Pub Date : 2025-12-22DOI: 10.1080/19490976.2025.2606477
Haengdueng Jeong,Yura Lee,Ki Taek Nam
The gut microbiota plays a pivotal role in maintaining gastrointestinal (GI) homeostasis by influencing epithelial integrity, immunity, and metabolism. Recent studies have uncovered that gut microbiota can directly or indirectly modulate the behavior and function of adult stem cells across the GI tract, which are essential for tissue regeneration and disease prevention. Moreover, key microbial metabolites including short-chain fatty acids (SCFAs), tryptophan-derived indoles, succinate, secondary bile acids, and retinoic acid exert diverse effects on stem cell quiescence, proliferation, and differentiation. This review provides current knowledge on the interaction between gut microbiota and host stem cells in the stomach, intestine, and colon.
{"title":"Impact of gut microbiota on host stem cells across the gastrointestinal tract.","authors":"Haengdueng Jeong,Yura Lee,Ki Taek Nam","doi":"10.1080/19490976.2025.2606477","DOIUrl":"https://doi.org/10.1080/19490976.2025.2606477","url":null,"abstract":"The gut microbiota plays a pivotal role in maintaining gastrointestinal (GI) homeostasis by influencing epithelial integrity, immunity, and metabolism. Recent studies have uncovered that gut microbiota can directly or indirectly modulate the behavior and function of adult stem cells across the GI tract, which are essential for tissue regeneration and disease prevention. Moreover, key microbial metabolites including short-chain fatty acids (SCFAs), tryptophan-derived indoles, succinate, secondary bile acids, and retinoic acid exert diverse effects on stem cell quiescence, proliferation, and differentiation. This review provides current knowledge on the interaction between gut microbiota and host stem cells in the stomach, intestine, and colon.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"45 1","pages":"2606477"},"PeriodicalIF":12.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801334","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 : 2025-12-19DOI: 10.1080/19490976.2025.2597567
Marcus Petersson,Jens Sivkær Pettersen,Helena Bay Henriksen,Ágnes Duzs,Monica L Fernández-Quintero,Nick Jean Burlet,Natalia Mojica,Ute Krengel,Timothy P Jenkins,Andrew B Ward,Thomas Emil Andersen,Jakob Møller-Jensen,Lone Gram,Andreas Hougaard Laustsen,Sandra Wingaard Thrane
Bacterial enteric pathogens are major contributors to the global burden of diarrheal diseases and the associated consequences for human health including malnutrition, growth stunting, morbidity, and mortality. While mortality from diarrhea has decreased, incidence remains high, and better interventions for preventing disease are needed. Single-domain antibodies (i.e., VHHs), functioning as target-binding proteins in the gastrointestinal tract, have been proposed as a potential approach to mitigate bacterial pathogenesis. Here, we describe a mitigation strategy where precision binding of a bivalent VHH to the receptor-binding B-pentamer of heat-labile enterotoxin aggregates the AB5 toxin and impairs enterotoxigenic Escherichia coli colonization in a flow chamber model simulating the human intestine. The VHH construct also binds to the structurally similar cholera toxin and effectively abrogates its intestinal cell cytotoxicity in vitro. Based on these results, we believe that targeting virulence could emerge as a new strategy for the management of bacterial enteric pathogens, supporting gut health in at-risk populations alongside vaccination campaigns or in populations without access to vaccines.
{"title":"Attenuating ETEC virulence using a heat-labile enterotoxin-blocking binding protein.","authors":"Marcus Petersson,Jens Sivkær Pettersen,Helena Bay Henriksen,Ágnes Duzs,Monica L Fernández-Quintero,Nick Jean Burlet,Natalia Mojica,Ute Krengel,Timothy P Jenkins,Andrew B Ward,Thomas Emil Andersen,Jakob Møller-Jensen,Lone Gram,Andreas Hougaard Laustsen,Sandra Wingaard Thrane","doi":"10.1080/19490976.2025.2597567","DOIUrl":"https://doi.org/10.1080/19490976.2025.2597567","url":null,"abstract":"Bacterial enteric pathogens are major contributors to the global burden of diarrheal diseases and the associated consequences for human health including malnutrition, growth stunting, morbidity, and mortality. While mortality from diarrhea has decreased, incidence remains high, and better interventions for preventing disease are needed. Single-domain antibodies (i.e., VHHs), functioning as target-binding proteins in the gastrointestinal tract, have been proposed as a potential approach to mitigate bacterial pathogenesis. Here, we describe a mitigation strategy where precision binding of a bivalent VHH to the receptor-binding B-pentamer of heat-labile enterotoxin aggregates the AB5 toxin and impairs enterotoxigenic Escherichia coli colonization in a flow chamber model simulating the human intestine. The VHH construct also binds to the structurally similar cholera toxin and effectively abrogates its intestinal cell cytotoxicity in vitro. Based on these results, we believe that targeting virulence could emerge as a new strategy for the management of bacterial enteric pathogens, supporting gut health in at-risk populations alongside vaccination campaigns or in populations without access to vaccines.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"111 1","pages":"2597567"},"PeriodicalIF":12.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777415","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}
