Pub Date : 2025-12-24DOI: 10.1080/19490976.2025.2601430
Lena K Siewert,Kristina Berve,Elisabeth Pössnecker,Julia Dyckow,Amel Zulji,Ryan Baumann,Aida Munoz-Blazquez,Gurumoorthy Krishnamoorthy,David Schreiner,Sharon Sagan,Charlotte Nelson,Joseph J Sabatino,Kazuki Nagashima,Médéric Diard,Andrew J Macpherson,Stephanie C Ganal-Vonarburg,Michael A Fischbach,Scott S Zamvil,Lucas Schirmer,Sergio E Baranzini,Anne-Katrin Pröbstel
Microbiome-based therapies are promising new treatment avenues. While global alterations in microbiota composition have been shown in multiple sclerosis, whether and how gut microbiota influence autoimmune responses in an antigen-specific manner is unclear. Here, we genetically engineered gut bacteria to express a brain antigen and dissect their pathogenic potential in a murine model of autoimmune neuroinflammation. Colonization with bacteria expressing myelin - but not ovalbumin-peptide exacerbates an encephalitogenic immune response in the gut by activating antigen-specific T cells as well as B cells leading to accelerated neuroinflammatory disease. These results demonstrate how antigen-specific microbial modulation can influence autoimmunity, providing insight for development of therapeutic strategies targeting specific bacterial taxa for treatment of MS and other autoimmune diseases.
{"title":"Antigen-specific activation of gut immune cells drives autoimmune neuroinflammation.","authors":"Lena K Siewert,Kristina Berve,Elisabeth Pössnecker,Julia Dyckow,Amel Zulji,Ryan Baumann,Aida Munoz-Blazquez,Gurumoorthy Krishnamoorthy,David Schreiner,Sharon Sagan,Charlotte Nelson,Joseph J Sabatino,Kazuki Nagashima,Médéric Diard,Andrew J Macpherson,Stephanie C Ganal-Vonarburg,Michael A Fischbach,Scott S Zamvil,Lucas Schirmer,Sergio E Baranzini,Anne-Katrin Pröbstel","doi":"10.1080/19490976.2025.2601430","DOIUrl":"https://doi.org/10.1080/19490976.2025.2601430","url":null,"abstract":"Microbiome-based therapies are promising new treatment avenues. While global alterations in microbiota composition have been shown in multiple sclerosis, whether and how gut microbiota influence autoimmune responses in an antigen-specific manner is unclear. Here, we genetically engineered gut bacteria to express a brain antigen and dissect their pathogenic potential in a murine model of autoimmune neuroinflammation. Colonization with bacteria expressing myelin - but not ovalbumin-peptide exacerbates an encephalitogenic immune response in the gut by activating antigen-specific T cells as well as B cells leading to accelerated neuroinflammatory disease. These results demonstrate how antigen-specific microbial modulation can influence autoimmunity, providing insight for development of therapeutic strategies targeting specific bacterial taxa for treatment of MS and other autoimmune diseases.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"1 1","pages":"2601430"},"PeriodicalIF":12.2,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813473","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}
Gut microbiota dysbiosis contributes to acute pancreatitis (AP) severity, but the specific microbes and mechanisms remain unclear. In this study, we employed both germ-free (GF) and specific-pathogen-free (SPF) murine models of AP to investigate the role of the intestinal microbiota. Our findings demonstrate that GF mice exhibited markedly attenuated pancreatic injury, inflammatory cell infiltration, and neutrophil extracellular traps (NETs) formation. Through fecal microbiota transplantation (FMT) from AP patients, differential antibiotic modulation, and single-bacterial colonization experiments, we identified Gram-negative bacteria, particularly Escherichia coli (E. coli), as critical microbial drivers of disease exacerbation. Single-cell RNA sequencing revealed that microbiota dysbiosis profoundly reprogrammed both local pancreatic and systemic immune landscapes. Specifically, dysbiosis promoted emergency granulopoiesis in the bone marrow, enhanced neutrophil mobilization and activation, and facilitated the expansion of pro-inflammatory neutrophil subpopulations (Neutrophils_2 and Neutrophils_3). These subsets exhibited upregulated signaling through NETosis-associated pathways, including TLR, NF-κB, and IL-17 axes. Conversely, in GF conditions, we observed a predominance of an anti-inflammatory neutrophil subset (Neutrophils_4), characterized by the expression of tissue repair-associated genes such as Reg1 and Reg2. Shotgun metagenomic profiling of fecal samples from patients with AP revealed an enrichment of E. coli during the acute phase, positively correlating with circulating cell-free DNA, a marker of NETosis. Together, these insights suggest that gut microbiota dysbiosis, notably increased E. coli abundance, may aggravate AP by reshaping immunity and promoting aberrant NETs formation, supporting microbiota or NETs targeted therapies.
