Pub Date : 2025-12-08DOI: 10.1080/19490976.2025.2587966
Mirabeau M. Ngwese, Bayode R. Adegbite, Jeannot F. Zinsou, J. Liam Fitzstevens, Victor T. Schmidt, Paul Alvyn N. Moure, Moustapha N. Maloum, Alexander V. Tyakht, Kelsey E. Huus, Nicholas D. Youngblut, Peter G. Kremsner, Ayola A. Adegnika, Ruth E. Ley
{"title":"Infection with gut parasites correlates with gut microbiome diversity across human populations in Africa","authors":"Mirabeau M. Ngwese, Bayode R. Adegbite, Jeannot F. Zinsou, J. Liam Fitzstevens, Victor T. Schmidt, Paul Alvyn N. Moure, Moustapha N. Maloum, Alexander V. Tyakht, Kelsey E. Huus, Nicholas D. Youngblut, Peter G. Kremsner, Ayola A. Adegnika, Ruth E. Ley","doi":"10.1080/19490976.2025.2587966","DOIUrl":"https://doi.org/10.1080/19490976.2025.2587966","url":null,"abstract":"","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"130 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1080/19490976.2025.2596807
Aya Misaki,Shunya Suzuki,Shintaro Maeno,Akihito Endo,Yasuko Sasaki,Gen Enomoto,Kenji Yokota,Akinobu Kajikawa
Ligilactobacillus ruminis is a flagellated lactic acid bacterium found in the intestines of various mammals, including humans. Although this species harbors a complete flagellar gene cluster, flagella formation has not been observed in human-derived strains, and the underlying regulatory mechanisms remain unknown. Here, we isolated a motility-acquired mutant of L. ruminis ATCC 25644 that exhibited full flagellation and a measurable chemotactic response under acidic conditions (pH 3.0). Whole-genome sequencing revealed a ~35 kb deletion encompassing multiple regulatory genes. Functional complementation identified a single response regulator, designated FpsR (flagellation-piliation switchover regulator), as a central switch that suppresses flagella formation while promoting pilus expression. The motility-acquired mutant displayed reduced pilus production, diminished adhesion to murine intestinal mucus and fibronectin, and increased susceptibility to acid (pH 3.0) and bile (0.25-0.5%), resulting in a complete loss of intestinal colonization in a murine model. Furthermore, while flagellin from the motile strain activated TLR5 and induced proinflammatory responses comparable to those of pathogenic bacteria, no such inflammation was observed in vivo, likely due to the strain's colonization failure. These findings reveal FpsR as a previously unrecognized genetic mechanism that coordinates motility and mucosal colonization in a human commensal bacterium and provide insight into how flagella are regulated and silenced in the gut environment to support host-microbe symbiosis.
{"title":"The response regulator FpsR controls the flagella-pili transition and mucosal colonization in Ligilactobacillus ruminis.","authors":"Aya Misaki,Shunya Suzuki,Shintaro Maeno,Akihito Endo,Yasuko Sasaki,Gen Enomoto,Kenji Yokota,Akinobu Kajikawa","doi":"10.1080/19490976.2025.2596807","DOIUrl":"https://doi.org/10.1080/19490976.2025.2596807","url":null,"abstract":"Ligilactobacillus ruminis is a flagellated lactic acid bacterium found in the intestines of various mammals, including humans. Although this species harbors a complete flagellar gene cluster, flagella formation has not been observed in human-derived strains, and the underlying regulatory mechanisms remain unknown. Here, we isolated a motility-acquired mutant of L. ruminis ATCC 25644 that exhibited full flagellation and a measurable chemotactic response under acidic conditions (pH 3.0). Whole-genome sequencing revealed a ~35 kb deletion encompassing multiple regulatory genes. Functional complementation identified a single response regulator, designated FpsR (flagellation-piliation switchover regulator), as a central switch that suppresses flagella formation while promoting pilus expression. The motility-acquired mutant displayed reduced pilus production, diminished adhesion to murine intestinal mucus and fibronectin, and increased susceptibility to acid (pH 3.0) and bile (0.25-0.5%), resulting in a complete loss of intestinal colonization in a murine model. Furthermore, while flagellin from the motile strain activated TLR5 and induced proinflammatory responses comparable to those of pathogenic bacteria, no such inflammation was observed in vivo, likely due to the strain's colonization failure. These findings reveal FpsR as a previously unrecognized genetic mechanism that coordinates motility and mucosal colonization in a human commensal bacterium and provide insight into how flagella are regulated and silenced in the gut environment to support host-microbe symbiosis.