles of interstitial cells of Cajal in the GI tract of rats.","authors":"Sung Jin Hwang, Joong Goo Kwon, Elizabeth A H Beckett, Minkyung Kim, Tom Herbert, Kenton M Sanders, Sean M Ward","doi":"10.1152/ajpgi.00036.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00036.2025","url":null,"abstract":"<p><p>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 <i>Kit</i> mutation in <i>Ws/Ws</i> rats had consequences on ICC populations in the stomach, small intestine, and colon and whether loss of ICC resulted in functional defects similar to <i>Kit</i> 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 <i>Ws/Ws</i> 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, <i>Ws/Ws</i> rats have lesions in ICC and functional deficits similar to, but not identical to, <i>Kit</i> 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.<b>NEW & NOTEWORTHY</b> 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. <i>Ws/Ws</i> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 6","pages":"G677-G695"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961356","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":"Fructooligosaccharides slow colonic motility and activate myenteric neurons via calcium sensing and 5-HT₃ receptors in the proximal colon.","authors":"Preedajit Wongkrasant, Laurie E Wallace, Wallace K MacNaughton, Keith A Sharkey","doi":"10.1152/ajpgi.00039.2025","DOIUrl":"10.1152/ajpgi.00039.2025","url":null,"abstract":"<p><p>Calcium-sensing receptors (CaSR) regulate a variety of functions in the gastrointestinal tract. Recently, prebiotic-independent effects of fructooligosaccharides (FOS) on epithelial barrier function were found to be mediated by CaSR. Here, we tested the hypothesis that FOS acts via the CaSR to regulate colonic motility and neuronal activity in the enteric nervous system. Using immunohistochemistry, we determined that CaSR were localized on the colonic epithelium of the mouse proximal colon and that a small proportion of enterochromaffin cells coexpress CaSR. We demonstrated that intraluminal administration of FOS slows colonic motility in vivo in male and female mice, an effect that is mediated by both CaSR and 5-HT₃ receptors. We assessed neuronal activity in response to luminally perfused FOS in intact segments of the proximal colon from male and female mice expressing a genetically encoded fluorescent calcium reporter in intrinsic primary afferent neurons (Calb1-GCaMP6 mice) or in all enteric neurons (Wnt1-GCaMP6 mice) using live cell confocal imaging. In both Calb1-GCaMP6 mice and Wnt1-GCaMP6 mice, intraluminal FOS perfusion induced a sustained elevation of intracellular Ca²⁺ in neurons of the myenteric plexus. This effect was sensitive to tetrodotoxin and mediated by CaSR and 5-HT₃ receptors. Serosal application of FOS was without effect. Our results demonstrate that FOS acts acutely to slow colonic motility in vivo and activates the enteric nervous system via CaSR and 5-HT₃ receptors.<b>NEW & NOTEWORTHY</b> Calcium-sensing receptors regulate a variety of functions in the gastrointestinal tract. Here, we demonstrate a novel action of fructooligosaccharides to regulate colonic motility in vivo and activate the enteric nervous system. These effects are mediated by calcium-sensing and 5-HT₃ receptors.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G734-G745"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973346","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":"Hepatic and intestinal tissue-specific <i>Fxr</i> deficiency alters bile acid homeostasis in female mice.","authors":"Jiarui Jiang, Mingjie Fan, Weian Yuan, Dawei Yue, Zhengtao Wang, Li Yang, Wendong Huang, Lihua Jin, Xu Wang, Lili Ding","doi":"10.1152/ajpgi.00387.2024","DOIUrl":"10.1152/ajpgi.00387.2024","url":null,"abstract":"<p><p>Farnesoid X receptor (FXR), predominantly expressed in the liver and intestine, plays a crucial role in regulating bile acid (BA) metabolism. However, the specific contributions of FXR in different tissues to BA homeostasis remain unclear. To elucidate the comprehensive roles of FXR, we developed a novel double tissue-specific knockout (KO) mouse model of <i>Fxr</i> in both liver and intestine (<i>Fxr</i>^ΔL/ΔIN). Notably, <i>Fxr</i>^ΔL/ΔIN mice exhibited significantly increased BA levels in the serum and liver, which were consistent with <i>Fxr</i> whole body KO mice (<i>Fxr</i>^-/-). However, <i>Fxr</i>^ΔL mice only showed elevated hepatic BA concentration, whereas <i>Fxr</i>^ΔIN displayed remarkably increased BA concentration in feces. <i>Fxr</i> deletion increased the BA synthesis genes mRNA level, such as <i>Cyp7a1</i> and <i>Cyp8b1</i>, but reduced the expression of FXR downstream target genes <i>Shp</i> and <i>Fgf15</i>. These findings provide a valuable model to underscore the pivotal functions of tissue-specific FXR in maintaining BA homeostasis. Moreover, these insights facilitate the development of FXR-targeted therapeutic strategies for the BA dysregulation disease treatment.<b>NEW & NOTEWORTHY</b> We successfully developed a double tissue-specific <i>Fxr</i> knockout (DKO) mouse model, which provides a novel tool for investigation of FXR functions in the liver and intestine. Unlike whole body KO, the DKO model excludes the FXR impact on other tissues. <i>Fxr</i>^ΔL/ΔIN mice exhibited significantly increased BA levels in the serum and liver, which were consistent with <i>Fxr</i>^-/- mice. We established a powerful tool for therapeutic strategies for bile acid metabolism disorders associated with FXR.