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}
Pub Date : 2025-12-11DOI: 10.1080/19490976.2025.2597628
Anna H Behling,Theo Portlock,Daniel Ho,Brooke C Wilson,Sudarshan Paramsothy,Michael A Kamm,Wayne S Cutfield,Nadeem O Kaakoush,Justin M O'Sullivan,Tommi Vatanen
Disrupted human gut microbiota have been associated with the development of certain disease states, including obesity and ulcerative colitis (UC). Faecal microbiota transplantation (FMT) from healthy donors is a promising avenue to shift the microbiome profile of the recipient towards that of the donor, potentially ameliorating related symptoms. Several recent meta-analyses have investigated the clinical and microbial determinants that influence the retention of transplanted donor microbial strains within the recipient gut microbiome following FMT (i.e. engraftment). However, the specific factors that affect donor strain engraftment in different disease states require further exploration. Here, we perform a strain engraftment analysis on data from two multi-donor FMT clinical trials: the Gut Bugs Trial for obesity and the FOCUS Trial for UC. Using donor strain matching, the donor-recipient pairings of the FOCUS Trial were first predicted in a blinded manner. The subsequent, unblinded, strain engraftment analysis of both datasets highlighted a differential effect of donor-recipient microbiome complementarity on engraftment across the two disease cohorts; greater engraftment efficiency was associated with increased donor-recipient microbial similarity in the FOCUS Trial, and decreased similarity in the Gut Bugs Trial, suggesting that the factors influencing engraftment may differ across disease cohorts.
{"title":"Cohort-specific determinants of donor strain engraftment following multi-donor faecal microbiota transplantation in two randomised clinical trials.","authors":"Anna H Behling,Theo Portlock,Daniel Ho,Brooke C Wilson,Sudarshan Paramsothy,Michael A Kamm,Wayne S Cutfield,Nadeem O Kaakoush,Justin M O'Sullivan,Tommi Vatanen","doi":"10.1080/19490976.2025.2597628","DOIUrl":"https://doi.org/10.1080/19490976.2025.2597628","url":null,"abstract":"Disrupted human gut microbiota have been associated with the development of certain disease states, including obesity and ulcerative colitis (UC). Faecal microbiota transplantation (FMT) from healthy donors is a promising avenue to shift the microbiome profile of the recipient towards that of the donor, potentially ameliorating related symptoms. Several recent meta-analyses have investigated the clinical and microbial determinants that influence the retention of transplanted donor microbial strains within the recipient gut microbiome following FMT (i.e. engraftment). However, the specific factors that affect donor strain engraftment in different disease states require further exploration. Here, we perform a strain engraftment analysis on data from two multi-donor FMT clinical trials: the Gut Bugs Trial for obesity and the FOCUS Trial for UC. Using donor strain matching, the donor-recipient pairings of the FOCUS Trial were first predicted in a blinded manner. The subsequent, unblinded, strain engraftment analysis of both datasets highlighted a differential effect of donor-recipient microbiome complementarity on engraftment across the two disease cohorts; greater engraftment efficiency was associated with increased donor-recipient microbial similarity in the FOCUS Trial, and decreased similarity in the Gut Bugs Trial, suggesting that the factors influencing engraftment may differ across disease cohorts.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"40 1","pages":"2597628"},"PeriodicalIF":12.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718018","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 : 2025-12-11DOI: 10.1080/19490976.2025.2597626
Kui Yang,Zhenni Liu,Huijun Wang,Zhengtao Xiao,Wei Zhao,Wenbin Gong
Chronic inflammation is closely related to the occurrence and development of many tumors, including colorectal cancer (CRC), a typical inflammation-dependent cancer. The gut bacteria and their metabolites, as signaling molecules or substrates of metabolic processes, have attracted increasing attention during the colorectal inflammation-cancer transformation process. However, how commensal microbiota-derived metabolites create a favorable internal environment for carcinogenesis through the chronic inflammatory response is not entirely understood. Here, we conducted multiomics analysis, including single-cell RNA-sequencing (scRNA-seq), microbiome and metabolome to explore the intricate cross-talk of host-microbe-metabolite. By employing colitis-associated CRC mice models, as well as patient-derived CRC organoids, we identified that trimethylamine n-oxide (TMAO), a metabolic product derived from the gut microbiota, was crucial for inflammation-mediated colorectal carcinogenesis by enhancing Wnt signaling. Further mechanistic studies revealed that TMAO interacted with heat shock protein family A member 8 (Hspa8, also known as Hsc70), a molecular chaperone that mediates autophagy, to block the lysosomal degradation of the β-catenin protein, leading to an increase in the downstream targets cyclin D1 and c-Myc, thus contributing to colorectal carcinogenesis. Our results indicated that TMAO serves as a bridge to establish the connection between microbiota and colorectal carcinogenesis, playing a critical pathogenic role during CRC progression and therefore provides novel mechanistic insights into the intestinal inflammation in colorectal neoplasia progression.