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"142 1","pages":"2596807"},"PeriodicalIF":12.2,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EspH is an effector protein secreted by the type III secretion system of various pathogenic Escherichia coli strains, including enteropathogenic E. coli (EPEC). The ability of EspH to inhibit host RhoGTPases, disrupt the actin cytoskeleton, and induce host cell cytotoxicity has been well-documented. Mass spectrometry analysis of EspH translocated into EPEC-infected cells revealed that a lysine at position 106 (K106) is modified with ubiquitin. Immunoblotting using the FK2 anti-ubiquitin antibodies has confirmed these results, suggesting that EspH undergoes polyubiquitylation. Prediction algorithms have identified a single ubiquitylation site at K106 and a phosphodegron in EspH. Moreover, we show that wild-type (EspHwt), but not the EspHK106R mutant, is subjected to degradation following translocation in an MG132-sensitive manner, indicating that the proteasome degrades the polyubiquitylated effector following translocation. Finally, we show that translocated EspHK106R induces higher cytotoxicity than translocated EspHwt. EspHwt translocated into MG132-pretreated cells also displayed higher cytotoxicity levels than EspHwt in untreated cells. These data reinforce the idea that EspH is polyubiquitylated and that the host proteasome degrades the translocated effector, possibly limiting its ability to toxicate the host cells. Additional implications of these effects on bacterial-host interactions are discussed.
{"title":"The ubiquitin system targets translocated EspH to proteasomal degradation.","authors":"Ipsita Nandi,Efrat Zlotkin-Rivkin,Hanan Schoffman,Benjamin Aroeti","doi":"10.1080/19490976.2025.2595775","DOIUrl":"https://doi.org/10.1080/19490976.2025.2595775","url":null,"abstract":"EspH is an effector protein secreted by the type III secretion system of various pathogenic Escherichia coli strains, including enteropathogenic E. coli (EPEC). The ability of EspH to inhibit host RhoGTPases, disrupt the actin cytoskeleton, and induce host cell cytotoxicity has been well-documented. Mass spectrometry analysis of EspH translocated into EPEC-infected cells revealed that a lysine at position 106 (K106) is modified with ubiquitin. Immunoblotting using the FK2 anti-ubiquitin antibodies has confirmed these results, suggesting that EspH undergoes polyubiquitylation. Prediction algorithms have identified a single ubiquitylation site at K106 and a phosphodegron in EspH. Moreover, we show that wild-type (EspHwt), but not the EspHK106R mutant, is subjected to degradation following translocation in an MG132-sensitive manner, indicating that the proteasome degrades the polyubiquitylated effector following translocation. Finally, we show that translocated EspHK106R induces higher cytotoxicity than translocated EspHwt. EspHwt translocated into MG132-pretreated cells also displayed higher cytotoxicity levels than EspHwt in untreated cells. These data reinforce the idea that EspH is polyubiquitylated and that the host proteasome degrades the translocated effector, possibly limiting its ability to toxicate the host cells. Additional implications of these effects on bacterial-host interactions are discussed.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"128 1","pages":"2595775"},"PeriodicalIF":12.2,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OBJECTIVESWhite adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis. We previously demonstrated that desaminotyrosine (DAT), a microbial metabolite, prevents high-fat diet (HFD)-induced body weight gain in mice, but the role of DAT on white adipocyte is unknown. Here, we investigated the role of DAT in host metabolic health and its therapeutic potentials in treating obesity.METHODSIn this study, we employed a pharmacological approach by administering DAT to mice. These mice were subjected to HFD feeding to establish overweight model, followed by DAT treatment. The effect of DAT on white adipocytes were studied using both in vivo and in vitro models.RESULTSOur data indicated that DAT is a potent weight loss chemical for obesity treatment. This is related to DAT's dual-function in regulating white adipose tissue remodeling. DAT enhances mature white adipocyte-autonomous fat disposal through sustained lipolysis and augmented expression of carnitine palmitoyltransferase I family protein CPT1A, a critical enzyme facilitating fatty acid oxidation (FAO), especially under lipolytic-inducing conditions. In the meantime, it blocks white adipogenesis via FAO-dependent pathway potentiation.CONCLUSIONSCollectively, these data demonstrate that DAT is a potent antiobesity agent with potential effects on white adipose tissue remodeling. This study provides a novel pharmacological strategy targeting white adipocyte plasticity for treating metabolic disorders.