Alzheimer's disease (AD) is the most common form of dementia, with a higher prevalence in women than in men. It has been suggested that the decline in estrogen production after menopause may increase the risk of developing dementia. Additionally, patients with AD often display dysbiosis of the gut microbiota (GM), even in the early stages of the disease. The GM plays a crucial role in modulating systemic estrogen levels through a mechanism known as the estrobolome. However, it remains unclear whether gut dysbiosis contributes to estrogen imbalance and subsequent cognitive decline in women. In this study, we aim to investigate whether alterations in the GM impact estrogen availability and cognitive function in 6-month-old female APP/PS1 (TG) mice compared to age-matched wild-type (WT) littermates. We included a group of both WT and TG mice treated with a broad-spectrum antibiotic cocktail (ABX) for one month to modify their GM composition. Our results revealed that TG mice exhibited a dysfunctional estrobolome characterized by a decreased abundance of Limosilactobacillus and Lactobacillus, an increased abundance of Ligilactobacillus, and reduced activity of the β-glucuronidase enzyme in fecal samples. Additionally, TG female mice showed low bioavailability of estradiol, disrupted estrous cycle, and cognitive impairments. Notably, WT-ABX mice displayed gut dysbiosis, marked by a decrease in the relative abundances of Limosilactobacillus and Lactobacillus, as well as reduced β-glucuronidase activity. Moreover, WT-ABX exhibited altered estradiol levels and cognitive impairments compared to WT controls. Therefore, our findings suggest that gut dysbiosis may be a contributing factor to female vulnerability in developing dementia by disrupting hormonal levels and cognitive function.
{"title":"Gut dysbiosis impacts estrogen levels in APP/PS1 transgenic female mice.","authors":"Ivonne Sagrario Romero-Flores,Jaime García-Mena,Claudia Perez-Cruz","doi":"10.1080/19490976.2025.2599525","DOIUrl":"https://doi.org/10.1080/19490976.2025.2599525","url":null,"abstract":"Alzheimer's disease (AD) is the most common form of dementia, with a higher prevalence in women than in men. It has been suggested that the decline in estrogen production after menopause may increase the risk of developing dementia. Additionally, patients with AD often display dysbiosis of the gut microbiota (GM), even in the early stages of the disease. The GM plays a crucial role in modulating systemic estrogen levels through a mechanism known as the estrobolome. However, it remains unclear whether gut dysbiosis contributes to estrogen imbalance and subsequent cognitive decline in women. In this study, we aim to investigate whether alterations in the GM impact estrogen availability and cognitive function in 6-month-old female APP/PS1 (TG) mice compared to age-matched wild-type (WT) littermates. We included a group of both WT and TG mice treated with a broad-spectrum antibiotic cocktail (ABX) for one month to modify their GM composition. Our results revealed that TG mice exhibited a dysfunctional estrobolome characterized by a decreased abundance of Limosilactobacillus and Lactobacillus, an increased abundance of Ligilactobacillus, and reduced activity of the β-glucuronidase enzyme in fecal samples. Additionally, TG female mice showed low bioavailability of estradiol, disrupted estrous cycle, and cognitive impairments. Notably, WT-ABX mice displayed gut dysbiosis, marked by a decrease in the relative abundances of Limosilactobacillus and Lactobacillus, as well as reduced β-glucuronidase activity. Moreover, WT-ABX exhibited altered estradiol levels and cognitive impairments compared to WT controls. Therefore, our findings suggest that gut dysbiosis may be a contributing factor to female vulnerability in developing dementia by disrupting hormonal levels and cognitive function.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"34 1","pages":"2599525"},"PeriodicalIF":12.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777426","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}
Lifestyle factors influence both gut microbiome composition and host metabolism, yet their combined and mediating effects on host phenotypes remain poorly characterized in cardiometabolic populations. In 1,643 participants from the MetaCardis study, we developed a composite lifestyle score (QASD: dietary quality, physical activity, smoking, and diet diversity) that outperformed individual lifestyle variables in explaining microbial gene richness and exhibited a significant impact on the gut microbiome composition. While bidirectional pathways linking the QASD score, host phenotypes, and microbiome composition were assessed, causal inference-based mediation analyses indicated stronger effects when the microbiome was modeled as the mediator variable, particularly in relation to the insulin resistance-associated profile. Microbiome gene richness emerged as a key mediator explaining 27.8% of QASD score's effect on the insulin resistance marker (HOMA-IR), while no significant mediation was observed on BMI. Extended mediation analyses on microbial species and serum metabolomics deconfounded for drug use and clinical profiles identified 47 mediations where microbial taxa mediated more than 20% of the effect of the QASD score on serum metabolites associated with insulin resistance. Notably, several Faecalibacterium lineages enriched in individuals with high QASD score played a significant mediatory role in increasing the serum biomarkers of microbiome diversity (as cinnamoylglycine or 3-phenylpropionate). Conversely, elevated levels of secondary bile acids in individuals with low QASD scores were strongly mediated by high levels of Clostridium bolteae. These findings highlight distinct and clinically relevant microbiome pathways linking lifestyle behaviors to cardiometabolic risks.One sentence summary:The gut microbiome mediates the impact of diet quality and diversity, physical activity and smoking status - combined in a composite lifestyle score - on cardiometabolic phenotypes.