{"title":"Microbial metabolite trimethylamine-N-oxide facilitates colorectal inflammation-cancer transformation by blocking lysosomal degradation of Wnt signaling.","authors":"Kui Yang,Zhenni Liu,Huijun Wang,Zhengtao Xiao,Wei Zhao,Wenbin Gong","doi":"10.1080/19490976.2025.2597626","DOIUrl":"https://doi.org/10.1080/19490976.2025.2597626","url":null,"abstract":"Chronic inflammation is closely related to the occurrence and development of many tumors, including colorectal cancer (CRC), a typical inflammation-dependent cancer. The gut bacteria and their metabolites, as signaling molecules or substrates of metabolic processes, have attracted increasing attention during the colorectal inflammation-cancer transformation process. However, how commensal microbiota-derived metabolites create a favorable internal environment for carcinogenesis through the chronic inflammatory response is not entirely understood. Here, we conducted multiomics analysis, including single-cell RNA-sequencing (scRNA-seq), microbiome and metabolome to explore the intricate cross-talk of host-microbe-metabolite. By employing colitis-associated CRC mice models, as well as patient-derived CRC organoids, we identified that trimethylamine n-oxide (TMAO), a metabolic product derived from the gut microbiota, was crucial for inflammation-mediated colorectal carcinogenesis by enhancing Wnt signaling. Further mechanistic studies revealed that TMAO interacted with heat shock protein family A member 8 (Hspa8, also known as Hsc70), a molecular chaperone that mediates autophagy, to block the lysosomal degradation of the β-catenin protein, leading to an increase in the downstream targets cyclin D1 and c-Myc, thus contributing to colorectal carcinogenesis. Our results indicated that TMAO serves as a bridge to establish the connection between microbiota and colorectal carcinogenesis, playing a critical pathogenic role during CRC progression and therefore provides novel mechanistic insights into the intestinal inflammation in colorectal neoplasia progression.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"145 1","pages":"2597626"},"PeriodicalIF":12.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718020","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 utilization of gut microbiota in cancer therapy has attracted considerable attention as an emerging therapeutic frontier. In this study, we systematically evaluated the antitumor effects of nine bacterial strains isolated from the intestines of amphibians (Dryophytes japonicus and Cynops pyrrhogaster) and a reptile (Takydromus tachydromoides). Among the isolates, Ewingella americana exhibited remarkably potent cytotoxic activity with selective tumor-targeting ability characteristic of facultative anaerobic bacteria. Mechanistic investigations revealed that E. americana functions through a dual-action mechanism: direct tumor cell killing and robust activation of host immunity, leading to enhanced T cell, neutrophil, and B cell-mediated tumor attack. Treatment with E. americana significantly outperformed standard therapies, including anti-PD-L1 antibody and doxorubicin, in tumor regression studies. Importantly, comprehensive safety evaluations in murine models demonstrated that the gut-derived E. americana strain exhibits minimal pathogenicity and exerts no significant adverse effects at therapeutically effective doses, contrasting favorably with genetically modified bacterial therapeutics. Comparative analysis revealed superior therapeutic efficacy of E. americana over conventional treatments while maintaining an excellent safety profile. These findings suggest that gut microbiomes of lower vertebrates harbor numerous uncharacterized bacterial species with exceptional therapeutic potential. Our study establishes a foundation for developing naturally occurring, non-pathogenic bacterial therapeutics and underscores the critical importance of microbial biodiversity in advancing cancer treatment strategies.