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G774-G790"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962155","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":"Costimulation with high-fat diet and acidic bile salts may promote Warburg effect in gastric carcinogenesis around the squamocolumnar junction in Gan mice.","authors":"Koichiro Sudo, Kaname Uno, Toru Tamahara, Naoki Asano, Keisuke Kusano, Mizuki Tanabe, Kouya Ogasawara, Takeshi Kanno, Tomoyuki Koike, Ritsuko Shimizu, Atsushi Masamune","doi":"10.1152/ajpgi.00305.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00305.2024","url":null,"abstract":"<p><p>Epidemiological studies demonstrated relationships between gastric cardia adenocarcinoma (GCA) and metabolic syndrome (MetS). We aimed to clarify the mechanism underlying their relationship. To investigate whether systemic inflammation against high-fat diet (HFD)-related dysbiosis promotes the Warburg effect in tumors at the squamocolumnar junction (SCJ), we applied K19-Wnt1/C2mE (Gan) mice, fed either HFD or control diet ± acidic bile salts (ABS) with/without clodronate liposomes (CLs), and in vitro studies using MKN7 cells with/without THP1-derived macrophages. Then, we assessed the involvement of oxidative stress (OS) in the Warburg effect by comparing nuclear factor-erythroid 2-related factor 2 (Nrf2) knockout Gan mice with Gan mice. Tumors with macrophage infiltration in the HFD + ABS group were larger than in the control group. Gene Set Enrichment Analysis revealed enhancement of the OS signaling in tumor of the HFD + ABS group. The HFD + ABS group mice demonstrated induction of OS, Nqo1, tumor necrosis factor alpha (TNFα), and the Warburg effect in tumors and mucosal barrier dysfunction of dysbiotic gut. All of them were abolished with diminishing macrophage infiltration by additional CL treatment. Stimulation with TNFα, but not ABS nor lipopolysaccharide, on MKN7 cells activated the Warburg effect. In MKN7 cells cocultured with the macrophages whose TNFα expression was induced by the lipopolysaccharide pretreatment, the Warburg effect was enhanced in TNFα concentration-dependent manners. In Nrf2 knockout Gan mice, tumors shrank with reducing OS, TNFα, and Warburg effect, along with decreasing macrophage infiltration. Accordingly, MetS may develop GCA through the Nrf2-related Warburg effect under the TNFα stimulation from the macrophages activated by both local ABS exposure and systemic lipopolysaccharide exposure from leaky gut with HFD-related dysbiosis.<b>NEW & NOTEWORTHY</b> In K19-Wnt1/C2mE (Gan) mice, a high-fat diet accompanied by orally taking acidic bile salts (ABS) promoted inflammation-associated carcinogenesis at the squamocolumnar junction (SCJ), maybe due to transudates from dysbiotic gut into systemic circulation. Systemic lipopolysaccharide exposure and local ABS exposure at the SCJ activate macrophages to induce the expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) and TNFα, which might promote Warburg effect in cancer cells. These phenomena were abolished in the Nrf2-knockout Gan mice.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 6","pages":"G645-G662"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959921","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":"Gut microbiota dysbiosis in a novel mouse model of colitis potentially increases the risk of colorectal cancer.","authors":"Abrory A C Pramana, Guanying Bianca Xu, Siyuan Liang, Erick Omar Garcia Vazquez, Jacob M Allen, Brett R Loman, Wenyan Mei, Yuan-Xiang Pan, Hong Chen","doi":"10.1152/ajpgi.00040.2025","DOIUrl":"10.1152/ajpgi.00040.2025","url":null,"abstract":"&lt;p&gt;&lt;p&gt;This research investigates the gut microbiota profile in a novel mouse model of colitis with a specific knockout (KO) of the &lt;i&gt;hnRNPI&lt;/i&gt; gene in intestinal epithelial cells. This KO mouse model is characterized by activation of the NF-κB pathway and early-onset colitis. Although the influence of gut microbiota on colitis pathophysiology is well established, its role in &lt;i&gt;hnRNPI&lt;/i&gt; KO mice remains unexplored. To address this, we used 16S rRNA gene amplicon sequencing to compare the gut microbiota between &lt;i&gt;hnRNPI&lt;/i&gt; KO and wild-type (WT) mice at baseline and following a dextran sodium sulfate (DSS) challenge. Untargeted metabolomics was also used to profile bacterial metabolites identified in the 16S rRNA analysis. Fecal DNA was extracted and analyzed to determine gut microbiota composition. Body weight and the disease activity index (DAI) were measured, while organ samples, including liver, spleen, and colon, were collected during necropsy for analysis. Representative bacteria identified from 16S-rRNA gene sequencing were cultured in designated media to further characterize their metabolite profiles. Initial findings on 16S-rRNA gene analysis revealed significant disparities in the gut microbiota between KO and WT mice. Notably, KO mice exhibited lower levels of &lt;i&gt;Dubosiella&lt;/i&gt; sp. but higher levels of &lt;i&gt;Paraclostridium bifermentans&lt;/i&gt; and &lt;i&gt;Enterococcus