{"title":"The microbial metabolite desaminotyrosine is a potent antiobesity agent with potential effects on white adipose tissue remodeling in mice.","authors":"Haohan Huang,Huimin Bu,Longxiang Liao,Yaoyao Xiang,Qiuchong Chen,Guiling Fu,Wanpeng Cheng,Yanbo Kou,Zhuanzhuan Liu,Kuiyang Zheng,Yugang Wang,Yanxia Wei","doi":"10.1080/19490976.2025.2587400","DOIUrl":"https://doi.org/10.1080/19490976.2025.2587400","url":null,"abstract":"OBJECTIVESWhite adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis. We previously demonstrated that desaminotyrosine (DAT), a microbial metabolite, prevents high-fat diet (HFD)-induced body weight gain in mice, but the role of DAT on white adipocyte is unknown. Here, we investigated the role of DAT in host metabolic health and its therapeutic potentials in treating obesity.METHODSIn this study, we employed a pharmacological approach by administering DAT to mice. These mice were subjected to HFD feeding to establish overweight model, followed by DAT treatment. The effect of DAT on white adipocytes were studied using both in vivo and in vitro models.RESULTSOur data indicated that DAT is a potent weight loss chemical for obesity treatment. This is related to DAT's dual-function in regulating white adipose tissue remodeling. DAT enhances mature white adipocyte-autonomous fat disposal through sustained lipolysis and augmented expression of carnitine palmitoyltransferase I family protein CPT1A, a critical enzyme facilitating fatty acid oxidation (FAO), especially under lipolytic-inducing conditions. In the meantime, it blocks white adipogenesis via FAO-dependent pathway potentiation.CONCLUSIONSCollectively, these data demonstrate that DAT is a potent antiobesity agent with potential effects on white adipose tissue remodeling. This study provides a novel pharmacological strategy targeting white adipocyte plasticity for treating metabolic disorders.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"55 1","pages":"2587400"},"PeriodicalIF":12.2,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vegan and omnivorous diets differ markedly in composition, but their effects on the gut microbiome, metabolome, and lipidome across populations remain insufficiently characterized. While both diet and country of origin influence these molecular layers, the relative contribution of diet versus country-specific factors has not yet been systematically evaluated within a multi-omics framework.In this cross-sectional, bicentric, observational study, we profiled healthy vegans (n = 100) and omnivores (n = 73) from the Czech Republic and Italy using integrated microbiome, metabolome, and lipidome analyses. Findings were subsequently validated in an independent cohort (n = 142).Significant differences across all omics layers were observed for both country and diet. The predictive models confirmed diet-associated separation, with validation cohort AUCs of 0.99 (lipidome), 0.89 (metabolome), and 0.87 (microbiome). Functional metagenome analysis revealed enrichment of amino acid biosynthesis, inositol degradation, and the pentose phosphate pathway in vegans, while omnivores presented greater potential for amino acid fermentation, fatty acid biosynthesis, and propanoate metabolism. Linear models identified a robust, country-independent "vegan signature" consisting of 27 lipid metabolites, five non-lipid metabolites, and 11 bacterial species. Several lipid features associated with an omnivorous diet were inversely related to the duration of vegan diet adherence. Some of the vegan-associated metabolites and bacteria have been previously linked to favorable cardiometabolic profiles, although causality remains to be established.These findings demonstrate that vegan diets are associated with reproducible, country-independent molecular and microbial signatures. Our results highlight diet-driven shifts in host-microbiota interactions and provide a framework for understanding how dietary patterns relate to host-microbiota interactions.