{"title":"Gut microbiota dysbiosis exacerbates acute pancreatitis via Escherichia coli-driven neutrophil heterogeneity and NETosis.","authors":"Yaoyu Zou,Nianshuang Li,Xueyang Li,Maobin Kuang,Xin Xu,Langyi Guan,Xin Li,Pan Zheng,Leyan Li,Jianhua Wan,Nonghua Lu,Jianping Liu,Cong He,Yin Zhu","doi":"10.1080/19490976.2025.2606480","DOIUrl":"https://doi.org/10.1080/19490976.2025.2606480","url":null,"abstract":"Gut microbiota dysbiosis contributes to acute pancreatitis (AP) severity, but the specific microbes and mechanisms remain unclear. In this study, we employed both germ-free (GF) and specific-pathogen-free (SPF) murine models of AP to investigate the role of the intestinal microbiota. Our findings demonstrate that GF mice exhibited markedly attenuated pancreatic injury, inflammatory cell infiltration, and neutrophil extracellular traps (NETs) formation. Through fecal microbiota transplantation (FMT) from AP patients, differential antibiotic modulation, and single-bacterial colonization experiments, we identified Gram-negative bacteria, particularly Escherichia coli (E. coli), as critical microbial drivers of disease exacerbation. Single-cell RNA sequencing revealed that microbiota dysbiosis profoundly reprogrammed both local pancreatic and systemic immune landscapes. Specifically, dysbiosis promoted emergency granulopoiesis in the bone marrow, enhanced neutrophil mobilization and activation, and facilitated the expansion of pro-inflammatory neutrophil subpopulations (Neutrophils_2 and Neutrophils_3). These subsets exhibited upregulated signaling through NETosis-associated pathways, including TLR, NF-κB, and IL-17 axes. Conversely, in GF conditions, we observed a predominance of an anti-inflammatory neutrophil subset (Neutrophils_4), characterized by the expression of tissue repair-associated genes such as Reg1 and Reg2. Shotgun metagenomic profiling of fecal samples from patients with AP revealed an enrichment of E. coli during the acute phase, positively correlating with circulating cell-free DNA, a marker of NETosis. Together, these insights suggest that gut microbiota dysbiosis, notably increased E. coli abundance, may aggravate AP by reshaping immunity and promoting aberrant NETs formation, supporting microbiota or NETs targeted therapies.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"45 1","pages":"2606480"},"PeriodicalIF":12.2,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813470","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 : 2025-12-23DOI: 10.1080/19490976.2025.2604871
Jarrah M Dowrick,Nicole C Roy,Caterina Carco,Shanalee C James,Phoebe E Heenan,Chris M A Frampton,Karl Fraser,Wayne Young,Janine Cooney,Tania Trower,Jacqueline I Keenan,Warren C McNabb,Jane A Mullaney,Simone B Bayer,Nicholas J Talley,Richard B Gearry,Timothy R Angeli-Gordon
Rome IV disorders of gut-brain interaction (DGBI) subtypes are known to be unstable and demonstrate high rates of non-treatment response, likely indicating patient heterogeneity. Cluster analysis, a type of unsupervised machine learning, can identify homogeneous sub-populations. Independent cluster analyses of symptom and biological data have highlighted its value in predicting patient outcomes. Integrated clustering of symptom and biological data may provide a unique multimodal perspective that better captures the complexity of DGBI. Here, integrated symptom and multi-omic cluster analysis was performed on a cohort of healthy controls and patients with lower-gastrointestinal tract DGBI. Cluster stability was assessed by considering how frequently pairs of participants appeared in the same cluster between different bootstrapped datasets. Functional enrichment analysis was performed on the biological signatures of stable DGBI-predominant clusters, implicating disrupted ammonia handling and metabolism as possible pathophysiologies present in a subset of patients with DGBI. Integrated clustering revealed subtypes that were not apparent using a singular modality, suggesting a symptom-only classification is prone to capturing heterogeneous sub-populations.