{"title":"Discovery and characterization of antitumor gut microbiota from amphibians and reptiles: Ewingella americana as a novel therapeutic agent with dual cytotoxic and immunomodulatory properties.","authors":"Seigo Iwata,Nagi Yamasita,Kensuke Asukabe,Matomo Sakari,Eijiro Miyako","doi":"10.1080/19490976.2025.2599562","DOIUrl":"https://doi.org/10.1080/19490976.2025.2599562","url":null,"abstract":"The utilization of gut microbiota in cancer therapy has attracted considerable attention as an emerging therapeutic frontier. In this study, we systematically evaluated the antitumor effects of nine bacterial strains isolated from the intestines of amphibians (Dryophytes japonicus and Cynops pyrrhogaster) and a reptile (Takydromus tachydromoides). Among the isolates, Ewingella americana exhibited remarkably potent cytotoxic activity with selective tumor-targeting ability characteristic of facultative anaerobic bacteria. Mechanistic investigations revealed that E. americana functions through a dual-action mechanism: direct tumor cell killing and robust activation of host immunity, leading to enhanced T cell, neutrophil, and B cell-mediated tumor attack. Treatment with E. americana significantly outperformed standard therapies, including anti-PD-L1 antibody and doxorubicin, in tumor regression studies. Importantly, comprehensive safety evaluations in murine models demonstrated that the gut-derived E. americana strain exhibits minimal pathogenicity and exerts no significant adverse effects at therapeutically effective doses, contrasting favorably with genetically modified bacterial therapeutics. Comparative analysis revealed superior therapeutic efficacy of E. americana over conventional treatments while maintaining an excellent safety profile. These findings suggest that gut microbiomes of lower vertebrates harbor numerous uncharacterized bacterial species with exceptional therapeutic potential. Our study establishes a foundation for developing naturally occurring, non-pathogenic bacterial therapeutics and underscores the critical importance of microbial biodiversity in advancing cancer treatment strategies.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"144 1","pages":"2599562"},"PeriodicalIF":12.2,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718243","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 isolated and characterized gut phages remain rare. Most of the gut phages that have been isolated and propagated thus far are lytic phages, leaving significant gaps in the study of gut temperate phages. In this study, we successfully isolated a large-scale collection of gut bacteria and phages, containing 1,679 bacterial strains from 86 species and 79 phages that infect bacteria from 26 different species. Among the phage isolates, 32 are temperate phages and two of these temperate phages were directly isolated from faecal samples of healthy human donors. Sequence comparisons and analysis show that the isolated temperate phages are characterized with highly diverse genomes and significantly higher prevalence in the human gut when compared with these characterised lytic gut phages. Further analysis shows that most of these temperate phages contain unique diversity-generating retroelements (DGRs) and may have a broad host range. Additionally, by combining sequence and structural similarity we developed a pipeline that can significantly enhance the annotation rate of our gut phage genomes. The annotation pipeline helps to identify a candidate phage family, "Bacteroiduroviridae", that diverged from other bacteriophages early in the evolutionary process.
{"title":"Extensive cultivation of human gut phages revealing undescribed Bacteroidaceae phages.","authors":"Zhe Liu,Yaoyu Yang,Sihong Mao,Zhaoqi Wang,Qiheng Zhu,Yuyu Yuan,Ye Xiang","doi":"10.1080/19490976.2025.2597614","DOIUrl":"https://doi.org/10.1080/19490976.2025.2597614","url":null,"abstract":"The isolated and characterized gut phages remain rare. Most of the gut phages that have been isolated and propagated thus far are lytic phages, leaving significant gaps in the study of gut temperate phages. In this study, we successfully isolated a large-scale collection of gut bacteria and phages, containing 1,679 bacterial strains from 86 species and 79 phages that infect bacteria from 26 different species. Among the phage isolates, 32 are temperate phages and two of these temperate phages were directly isolated from faecal samples of healthy human donors. Sequence comparisons and analysis show that the isolated temperate phages are characterized with highly diverse genomes and significantly higher prevalence in the human gut when compared with these characterised lytic gut phages. Further analysis shows that most of these temperate phages contain unique diversity-generating retroelements (DGRs) and may have a broad host range. Additionally, by combining sequence and structural similarity we developed a pipeline that can significantly enhance the annotation rate of our gut phage genomes. The annotation pipeline helps to identify a candidate phage family, \"Bacteroiduroviridae\", that diverged from other bacteriophages early in the evolutionary process.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"30 1","pages":"2597614"},"PeriodicalIF":12.2,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704312","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 : 2025-12-09DOI: 10.1080/19490976.2025.2596806
Patrick Müller,Verena Schmidtchen,Jacobo de la Cuesta-Zuluaga,Lucía Pérez Jiménez,Cordula Gekeler,André Mateus,Lisa Maier
Antibiotics are essential to modern medicine, but their broad-spectrum activity can unintentionally disrupt the gut microbiota. This collateral damage may be alleviated by antagonistic drug interactions, in which specific compounds used in combination therapies selectively protect beneficial gut microbes from antibiotic activity. Using efflux pump inhibitors, transcriptomic and proteomic analyses, and targeted gene deletions, we show that a variety of non-antibiotic pharmaceuticals-from diverse therapeutic classes and at sub-inhibitory concentrations-can protect multiple Bacteroidales species from macrolide antibiotics. In Bacteroidaceae, this protection is mediated by a resistance-nodulation-division (RND)-type efflux pump, which is induced by the non-antibiotic drug but not by macrolides alone. Notably, protection persists even after the non-antibiotic drug is removed, and prolonged exposure results in stable macrolide resistance that is dependent on the RND-type efflux pump. Our findings illustrate how non-antibiotic drugs can inadvertently activate otherwise silent detoxification systems in gut microbes, uncovering resistance mechanisms that arise without antibiotic selection or gene transfer. While this can be harnessed to protect the microbiome during antibiotic therapy, it also reveals hidden resistance phenotypes that may escape detection in standard antimicrobial resistance assays.