{"title":"Prominent mediatory role of gut microbiome in the effect of lifestyle on host metabolic phenotypes.","authors":"Solia Adriouch,Eugeni Belda,Timothy D Swartz,Sofia Forslund,Edi Prifti,Judith Aron-Wisnewsky,Rima Chakaroun,Trine Nielsen,Christine Poitou,Pierre Bel-Lassen,Christine Rouault,Tiphaine Le Roy,Petros Andrikopoulos,Kanta Chechi,Francesc Puig-Castellví,Inés Castro Dionicio,Philippe Froguel,Bridget Holmes,Rohia Alili,Fabrizio Andreelli,Hedi Soula,Joe-Elie Salem,Gwen Falony,Sara Vieira-Silva, ,Jeroen Raes,Peer Bork,Michael Stumvoll,Oluf Pedersen,S Dusko Ehrlich,Marc-Emmanuel Dumas,Jean-Michel Oppert,Maria Carlota Dao,Jean-Daniel Zucker,Karine Clément","doi":"10.1080/19490976.2025.2599565","DOIUrl":"https://doi.org/10.1080/19490976.2025.2599565","url":null,"abstract":"Lifestyle factors influence both gut microbiome composition and host metabolism, yet their combined and mediating effects on host phenotypes remain poorly characterized in cardiometabolic populations. In 1,643 participants from the MetaCardis study, we developed a composite lifestyle score (QASD: dietary quality, physical activity, smoking, and diet diversity) that outperformed individual lifestyle variables in explaining microbial gene richness and exhibited a significant impact on the gut microbiome composition. While bidirectional pathways linking the QASD score, host phenotypes, and microbiome composition were assessed, causal inference-based mediation analyses indicated stronger effects when the microbiome was modeled as the mediator variable, particularly in relation to the insulin resistance-associated profile. Microbiome gene richness emerged as a key mediator explaining 27.8% of QASD score's effect on the insulin resistance marker (HOMA-IR), while no significant mediation was observed on BMI. Extended mediation analyses on microbial species and serum metabolomics deconfounded for drug use and clinical profiles identified 47 mediations where microbial taxa mediated more than 20% of the effect of the QASD score on serum metabolites associated with insulin resistance. Notably, several Faecalibacterium lineages enriched in individuals with high QASD score played a significant mediatory role in increasing the serum biomarkers of microbiome diversity (as cinnamoylglycine or 3-phenylpropionate). Conversely, elevated levels of secondary bile acids in individuals with low QASD scores were strongly mediated by high levels of Clostridium bolteae. These findings highlight distinct and clinically relevant microbiome pathways linking lifestyle behaviors to cardiometabolic risks.One sentence summary:The gut microbiome mediates the impact of diet quality and diversity, physical activity and smoking status - combined in a composite lifestyle score - on cardiometabolic phenotypes.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"1 1","pages":"2599565"},"PeriodicalIF":12.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771397","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 is a key modulator of host immunity, in part through the production of structurally diverse and largely still uncharacterized bacterial lipids and metabolites with potential immunoregulatory properties. Using a gnotobiotic Oligo-Mouse-Microbiota (OMM12) mouse model infected with the Citrobacter rodentium pathogen, we investigated metabolomic changes associated with colitis. Untargeted metabolomics revealed an accumulation of host-derived lipids in the inflamed colon, while several bacterial lipid classes, including sphingolipids, glycerophospholipids, and fatty acyls were depleted. Among the bacterial lipids, ornithine-containing lipids (OLs) produced by Akkermansia muciniphila were significantly reduced during inflammation. Isolation, structural characterization, and chemical synthesis revealed OL 16:0/15:0 as a membrane-associated lipid from A. muciniphila. This lipid contains an L-ornithine head group, with its α-amino group forming an amide bond with 3(R)-hydroxypalmitic acid, while the 3(R)-hydroxyl position is esterified with pentadecanoic acid. Functional studies showed that macrophages internalize and partially metabolize OL 16:0/15:0 into Nα-(3-hydroxypalmitoyl)-L-ornithine and 3(R)-hydroxypalmitic acid. In LPS-stimulated macrophages, a 1:1 mixture of OL diastereomers (3R,S + 3S,S) reduced Il6 and Il1b gene expression and decreased IL-6 secretion, without triggering IL-1β release. Interestingly, this diastereomeric mixture exhibited an opposite effect to the natural (3R,S)-epimer, which selectively promoted IL-1β secretion in LPS-primed macrophages. These results uncover a possible stereoselective modulation of IL-1β production by bacterial OLs. Overall, OL 16:0/15:0 is dynamically regulated during inflammation and may play a role in the immunomodulation of host-microbiota interactions.