{"title":"Integrated multi-omic and symptom clustering reveals lower-gastrointestinal disorders of gut-brain interaction heterogeneity.","authors":"Jarrah M Dowrick,Nicole C Roy,Caterina Carco,Shanalee C James,Phoebe E Heenan,Chris M A Frampton,Karl Fraser,Wayne Young,Janine Cooney,Tania Trower,Jacqueline I Keenan,Warren C McNabb,Jane A Mullaney,Simone B Bayer,Nicholas J Talley,Richard B Gearry,Timothy R Angeli-Gordon","doi":"10.1080/19490976.2025.2604871","DOIUrl":"https://doi.org/10.1080/19490976.2025.2604871","url":null,"abstract":"Rome IV disorders of gut-brain interaction (DGBI) subtypes are known to be unstable and demonstrate high rates of non-treatment response, likely indicating patient heterogeneity. Cluster analysis, a type of unsupervised machine learning, can identify homogeneous sub-populations. Independent cluster analyses of symptom and biological data have highlighted its value in predicting patient outcomes. Integrated clustering of symptom and biological data may provide a unique multimodal perspective that better captures the complexity of DGBI. Here, integrated symptom and multi-omic cluster analysis was performed on a cohort of healthy controls and patients with lower-gastrointestinal tract DGBI. Cluster stability was assessed by considering how frequently pairs of participants appeared in the same cluster between different bootstrapped datasets. Functional enrichment analysis was performed on the biological signatures of stable DGBI-predominant clusters, implicating disrupted ammonia handling and metabolism as possible pathophysiologies present in a subset of patients with DGBI. Integrated clustering revealed subtypes that were not apparent using a singular modality, suggesting a symptom-only classification is prone to capturing heterogeneous sub-populations.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"37 1","pages":"2604871"},"PeriodicalIF":12.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807589","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 : 2025-12-23DOI: 10.1080/19490976.2025.2604867
Sakha Al-Btoosh,Ryan F Donnelly,Stephen A Kelly
The human gut microbiome plays a critical role in modulating pharmacological and toxicological responses to medications. With a gene pool vastly exceeding that of the human host, the gut microbiome acts as a metabolically active organ capable of transforming, inactivating, or accumulating drugs. This review explores the bidirectional interplay between prescription medicines and the gut microbiome, encompassing three key mechanisms: direct biotransformation by microbial enzymes, indirect modulation of host metabolism and signaling pathways, and drug bioaccumulation within microbial cells. Particular attention is given to six major drug classes: immunotherapeutics, chemotherapeutics, antidepressants, statins, hypoglycemics, and antihypertensives. The ways in which individual microbial profiles can influence therapeutic outcomes are also reviewed. We examined how common non-antibiotic pharmaceuticals can significantly alter microbial diversity and promote antimicrobial resistance. Strategies to enhance drug efficacy through microbiome modulation, including probiotics, prebiotics, and fecal microbiota transplantation (FMT), are critically assessed. Experimental models ranging from in vitro batch and chemostat systems to animal and clinical studies are compared in terms of their utility for studying drug‒microbiome interactions. Finally, emerging evidence suggesting the gut microbiota composition may serve as a predictive biomarker for personalized medicine and therapeutic success is highlighted. Understanding and harnessing the complex interrelationships between medicines and microorganisms could offer novel avenues to optimize treatment outcomes and mitigate adverse drug effects.