{"title":"A vegan diet signature from a multi-omics study on different European populations is related to favorable metabolic outcomes.","authors":"Anna Ouradova,Giulio Ferrero,Miriam Bratova,Nikola Daskova,Alena Bohdanecka,Klara Dohnalova,Marie Heczkova,Karel Chalupsky,Maria Kralova,Marek Kuzma,István Modos,Filip Tichanek,Lucie Najmanova,Barbara Pardini,Helena Pelantová,Sonia Tarallo,Petra Videnska,Jan Gojda,Alessio Naccarati,Monika Cahova","doi":"10.1080/19490976.2025.2593050","DOIUrl":"https://doi.org/10.1080/19490976.2025.2593050","url":null,"abstract":"Vegan and omnivorous diets differ markedly in composition, but their effects on the gut microbiome, metabolome, and lipidome across populations remain insufficiently characterized. While both diet and country of origin influence these molecular layers, the relative contribution of diet versus country-specific factors has not yet been systematically evaluated within a multi-omics framework.In this cross-sectional, bicentric, observational study, we profiled healthy vegans (n = 100) and omnivores (n = 73) from the Czech Republic and Italy using integrated microbiome, metabolome, and lipidome analyses. Findings were subsequently validated in an independent cohort (n = 142).Significant differences across all omics layers were observed for both country and diet. The predictive models confirmed diet-associated separation, with validation cohort AUCs of 0.99 (lipidome), 0.89 (metabolome), and 0.87 (microbiome). Functional metagenome analysis revealed enrichment of amino acid biosynthesis, inositol degradation, and the pentose phosphate pathway in vegans, while omnivores presented greater potential for amino acid fermentation, fatty acid biosynthesis, and propanoate metabolism. Linear models identified a robust, country-independent \"vegan signature\" consisting of 27 lipid metabolites, five non-lipid metabolites, and 11 bacterial species. Several lipid features associated with an omnivorous diet were inversely related to the duration of vegan diet adherence. Some of the vegan-associated metabolites and bacteria have been previously linked to favorable cardiometabolic profiles, although causality remains to be established.These findings demonstrate that vegan diets are associated with reproducible, country-independent molecular and microbial signatures. Our results highlight diet-driven shifts in host-microbiota interactions and provide a framework for understanding how dietary patterns relate to host-microbiota interactions.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"55 1","pages":"2593050"},"PeriodicalIF":12.2,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The gut microbiota plays a crucial role in lipid metabolism in both humans and animals. However, the specific contributions of gut microbiota and their associated metabolites to fat deposition, as well as the underlying mechanisms, remain largely unexplored. In this study, we demonstrated that the intestinal microbiota mediated the heterogeneity of mesenteric fat index (MFI), as evidenced by fecal microbiota transplantation (FMT) experiments. Notably, analysis of the 16S rRNA gene amplicon sequencing of 44 samples revealed a significantly higher abundance of Cetobacterium somerae in the Low MFI group, with a positive correlation to reduced MFI. Serum metabolomics analysis confirmed that L-Carnitine emerged as the most differentially abundant metabolite in the Low MFI group and exhibited a strong positive correlation with C. somerae abundance. Metagenomic analysis showed that microbial genes related to L-Carnitine biosynthesis were significantly enriched in the Low MFI group. Further, C. somerae was isolated and cultured, and its subsequent monocolonization in germ-free zebrafish and tilapia demonstrated its lipid-lowering effects by enhancing mitochondrial fatty acid β-oxidation. Whole genome sequencing demonstrated C. somerae could encode the [EC:1.2.1.3] gene, which promotes the production of 4-trimethylammoniobutanoate, a precursor of L-Carnitine, thereby enhancing L-Carnitine biosynthesis by the host and gut microbiota, leading to the reduced fat deposition in Nile tilapia. In conclusion, C. somerae, a core gut microbe with high abundance in aquatic teleost intestines, plays an important role in host lipid metabolism. This study advances our understanding of how core gut microbes shape host phenotypes and provides novel insights into manipulating core gut colonizers to reduce fat deposition.