faecalis&lt;/i&gt; compared with WT mice. The DSS challenge exacerbated colitis in KO mice and led to further alterations in gut microbiota diversity and composition. After DSS treatment, significant shifts were observed in five bacterial species. Specifically, &lt;i&gt;Dubosiella&lt;/i&gt; sp. remained consistently low, whereas &lt;i&gt;P. bifermentans&lt;/i&gt; persisted at high levels in DSS-treated KO mice. In addition, elevated levels of &lt;i&gt;Clostridium paraputrificum&lt;/i&gt; and &lt;i&gt;Lactococcus garvieae&lt;/i&gt; were detected in KO mice, whereas &lt;i&gt;Malacoplasma muris&lt;/i&gt; was significantly higher in WT mice. The metabolomic analysis highlighted distinct bacterial metabolic profiles between &lt;i&gt;P. bifermentans&lt;/i&gt; and &lt;i&gt;Dubosiella newyorkensis&lt;/i&gt;. &lt;i&gt;P. bifermentans&lt;/i&gt; were found to produce higher levels of glycocholate, urocanate, and deoxycholate, whereas &lt;i&gt;D. newyorkensis&lt;/i&gt; predominantly produced N-formyltryptophan, indole-3-carboxaldehyde, and glycyl-l-norleucine. Importantly, an imbalance in the abundance of &lt;i&gt;Dubosiella&lt;/i&gt; sp. and &lt;i&gt;P. bifermentans&lt;/i&gt; was observed in KO mice, suggesting a potential role in colitis pathogenesis. Comprehensive pathway analysis based on 16S rRNA gene sequences revealed disturbances in several pathways, including those related to human diseases such as cancer, which were notably increased in &lt;i&gt;hnRNPI&lt;/i&gt; KO mice after the DSS challenge. These findings underscore the disrupted microbiome balance in KO mice, particularly the altered levels of &lt;i&gt;Dubosiella&lt;/i&gt; sp., which may play a pivotal role in gut health and colitis development.&lt;b&gt;NEW & NOTEWORTHY&lt;/b&gt; Ablation of &lt;i&gt;hn","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G831-G847"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973348","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":"Gut neuropeptide involvement in Parkinson's disease.","authors":"Hayley N Templeton, Stuart A Tobet, Luke A Schwerdtfeger","doi":"10.1152/ajpgi.00383.2024","DOIUrl":"10.1152/ajpgi.00383.2024","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder affecting over 10 million people. A key pathological feature of PD is the accumulation of misfolded α-synuclein (aSyn) protein in the substantia nigra pars compacta. Aggregation of aSyn can form Lewy bodies that contribute to dopaminergic neuron degeneration and motor symptoms, such as tremor, rigidity, and bradykinesia. Beyond the central nervous system, aSyn aggregates have been detected in the gastrointestinal (GI) tract, suggesting a link between peripheral aSyn and nonmotor PD symptoms. GI symptoms, often preceding motor symptoms by up to 20 years, highlight the bidirectional communication between the central nervous system and the enteric nervous system (gut-brain axis) in PD. Although microbiome alterations and intestinal inflammation have been associated with PD, functional impacts on gut-brain signaling or aSyn aggregation remain unclear. Intestinal neuropeptides are key modulators of gut-brain communication, alter immune response to pathogens and environmental toxins, and may contribute to the function of the luminal gut barrier. Dysregulation of gut neuropeptide signaling, including vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide, ghrelin, cholecystokinin, glucagon-like peptide 1, and substance P, have been associated with pathologic effects of PD in animal models. Despite their potential role in pathogenesis and disease modulation, gut neuropeptide roles in PD are underexplored. This article reviews current knowledge surrounding microbial metabolite and immune influences on gut neuropeptide signaling, aSyn aggregation in the enteric nervous system, and downstream neuroimmune pathway alterations within the context of PD and its mouse models.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G716-G733"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952218","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":"Host-microbial interactions in the esophagus.","authors":"Nonyelum Ebigbo, Rhonda F Souza","doi":"10.1152/ajpgi.00079.2025","DOIUrl":"10.1152/ajpgi.00079.2025","url":null,"abstract":"<p><p>Host-microbial interactions within the gastrointestinal tract are increasingly recognized as contributors to health and disease, yet our understanding of these interactions in the esophagus remains limited. Dysbiosis of the esophageal microbiome has been linked to esophageal disorders, but the precise mechanisms underlying microbial contributions to esophageal pathophysiology remain speculative. This review explores the mechanisms by which the esophageal microbiome modulates mucosal immunity, epithelial barrier integrity, and inflammatory responses. We highlight key host receptors that mediate these interactions and microbial metabolites that influence the local immune environment and epithelial function. By synthesizing current knowledge on how the microbiome impacts esophageal health, we identify significant knowledge gaps and propose areas for future research.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G848-G860"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958094","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}