{"title":"Ornithine lipids from Akkermansia muciniphila are dynamically modulated in colitis and shape macrophage inflammatory responses.","authors":"Habiba Selmi,Alesia Walker,Laurence Balas,Marianna Lucio,Markus Klotz,Aicha Jeridi,Anna G Burrichter,Devon Conti,Lorenzo Chaffringeon,Brice Beinsteiner,Marion Jasnin,Nicolas Vanthuyne,Thierry Durand,Ali Önder Yildirim,Bärbel Stecher,Laurent Debarbieux,Philippe Schmitt-Kopplin","doi":"10.1080/19490976.2025.2601376","DOIUrl":"https://doi.org/10.1080/19490976.2025.2601376","url":null,"abstract":"The gut microbiota is a key modulator of host immunity, in part through the production of structurally diverse and largely still uncharacterized bacterial lipids and metabolites with potential immunoregulatory properties. Using a gnotobiotic Oligo-Mouse-Microbiota (OMM12) mouse model infected with the Citrobacter rodentium pathogen, we investigated metabolomic changes associated with colitis. Untargeted metabolomics revealed an accumulation of host-derived lipids in the inflamed colon, while several bacterial lipid classes, including sphingolipids, glycerophospholipids, and fatty acyls were depleted. Among the bacterial lipids, ornithine-containing lipids (OLs) produced by Akkermansia muciniphila were significantly reduced during inflammation. Isolation, structural characterization, and chemical synthesis revealed OL 16:0/15:0 as a membrane-associated lipid from A. muciniphila. This lipid contains an L-ornithine head group, with its α-amino group forming an amide bond with 3(R)-hydroxypalmitic acid, while the 3(R)-hydroxyl position is esterified with pentadecanoic acid. Functional studies showed that macrophages internalize and partially metabolize OL 16:0/15:0 into Nα-(3-hydroxypalmitoyl)-L-ornithine and 3(R)-hydroxypalmitic acid. In LPS-stimulated macrophages, a 1:1 mixture of OL diastereomers (3R,S + 3S,S) reduced Il6 and Il1b gene expression and decreased IL-6 secretion, without triggering IL-1β release. Interestingly, this diastereomeric mixture exhibited an opposite effect to the natural (3R,S)-epimer, which selectively promoted IL-1β secretion in LPS-primed macrophages. These results uncover a possible stereoselective modulation of IL-1β production by bacterial OLs. Overall, OL 16:0/15:0 is dynamically regulated during inflammation and may play a role in the immunomodulation of host-microbiota interactions.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"1 1","pages":"2601376"},"PeriodicalIF":12.2,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759963","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 : 2025-12-15DOI: 10.1080/19490976.2025.2597568
Haya Abbas-Egbariya,Lubna Elwahidi,David Jessula Levy,Tzipi Braun,Nina Levhar,Rotem Hadar,Gilat Efroni,Maya Granot,Yael Leichtmann-Bardogoo,Ben M Maoz,Batia Weiss,Ohad Gal-Mor,Bella Agranovich,Ifat Abramovich,Lee Denson,Shomron Ben-Horin,Kelli L VanDussen,Amnon Amir,Yael Haberman
Despite epithelial involvement in inflammatory bowel disease (IBD) pathogenesis and the gaps in treatment goals with existing immune-directed therapy, epithelial-directed interventions are unavailable. Using patient-based models, we aimed to identify bioactive endogenous metabolites that can improve IBD epithelial dysfunction, are generally regarded as safe, and can enhance epithelial homeostasis. We pooled fecal material from subjects with and without IBD to capture patient heterogeneity and analyzed the fecal contents for microbiome composition and metabolomics. Epithelial cells (Caco-2 cells and patient-derived colonoids) were cultured, and fecal material was applied apically to replicate the gut's physiological orientation. Measurable epithelial outputs included epithelial proinflammatory signals, integrity, and cellular ATP levels. We show that fecal content pools from several independent IBD patients disturb epithelial functions significantly more than does the fecal content from controls. Improved epithelial readouts in the functional patient-based models were linked with several gut metabolite levels, and these findings were further validated in an independent published human biospecimen multi-omics in vivo cohort. This guided the supplementation of five prioritized metabolites (azelate, pyridoxal, fructose-6-phosphate, galactose 1-phosphate, and ribose 5-phosphate) into the IBD fecal content, which reversed the related IBD epithelial dysfunction. We streamline a proof-of-concept pipeline for the prioritization of epithelial-targeted metabolite interventions that can direct safe future novel adjunct interventions.