{"title":"Intestinal microbiota contributes to the heterogeneity of fat deposition by promoting mitochondrial fatty acid β-oxidation.","authors":"Lukuan Li,Nannan Zhou,Zhe Wang,Tong Wang,Yuexin Wang,Fang Qiao,Zhen-Yu Du,Mei-Ling Zhang","doi":"10.1080/19490976.2025.2593076","DOIUrl":"https://doi.org/10.1080/19490976.2025.2593076","url":null,"abstract":"The gut microbiota plays a crucial role in lipid metabolism in both humans and animals. However, the specific contributions of gut microbiota and their associated metabolites to fat deposition, as well as the underlying mechanisms, remain largely unexplored. In this study, we demonstrated that the intestinal microbiota mediated the heterogeneity of mesenteric fat index (MFI), as evidenced by fecal microbiota transplantation (FMT) experiments. Notably, analysis of the 16S rRNA gene amplicon sequencing of 44 samples revealed a significantly higher abundance of Cetobacterium somerae in the Low MFI group, with a positive correlation to reduced MFI. Serum metabolomics analysis confirmed that L-Carnitine emerged as the most differentially abundant metabolite in the Low MFI group and exhibited a strong positive correlation with C. somerae abundance. Metagenomic analysis showed that microbial genes related to L-Carnitine biosynthesis were significantly enriched in the Low MFI group. Further, C. somerae was isolated and cultured, and its subsequent monocolonization in germ-free zebrafish and tilapia demonstrated its lipid-lowering effects by enhancing mitochondrial fatty acid β-oxidation. Whole genome sequencing demonstrated C. somerae could encode the [EC:1.2.1.3] gene, which promotes the production of 4-trimethylammoniobutanoate, a precursor of L-Carnitine, thereby enhancing L-Carnitine biosynthesis by the host and gut microbiota, leading to the reduced fat deposition in Nile tilapia. In conclusion, C. somerae, a core gut microbe with high abundance in aquatic teleost intestines, plays an important role in host lipid metabolism. This study advances our understanding of how core gut microbes shape host phenotypes and provides novel insights into manipulating core gut colonizers to reduce fat deposition.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"359 1","pages":"2593076"},"PeriodicalIF":12.2,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1080/19490976.2025.2566978
Xiaobei Zhang,Tien S Dong,Gilbert C Gee,Lisa A Kilpatrick,Hiram Beltran-Sanchez,May C Wang,Allison Vaughan,Arpana Church
Social relationships play a crucial role in shaping health. To better understand the underlying mechanisms, we explored the independent and interactive effects of perceived emotional support (PES) and marital status on body mass index (BMI), eating behaviors, brain reactivity to food images, plasma oxytocin, and alterations in the brain-gut microbiome (BGM) system. Brain responses to food stimuli, fecal metabolites, and plasma oxytocin levels were measured in 94 participants. Structural equation modeling was used to determine the integrated pathways linking social factors to obesity-related outcomes. Marital status and PES interact and independently influence lower BMI, healthier eating behaviors, increased oxytocin levels, food-cue reactivity in frontal brain regions involved in craving inhibition and executive control, and tryptophan-pathway metabolites related to inflammation, immune regulation, and energy homeostasis. These findings suggest that supportive human relationships, particularly high-quality marital bonds, may regulate obesity risk through oxytocin-mediated alterations in brain and gut pathways.