{"title":"Microbes and medicines: interrelationships between pharmaceuticals and the gut microbiome.","authors":"Sakha Al-Btoosh,Ryan F Donnelly,Stephen A Kelly","doi":"10.1080/19490976.2025.2604867","DOIUrl":"https://doi.org/10.1080/19490976.2025.2604867","url":null,"abstract":"The human gut microbiome plays a critical role in modulating pharmacological and toxicological responses to medications. With a gene pool vastly exceeding that of the human host, the gut microbiome acts as a metabolically active organ capable of transforming, inactivating, or accumulating drugs. This review explores the bidirectional interplay between prescription medicines and the gut microbiome, encompassing three key mechanisms: direct biotransformation by microbial enzymes, indirect modulation of host metabolism and signaling pathways, and drug bioaccumulation within microbial cells. Particular attention is given to six major drug classes: immunotherapeutics, chemotherapeutics, antidepressants, statins, hypoglycemics, and antihypertensives. The ways in which individual microbial profiles can influence therapeutic outcomes are also reviewed. We examined how common non-antibiotic pharmaceuticals can significantly alter microbial diversity and promote antimicrobial resistance. Strategies to enhance drug efficacy through microbiome modulation, including probiotics, prebiotics, and fecal microbiota transplantation (FMT), are critically assessed. Experimental models ranging from in vitro batch and chemostat systems to animal and clinical studies are compared in terms of their utility for studying drug‒microbiome interactions. Finally, emerging evidence suggesting the gut microbiota composition may serve as a predictive biomarker for personalized medicine and therapeutic success is highlighted. Understanding and harnessing the complex interrelationships between medicines and microorganisms could offer novel avenues to optimize treatment outcomes and mitigate adverse drug effects.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"12 1","pages":"2604867"},"PeriodicalIF":12.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807588","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 : 2025-12-22DOI: 10.1080/19490976.2025.2587405
Liu Yang,Jianming Yang,Xueting Kong,Qiang Tang,Ruofan Song,Kaichen Zhou,Xiao-Jing Quan,Qiang Zhang,Yajie Zhang,Chunze Zhang,Geng Pei,Chunhui Miao,Kaiyuan Yu,Zhi-Song Zhang,Zhi Yao,Quan Wang
Akkermansia muciniphila is recognized as a promising probiotic that improves the symptoms of a variety of diseases. However, the role and mechanism of A. muciniphila in regulating intestinal homeostasis remain to be explored. Here, we discovered that A. muciniphila was dramatically increased during colitis recovery, and its colonization greatly increased goblet cells to protect the intestinal barrier in mice. Amuc_0904, a previously uncharacterized A. muciniphila outer membrane protein, was identified to induce goblet cell differentiation. Mechanistically, Amuc_0904 directly interacted with MET and decreased its phosphorylation in epithelia, leading to decreased Wnt/β-catenin signaling and enhanced oxidative phosphorylation and mitochondrial function. Furthermore, Amuc_0904 and engineered probiotic Escherichia coli Nissle 1917 expressing Amuc_0904 were demonstrated to protect mice from colitis and colitis-associated colorectal cancer. The study reveals a previously unknown mechanism of A. muciniphila-mediated intestinal homeostasis recovery and provides a bioactive molecule with the potential to treat intestinal disorders.
{"title":"Akkermansia muciniphila outer membrane protein Amuc_0904 modulates intestinal homeostasis by promoting goblet cell differentiation.","authors":"Liu Yang,Jianming Yang,Xueting Kong,Qiang Tang,Ruofan Song,Kaichen Zhou,Xiao-Jing Quan,Qiang Zhang,Yajie Zhang,Chunze Zhang,Geng Pei,Chunhui Miao,Kaiyuan Yu,Zhi-Song Zhang,Zhi Yao,Quan Wang","doi":"10.1080/19490976.2025.2587405","DOIUrl":"https://doi.org/10.1080/19490976.2025.2587405","url":null,"abstract":"Akkermansia muciniphila is recognized as a promising probiotic that improves the symptoms of a variety of diseases. However, the role and mechanism of A. muciniphila in regulating intestinal homeostasis remain to be explored. Here, we discovered that A. muciniphila was dramatically increased during colitis recovery, and its colonization greatly increased goblet cells to protect the intestinal barrier in mice. Amuc_0904, a previously uncharacterized A. muciniphila outer membrane protein, was identified to induce goblet cell differentiation. Mechanistically, Amuc_0904 directly interacted with MET and decreased its phosphorylation in epithelia, leading to decreased Wnt/β-catenin signaling and enhanced oxidative phosphorylation and mitochondrial function. Furthermore, Amuc_0904 and engineered probiotic Escherichia coli Nissle 1917 expressing Amuc_0904 were demonstrated to protect mice from colitis and colitis-associated colorectal cancer. The study reveals a previously unknown mechanism of A. muciniphila-mediated intestinal homeostasis recovery and provides a bioactive molecule with the potential to treat intestinal disorders.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"10 1","pages":"2587405"},"PeriodicalIF":12.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801333","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 : 2025-12-22DOI: 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}
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：