{"title":"Supplementation with endogenous healthy gut metabolites reverses the disruptions of in vitro and ex vivo epithelial functions induced by fecal content from IBD patients.","authors":"Haya Abbas-Egbariya,Lubna Elwahidi,David Jessula Levy,Tzipi Braun,Nina Levhar,Rotem Hadar,Gilat Efroni,Maya Granot,Yael Leichtmann-Bardogoo,Ben M Maoz,Batia Weiss,Ohad Gal-Mor,Bella Agranovich,Ifat Abramovich,Lee Denson,Shomron Ben-Horin,Kelli L VanDussen,Amnon Amir,Yael Haberman","doi":"10.1080/19490976.2025.2597568","DOIUrl":"https://doi.org/10.1080/19490976.2025.2597568","url":null,"abstract":"Despite epithelial involvement in inflammatory bowel disease (IBD) pathogenesis and the gaps in treatment goals with existing immune-directed therapy, epithelial-directed interventions are unavailable. Using patient-based models, we aimed to identify bioactive endogenous metabolites that can improve IBD epithelial dysfunction, are generally regarded as safe, and can enhance epithelial homeostasis. We pooled fecal material from subjects with and without IBD to capture patient heterogeneity and analyzed the fecal contents for microbiome composition and metabolomics. Epithelial cells (Caco-2 cells and patient-derived colonoids) were cultured, and fecal material was applied apically to replicate the gut's physiological orientation. Measurable epithelial outputs included epithelial proinflammatory signals, integrity, and cellular ATP levels. We show that fecal content pools from several independent IBD patients disturb epithelial functions significantly more than does the fecal content from controls. Improved epithelial readouts in the functional patient-based models were linked with several gut metabolite levels, and these findings were further validated in an independent published human biospecimen multi-omics in vivo cohort. This guided the supplementation of five prioritized metabolites (azelate, pyridoxal, fructose-6-phosphate, galactose 1-phosphate, and ribose 5-phosphate) into the IBD fecal content, which reversed the related IBD epithelial dysfunction. We streamline a proof-of-concept pipeline for the prioritization of epithelial-targeted metabolite interventions that can direct safe future novel adjunct interventions.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"16 1","pages":"2597568"},"PeriodicalIF":12.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752570","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 : 2025-12-15DOI: 10.1080/19490976.2025.2599517
Zehua Yan,Xiaohua Zhang,Tim Fat Shum,Jiawen Xie,Jiachi Chiou,Jun Yu,Xiangdong Li
Antibiotic-resistant bacteria (ARB) and food-residue-level antibiotics in food can disrupt gut homeostasis. However, the impact of co-exposure with food-residue-level antibiotics on compartment-specific colonization dynamics and associated risks of ARB in human gut remains unclear. Here, we isolated a ciprofloxacin (CIP)-resistant Staphylococcus aureus strain from edible fish parts in aquaculture environment and assessed exposure risks to luminal and mucosal microbiotas using the in vitro Mucosal Simulator of the Human Intestinal Microbial Ecosystem (M-SHIME; ProDigest, Belgium) under three treatments: S. aureus alone, food-residue-level CIP alone, and co-exposure to both. Food-residue-level CIP promoted the potential colonization of S. aureus and relative abundance of antibiotic resistance gene hosts in the mucosal microbiota and decreased absolute abundance of 16S rRNA genes in luminal microbiota. Accordingly, microbiota exhibited compartment-specific responses: luminal microbiota exhibited increased stress tolerance potential and a tightly connected network with fewer nodes, whereas mucosal microbiota displayed enhanced resource utilization potential and a more complex network with more nodes. To investigate the mechanisms underlying these compartment-specific responses, we analyzed the microbial interconnections and enriched functions in luminal and mucosal microbiota. Notably, mucosal microbiota showed stronger positive cohesions (i.e., abundance-weighted positive correlations) within community members and enriched functions related to biofilm formation and quorum sensing, indicative of heightened communication and potential cooperation, possibly driving these compartment-specific responses. Despite these differences, continuous mucin shedding may facilitate the translocation of resistant mucosal biofilms, contributing to colonization resistance in the lumen. Our study demonstrates that food-residue-level antibiotics could facilitate S. aureus colonization and pose compartment-specific risks to gut microbial communities, highlighting the crucial role of intestinal mucosa for ARB colonization in human gut.