{"title":"Social bonds and health: exploring the impact of social relations on oxytocin and brain-gut communication in shaping obesity.","authors":"Xiaobei Zhang,Tien S Dong,Gilbert C Gee,Lisa A Kilpatrick,Hiram Beltran-Sanchez,May C Wang,Allison Vaughan,Arpana Church","doi":"10.1080/19490976.2025.2566978","DOIUrl":"https://doi.org/10.1080/19490976.2025.2566978","url":null,"abstract":"Social relationships play a crucial role in shaping health. To better understand the underlying mechanisms, we explored the independent and interactive effects of perceived emotional support (PES) and marital status on body mass index (BMI), eating behaviors, brain reactivity to food images, plasma oxytocin, and alterations in the brain-gut microbiome (BGM) system. Brain responses to food stimuli, fecal metabolites, and plasma oxytocin levels were measured in 94 participants. Structural equation modeling was used to determine the integrated pathways linking social factors to obesity-related outcomes. Marital status and PES interact and independently influence lower BMI, healthier eating behaviors, increased oxytocin levels, food-cue reactivity in frontal brain regions involved in craving inhibition and executive control, and tryptophan-pathway metabolites related to inflammation, immune regulation, and energy homeostasis. These findings suggest that supportive human relationships, particularly high-quality marital bonds, may regulate obesity risk through oxytocin-mediated alterations in brain and gut pathways.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"30 1","pages":"2566978"},"PeriodicalIF":12.2,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Crohn's disease (CD), a chronic inflammatory bowel disorder, often progresses to intestinal fibrosis and stricture, yet no effective anti-fibrotic treatments exist. This study reveals dipeptidyl peptidase 4 (DPP4) as a pivotal driver of fibrosis through bioinformatics analysis, clinical samples, and experimental models. Elevated DPP4 expression was observed in stenotic intestinal tissues of CD patients and dextran sodium sulfate (DSS)-induced fibrotic mice. Mechanistically, both membrane-bound DPP4 and soluble DPP4 (sDPP4) activated human intestinal myofibroblasts (HIMFs) via the PI3K-AKT pathway, stimulating migration, proliferation, and extracellular matrix deposition. Importantly, metagenomic sequencing revealed enrichment of microbial Dpp4 genes in fecal samples from CD patients with stenosis, and in vivo colonization with engineered E. coli overexpressing microbial DPP4 exacerbated fibrotic remodeling, confirming microbiota-derived DPP4 (mDPP4) as a pathogenic driver. Furthermore, pharmacological inhibition of host DPP4 (sitagliptin) or selective blockade of mDPP4 (Dau-d4) attenuated fibrosis in murine models, with combined therapy showing enhanced efficacy. These findings underscore the roles of DPP4, originating from both host and microbiota, and existing in membrane-bound and soluble forms, in promoting CD-associated intestinal fibrosis. This study identifies DPP4 as a novel therapeutic target, proposing dual-source inhibition as a promising strategy to prevent stricture formation in CD patients, thereby addressing a critical unmet clinical need.
{"title":"Dual-source DPP4 drives intestinal fibrosis in Crohn's disease: synergistic therapeutic targeting of host and microbiota pathways.","authors":"Jiajia Li,Ying Xu,Mingyuan Wang,Junjie Lin,Junjian Sun,Jingjing Ma,Hongjie Zhang","doi":"10.1080/19490976.2025.2593119","DOIUrl":"https://doi.org/10.1080/19490976.2025.2593119","url":null,"abstract":"Crohn's disease (CD), a chronic inflammatory bowel disorder, often progresses to intestinal fibrosis and stricture, yet no effective anti-fibrotic treatments exist. This study reveals dipeptidyl peptidase 4 (DPP4) as a pivotal driver of fibrosis through bioinformatics analysis, clinical samples, and experimental models. Elevated DPP4 expression was observed in stenotic intestinal tissues of CD patients and dextran sodium sulfate (DSS)-induced fibrotic mice. Mechanistically, both membrane-bound DPP4 and soluble DPP4 (sDPP4) activated human intestinal myofibroblasts (HIMFs) via the PI3K-AKT pathway, stimulating migration, proliferation, and extracellular matrix deposition. Importantly, metagenomic sequencing revealed enrichment of microbial Dpp4 genes in fecal samples from CD patients with stenosis, and in vivo colonization with engineered E. coli overexpressing microbial DPP4 exacerbated fibrotic remodeling, confirming microbiota-derived DPP4 (mDPP4) as a pathogenic driver. Furthermore, pharmacological inhibition of host DPP4 (sitagliptin) or selective blockade of mDPP4 (Dau-d4) attenuated fibrosis in murine models, with combined therapy showing enhanced efficacy. These findings underscore the roles of DPP4, originating from both host and microbiota, and existing in membrane-bound and soluble forms, in promoting CD-associated intestinal fibrosis. This study identifies DPP4 as a novel therapeutic target, proposing dual-source inhibition as a promising strategy to prevent stricture formation in CD patients, thereby addressing a critical unmet clinical need.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"9 1","pages":"2593119"},"PeriodicalIF":12.2,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDOsteoporosis is an age-related disease. The relationship between gut microbiota (GM) homeostasis and bone health is well established, but the mechanism of GM dysbiosis contributes to senile osteoporosis remains elusive. The objective of this study is to investigate the relationship between GM, bile acids (BAs) and their effects on bone mass.RESULTS16S rRNA sequencing and untargeted and targeted metabolomics revealed a reduction in microbial diversity, accompanied by the change of BA profile. In particular, the abundance of Parabacteroides goldsteinii and hyodeoxycholic acid (HDCA) in old mice were markedly decreased, compared with young mice. And there was a strong positive correlation between the abundance of P. goldsteinii and HDCA and bone mass. Further, our results demonstrated that old mice cohoused with young mice, with/without coprophagy prevention, were unable to alter the GM composition or reverse age-related bone loss. The transplantation of GM from young mice into old mice, rather than the transplantation of P. goldsteinii alone, reconstructed the GM of old mice and preserved bone mass by inhibiting bone resorption. Mechanistically, HDCA inhibits osteoclast maturation in vitro and exerts the bone protection effect in vivo through the activation of the G protein-coupled bile acid receptor (TGR5). HDCA treatment has been shown to result in the internalization of TGR5, thereby inhibiting the nuclear translocation of P65 in vivo. Knockout of TGR5 attenuated the effects of HDCA on bone microstructure, confirming these findings.CONCLUSIONSThis study identified the GM-HDCA-TGR5 axis is a key pathway that affects bone mass and targeted intervention of HDCA represents potential therapeutic option for osteoporosis.
{"title":"Gut microbiota preserves bone mass through modulating the hyodeoxycholic acid-TGR5 axis.","authors":"Xuan-Qi Zheng,Jie Huang,Wan-Qiong Yuan,Tong Wu,Huan Wang,Hao Liu,Yun-Di Zhang,Jin-Wen He,Chen Huang,Chun-Li Song","doi":"10.1080/19490976.2025.2593088","DOIUrl":"https://doi.org/10.1080/19490976.2025.2593088","url":null,"abstract":"BACKGROUNDOsteoporosis is an age-related disease. The relationship between gut microbiota (GM) homeostasis and bone health is well established, but the mechanism of GM dysbiosis contributes to senile osteoporosis remains elusive. The objective of this study is to investigate the relationship between GM, bile acids (BAs) and their effects on bone mass.RESULTS16S rRNA sequencing and untargeted and targeted metabolomics revealed a reduction in microbial diversity, accompanied by the change of BA profile. In particular, the abundance of Parabacteroides goldsteinii and hyodeoxycholic acid (HDCA) in old mice were markedly decreased, compared with young mice. And there was a strong positive correlation between the abundance of P. goldsteinii and HDCA and bone mass. Further, our results demonstrated that old mice cohoused with young mice, with/without coprophagy prevention, were unable to alter the GM composition or reverse age-related bone loss. The transplantation of GM from young mice into old mice, rather than the transplantation of P. goldsteinii alone, reconstructed the GM of old mice and preserved bone mass by inhibiting bone resorption. Mechanistically, HDCA inhibits osteoclast maturation in vitro and exerts the bone protection effect in vivo through the activation of the G protein-coupled bile acid receptor (TGR5). HDCA treatment has been shown to result in the internalization of TGR5, thereby inhibiting the nuclear translocation of P65 in vivo. Knockout of TGR5 attenuated the effects of HDCA on bone microstructure, confirming these findings.CONCLUSIONSThis study identified the GM-HDCA-TGR5 axis is a key pathway that affects bone mass and targeted intervention of HDCA represents potential therapeutic option for osteoporosis.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"153 1","pages":"2593088"},"PeriodicalIF":12.2,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-02-16DOI: 10.1080/19490976.2025.2467235