{"title":"Food-residue-level antibiotics promote mucosal colonization of foodborne antibiotic-resistant Staphylococcus aureus in a simulated human gut.","authors":"Zehua Yan,Xiaohua Zhang,Tim Fat Shum,Jiawen Xie,Jiachi Chiou,Jun Yu,Xiangdong Li","doi":"10.1080/19490976.2025.2599517","DOIUrl":"https://doi.org/10.1080/19490976.2025.2599517","url":null,"abstract":"Antibiotic-resistant bacteria (ARB) and food-residue-level antibiotics in food can disrupt gut homeostasis. However, the impact of co-exposure with food-residue-level antibiotics on compartment-specific colonization dynamics and associated risks of ARB in human gut remains unclear. Here, we isolated a ciprofloxacin (CIP)-resistant Staphylococcus aureus strain from edible fish parts in aquaculture environment and assessed exposure risks to luminal and mucosal microbiotas using the in vitro Mucosal Simulator of the Human Intestinal Microbial Ecosystem (M-SHIME; ProDigest, Belgium) under three treatments: S. aureus alone, food-residue-level CIP alone, and co-exposure to both. Food-residue-level CIP promoted the potential colonization of S. aureus and relative abundance of antibiotic resistance gene hosts in the mucosal microbiota and decreased absolute abundance of 16S rRNA genes in luminal microbiota. Accordingly, microbiota exhibited compartment-specific responses: luminal microbiota exhibited increased stress tolerance potential and a tightly connected network with fewer nodes, whereas mucosal microbiota displayed enhanced resource utilization potential and a more complex network with more nodes. To investigate the mechanisms underlying these compartment-specific responses, we analyzed the microbial interconnections and enriched functions in luminal and mucosal microbiota. Notably, mucosal microbiota showed stronger positive cohesions (i.e., abundance-weighted positive correlations) within community members and enriched functions related to biofilm formation and quorum sensing, indicative of heightened communication and potential cooperation, possibly driving these compartment-specific responses. Despite these differences, continuous mucin shedding may facilitate the translocation of resistant mucosal biofilms, contributing to colonization resistance in the lumen. Our study demonstrates that food-residue-level antibiotics could facilitate S. aureus colonization and pose compartment-specific risks to gut microbial communities, highlighting the crucial role of intestinal mucosa for ARB colonization in human gut.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"93 1","pages":"2599517"},"PeriodicalIF":12.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752569","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}
BACKGROUNDFecal microbiota transplantation (FMT) is a promising treatment for inflammatory bowel disease (IBD), achieving clinical response rate of ~50% for ulcerative colitis (UC), and Crohn's disease (CD). While prior research has emphasized donor selection and treatment protocols, the role of the patient's native intestinal microbiota in FMT outcomes remains underexplored.METHODSThis study analyzed a retrospective cohort of 96 IBD patients (45 CD, 51 UC) undergoing FMT, with 192 paired stool samples collected pre- and post-treatment, alongside 332 healthy donor samples from 18 donors. A prospective cohort of 45 IBD patients provided 45 baseline stool samples, and a validation cohort of 112 non-IBD patients contributed 224 paired samples. Retrospective cohort patients were monitored for 4 weeks to assess FMT responsiveness and 52 weeks for treatment effectiveness. Microbiome analysis identified enterotype-specific bacteria and native bacterial genera influence FMT outcomes. Random forest, permissivity, and mathematical models predicted treatment response, characterized microbiome remodeling, and defined microecological remission thresholds.RESULTSThe FMT regimen was safe, with no serious adverse events reported. At week 4, the clinical response rates were 58.8% (26/45) for CD patients and 66.7% (34/51) for UC patients; by week 52, the remission rates were 82.4% (37/45) for CD patients and 84.4% (43/51) for UC patients. Microbiome analysis identified 54 bacterial genera linked to enterotype classification, 57 to UC response, and 93 to CD response. Notably, 38 high-frequency retentions of recipient native bacteria after FMT were predictive of FMT responsiveness. The permissivity model revealed a shift toward Bacteroidetes-dominated enterotypes in IBD patients post-FMT, which was validated in 112 non-IBD patients. The abundance ranges of recipients' native bacteria predictive of treatment responsewere determined by mathematical interpretation model.CONCLUSIONThe patient's native microbiota significantly influences FMT efficacy in IBD, influencing microbiome remodeling and clinical outcomes, highlighting the importance of baseline microbial profiles in predicting FMT responsiveness and optimizing therapy.