Han Gao, Mingming Sun, Ai Li, Qiaoyan Gu, Dengfeng Kang, Zhongsheng Feng, Xiaoyu Li, Xuehong Wang, Liang Chen, Hong Yang, Yingzi Cong, Zhanju Liu
The gut microbiota-derived metabolite indole-3-propionic acid (IPA) plays an important role in maintaining intestinal mucosal homeostasis, while the molecular mechanisms underlying IPA regulation on mucosal CD4+ T cell functions in inflammatory bowel disease (IBD) remain elusive. Here we investigated the roles of IPA in modulating mucosal CD4+ T cells and its therapeutic potential in treatment of human IBD. Leveraging metabolomics and microbial community analyses, we observed that the levels of IPA-producing microbiota (e.g. Peptostreptococcus, Clostridium, and Fournierella) and IPA were decreased, while the IPA-consuming microbiota (e.g. Parabacteroides, Erysipelatoclostridium, and Lachnoclostridium) were increased in the feces of IBD patients than those in healthy donors. Dextran sulfate sodium (DSS)-induced acute colitis and CD45RBhighCD4+ T cell transfer-induced chronic colitis models were then established in mice and treated orally with IPA to study its role in intestinal mucosal inflammation in vivo. We found that oral administration of IPA attenuated mucosal inflammation in both acute and chronic colitis models in mice, as characterized by increased body weight, and reduced levels of pro-inflammatory cytokines (e.g. TNF-α, IFN-γ, and IL-17A) and histological scores in the colon. We further utilized RNA sequencing, molecular docking simulations, and surface plasmon resonance analyses and identified that IPA exerts its biological effects by interacting with heat shock protein 70 (HSP70), leading to inducing Th1/Th17 cell apoptosis. Consistently, ectopic expression of HSP70 in CD4+ T cells conferred resistance to IPA-induced Th1/Th17 cell apoptosis. Therefore, these findings identify a previously unrecognized pathway by which IPA modulates intestinal inflammation and provide a promising avenue for the treatment of IBD.
{"title":"Microbiota-derived IPA alleviates intestinal mucosal inflammation through upregulating Th1/Th17 cell apoptosis in inflammatory bowel disease.","authors":"Han Gao, Mingming Sun, Ai Li, Qiaoyan Gu, Dengfeng Kang, Zhongsheng Feng, Xiaoyu Li, Xuehong Wang, Liang Chen, Hong Yang, Yingzi Cong, Zhanju Liu","doi":"10.1080/19490976.2025.2467235","DOIUrl":"10.1080/19490976.2025.2467235","url":null,"abstract":"<p><p>The gut microbiota-derived metabolite indole-3-propionic acid (IPA) plays an important role in maintaining intestinal mucosal homeostasis, while the molecular mechanisms underlying IPA regulation on mucosal CD4<sup>+</sup> T cell functions in inflammatory bowel disease (IBD) remain elusive. Here we investigated the roles of IPA in modulating mucosal CD4<sup>+</sup> T cells and its therapeutic potential in treatment of human IBD. Leveraging metabolomics and microbial community analyses, we observed that the levels of IPA-producing microbiota (e.g. <i>Peptostreptococcus</i>, <i>Clostridium</i>, and <i>Fournierella</i>) and IPA were decreased, while the IPA-consuming microbiota (e.g. <i>Parabacteroides</i>, <i>Erysipelatoclostridium</i>, and <i>Lachnoclostridium</i>) were increased in the feces of IBD patients than those in healthy donors. Dextran sulfate sodium (DSS)-induced acute colitis and CD45RB<sup>high</sup>CD4<sup>+</sup> T cell transfer-induced chronic colitis models were then established in mice and treated orally with IPA to study its role in intestinal mucosal inflammation <i>in vivo</i>. We found that oral administration of IPA attenuated mucosal inflammation in both acute and chronic colitis models in mice, as characterized by increased body weight, and reduced levels of pro-inflammatory cytokines (e.g. TNF-α, IFN-γ, and IL-17A) and histological scores in the colon. We further utilized RNA sequencing, molecular docking simulations, and surface plasmon resonance analyses and identified that IPA exerts its biological effects by interacting with heat shock protein 70 (HSP70), leading to inducing Th1/Th17 cell apoptosis. Consistently, ectopic expression of HSP70 in CD4<sup>+</sup> T cells conferred resistance to IPA-induced Th1/Th17 cell apoptosis. Therefore, these findings identify a previously unrecognized pathway by which IPA modulates intestinal inflammation and provide a promising avenue for the treatment of IBD.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2467235"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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