{"title":"Recipients' native bacteria determine the outcome of FMT treatment in inflammatory bowel disease.","authors":"Di Zhao,Xinjun Wang,Ke Wang,Bo Yang,Huiyuan Zhu,Yue Xu,Chen Ye,Long Li,Xiaoqiong Lv,Shailan Zhou,Chunlian Ma,Xia Chen,Fang Yin,Yefei Zhu,Zhan Cao,Ning Li,Tao Zuo,Huanlong Qin,Qiyi Chen","doi":"10.1080/19490976.2025.2600055","DOIUrl":"https://doi.org/10.1080/19490976.2025.2600055","url":null,"abstract":"BACKGROUNDFecal microbiota transplantation (FMT) is a promising treatment for inflammatory bowel disease (IBD), achieving clinical response rate of ~50% for ulcerative colitis (UC), and Crohn's disease (CD). While prior research has emphasized donor selection and treatment protocols, the role of the patient's native intestinal microbiota in FMT outcomes remains underexplored.METHODSThis study analyzed a retrospective cohort of 96 IBD patients (45 CD, 51 UC) undergoing FMT, with 192 paired stool samples collected pre- and post-treatment, alongside 332 healthy donor samples from 18 donors. A prospective cohort of 45 IBD patients provided 45 baseline stool samples, and a validation cohort of 112 non-IBD patients contributed 224 paired samples. Retrospective cohort patients were monitored for 4 weeks to assess FMT responsiveness and 52 weeks for treatment effectiveness. Microbiome analysis identified enterotype-specific bacteria and native bacterial genera influence FMT outcomes. Random forest, permissivity, and mathematical models predicted treatment response, characterized microbiome remodeling, and defined microecological remission thresholds.RESULTSThe FMT regimen was safe, with no serious adverse events reported. At week 4, the clinical response rates were 58.8% (26/45) for CD patients and 66.7% (34/51) for UC patients; by week 52, the remission rates were 82.4% (37/45) for CD patients and 84.4% (43/51) for UC patients. Microbiome analysis identified 54 bacterial genera linked to enterotype classification, 57 to UC response, and 93 to CD response. Notably, 38 high-frequency retentions of recipient native bacteria after FMT were predictive of FMT responsiveness. The permissivity model revealed a shift toward Bacteroidetes-dominated enterotypes in IBD patients post-FMT, which was validated in 112 non-IBD patients. The abundance ranges of recipients' native bacteria predictive of treatment responsewere determined by mathematical interpretation model.CONCLUSIONThe patient's native microbiota significantly influences FMT efficacy in IBD, influencing microbiome remodeling and clinical outcomes, highlighting the importance of baseline microbial profiles in predicting FMT responsiveness and optimizing therapy.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"20 1","pages":"2600055"},"PeriodicalIF":12.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759969","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 : 2025-12-15DOI: 10.1080/19490976.2025.2598957
Evan R Hutchison,Jillella Mallikarjun,Jung Ha Byun,Lauren N Lucas,Kazuyuki Kasahara,Michael Tallon,Qijun Zhang,Daniel Amador-Noguez,Yongjun Liu,Vanessa A Leone,Brian W Parks,Federico E Rey
Hypercholesterolemia contributes to the development of atherosclerosis and is a major risk factor for cardiovascular diseases (CVD). Dietary fiber can attenuate CVD, at least in part, by serving as a fermentable substrate for gut bacteria, leading to the production of short-chain fatty acids (SCFAs), such as butyrate and propionate, which have been linked to atheroprotective effects. SCFAs are sensed by G-protein coupled receptors including GPR41, GPR43, and GPR109A. To explore the role of these receptors in hypercholesterolemia and CVD, we examined atherosclerosis progression and lipid metabolism in Gpr41-/-, Gpr43-/-, and Gpr109a-/- mice using a proprotein convertase subtilisin/kexin type 9 adeno-associated virus (PCSK9-AAV) model of hypercholesterolemia. Deficiency of any single SCFA receptor did not significantly affect atherosclerotic plaque burden compared with wild-type (WT) littermates. However, male Gpr41-/- mice exhibited decreased gonadal fat, plasma triacylglycerol, and low-density lipoprotein cholesterol levels compared to their WT littermates. GPR41 deficiency in males was also associated with increased cecal propionate levels, reduced ileal expression of nutrient transporters such as Npc1l1 and a trend toward increased gut motility. In addition, male Gpr41-/- mice displayed altered gut microbiota composition and lower levels of microbially generated bile acids relative to their WT counterparts. Together, these findings highlight GPR41 as a key intestinal chemosensor regulating nutrient uptake, lipid storage, and microbiota composition.
{"title":"GPR41 deficiency alters the gut microbiota-bile acid axis, reduces ileal expression of Npc1l1, and attenuates hypercholesterolemia in male mice.","authors":"Evan R Hutchison,Jillella Mallikarjun,Jung Ha Byun,Lauren N Lucas,Kazuyuki Kasahara,Michael Tallon,Qijun Zhang,Daniel Amador-Noguez,Yongjun Liu,Vanessa A Leone,Brian W Parks,Federico E Rey","doi":"10.1080/19490976.2025.2598957","DOIUrl":"https://doi.org/10.1080/19490976.2025.2598957","url":null,"abstract":"Hypercholesterolemia contributes to the development of atherosclerosis and is a major risk factor for cardiovascular diseases (CVD). Dietary fiber can attenuate CVD, at least in part, by serving as a fermentable substrate for gut bacteria, leading to the production of short-chain fatty acids (SCFAs), such as butyrate and propionate, which have been linked to atheroprotective effects. SCFAs are sensed by G-protein coupled receptors including GPR41, GPR43, and GPR109A. To explore the role of these receptors in hypercholesterolemia and CVD, we examined atherosclerosis progression and lipid metabolism in Gpr41-/-, Gpr43-/-, and Gpr109a-/- mice using a proprotein convertase subtilisin/kexin type 9 adeno-associated virus (PCSK9-AAV) model of hypercholesterolemia. Deficiency of any single SCFA receptor did not significantly affect atherosclerotic plaque burden compared with wild-type (WT) littermates. However, male Gpr41-/- mice exhibited decreased gonadal fat, plasma triacylglycerol, and low-density lipoprotein cholesterol levels compared to their WT littermates. GPR41 deficiency in males was also associated with increased cecal propionate levels, reduced ileal expression of nutrient transporters such as Npc1l1 and a trend toward increased gut motility. In addition, male Gpr41-/- mice displayed altered gut microbiota composition and lower levels of microbially generated bile acids relative to their WT counterparts. Together, these findings highlight GPR41 as a key intestinal chemosensor regulating nutrient uptake, lipid storage, and microbiota composition.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"157 1","pages":"2598957"},"PeriodicalIF":12.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752522","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}
Helicobacter pylori (H. pylori) infection has been investigated as a potential risk factor for extragastric diseases, including metabolic dysfunction-associated fatty liver disease (MASLD). However, details of the underlying mechanisms remain inadequately understood. In this study, we elucidate that H. pylori infection exacerbates hepatic metabolic disorders both in vitro and in vivo, manifesting as increased lipid deposition and insulin resistance. Mechanistically, H. pylori infection upregulates hepatic m6A content, particularly increasing the expression of WTAP. Overexpression of hepatic WTAP promotes liver steatosis characteristics, including increased lipogenesis and decreased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Conversely, knockdown of hepatic WTAP mitigated hepato-steatosis and insulin resistance in high-fat diet (HFD) mice and hepatic cells. After H. pylori infection, lactate accumulates in the liver, which potently induces WTAP upregulation in HepG2 cells via H3K18 lactylation. Notably, we identified two lactylation modification sites, K99 and K134, on WTAP, which are essential for WTAP to regulate GLUT3 mRNA stability in an m6A-YTHDF1-dependent manner. The upregulation of GLUT3 subsequently enhanced glycolysis, establishing a feedback loop that resulted in increased lactate accumulation. In conclusion, our findings highlight the significance of lactylation-driven WTAP-mediated RNA m6A modification in the aggravation of hepatic steatosis due to H. pylori infection. Therefore, the status of H. pylori should be taken into account in MASLD treatment strategies. Furthermore, the WTAP-YTHDF1-GLUT3 axis may be a potentially promising therapeutic target for MASLD progression.
{"title":"Helicobacter pylori infection aggravates hepatic steatosis by lactylation-driven WTAP-mediated m6A modification.","authors":"Han Chen,Zi Wang,Yan Wang,Shuo Li,Wei Su,Yuting Shao,Guoxin Zhang,Yun Liu,Qiang Ye,Xiaoying Zhou","doi":"10.1080/19490976.2025.2599543","DOIUrl":"https://doi.org/10.1080/19490976.2025.2599543","url":null,"abstract":"Helicobacter pylori (H. pylori) infection has been investigated as a potential risk factor for extragastric diseases, including metabolic dysfunction-associated fatty liver disease (MASLD). However, details of the underlying mechanisms remain inadequately understood. In this study, we elucidate that H. pylori infection exacerbates hepatic metabolic disorders both in vitro and in vivo, manifesting as increased lipid deposition and insulin resistance. Mechanistically, H. pylori infection upregulates hepatic m6A content, particularly increasing the expression of WTAP. Overexpression of hepatic WTAP promotes liver steatosis characteristics, including increased lipogenesis and decreased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Conversely, knockdown of hepatic WTAP mitigated hepato-steatosis and insulin resistance in high-fat diet (HFD) mice and hepatic cells. After H. pylori infection, lactate accumulates in the liver, which potently induces WTAP upregulation in HepG2 cells via H3K18 lactylation. Notably, we identified two lactylation modification sites, K99 and K134, on WTAP, which are essential for WTAP to regulate GLUT3 mRNA stability in an m6A-YTHDF1-dependent manner. The upregulation of GLUT3 subsequently enhanced glycolysis, establishing a feedback loop that resulted in increased lactate accumulation. In conclusion, our findings highlight the significance of lactylation-driven WTAP-mediated RNA m6A modification in the aggravation of hepatic steatosis due to H. pylori infection. Therefore, the status of H. pylori should be taken into account in MASLD treatment strategies. Furthermore, the WTAP-YTHDF1-GLUT3 axis may be a potentially promising therapeutic target for MASLD progression.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"496 1","pages":"2599543"},"PeriodicalIF":12.2,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732740","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：