{"title":"Antagonistic drug interactions protect commensal Bacteroidaceae from macrolides via an RND-type efflux pump.","authors":"Patrick Müller,Verena Schmidtchen,Jacobo de la Cuesta-Zuluaga,Lucía Pérez Jiménez,Cordula Gekeler,André Mateus,Lisa Maier","doi":"10.1080/19490976.2025.2596806","DOIUrl":"https://doi.org/10.1080/19490976.2025.2596806","url":null,"abstract":"Antibiotics are essential to modern medicine, but their broad-spectrum activity can unintentionally disrupt the gut microbiota. This collateral damage may be alleviated by antagonistic drug interactions, in which specific compounds used in combination therapies selectively protect beneficial gut microbes from antibiotic activity. Using efflux pump inhibitors, transcriptomic and proteomic analyses, and targeted gene deletions, we show that a variety of non-antibiotic pharmaceuticals-from diverse therapeutic classes and at sub-inhibitory concentrations-can protect multiple Bacteroidales species from macrolide antibiotics. In Bacteroidaceae, this protection is mediated by a resistance-nodulation-division (RND)-type efflux pump, which is induced by the non-antibiotic drug but not by macrolides alone. Notably, protection persists even after the non-antibiotic drug is removed, and prolonged exposure results in stable macrolide resistance that is dependent on the RND-type efflux pump. Our findings illustrate how non-antibiotic drugs can inadvertently activate otherwise silent detoxification systems in gut microbes, uncovering resistance mechanisms that arise without antibiotic selection or gene transfer. While this can be harnessed to protect the microbiome during antibiotic therapy, it also reveals hidden resistance phenotypes that may escape detection in standard antimicrobial resistance assays.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"166 1","pages":"2596806"},"PeriodicalIF":12.2,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704313","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 and intestinal immune dysfunction contribute to the disease pathogenesis of ulcerative colitis (UC), therapeutic strategies aim to reshape microbial balance and reduce inflammation. It is unclear that how this bidirectional regulation between microbe-immune system is achieved and what is a possible nexus point for this regulation. Here, we demonstrated that palmatine (PAL) alleviates colitis by modulating interference competition between two microbes through the mediation of microbial tyrosine metabolites. Specifically, PAL directly inhibits B. acidifaciens while indirectly promoting the growth of B. stercorirosoris in mice with DSS-induced colitis. Notably, p-cresol (PC), a crucial microbial metabolite produced by B. acidifaciens, exacerbates colitis by promoting Th17 cells activation and inhibiting the growth of B. stercorirosoris. Furthermore, the immediate reduction in p-hydroxyphenylacetic acid, which is metabolized by B. stercorirosoris, contributes to the aggravation of colitis. Mechanistically, PC significantly inhibited the glycolysis of B. stercorirosoris, with downregulation of gene expression associated with glycolysis. In addition, we found that the inhibitory function of PC was offset by the addition of large amounts of polysaccharide and glucose in the medium of B. stercorirosoris. In summary, this study uncovers the mechanism by which palmatine‒microbiome‒host crosstalk cooperatively alleviate colitis through PC-mediated the bidirectional regulation. These findings propose that microbial metabolites function as regulators of microbiota‒host interactions, offering potential interventions for the treatment or prevention of dysbiosis-driven diseases.
{"title":"Bidirectional microbial regulation by tyrosine metabolism enhances palmatine-mediated colitis protection.","authors":"Daming Sun,Ziya Hua,Yunzhu Xiao,Dandan He,Hao Wu,Xin Lin,Qifan Chen,Ziguang Li,Yuanlong Hou","doi":"10.1080/19490976.2025.2596405","DOIUrl":"https://doi.org/10.1080/19490976.2025.2596405","url":null,"abstract":"Gut microbiota dysbiosis and intestinal immune dysfunction contribute to the disease pathogenesis of ulcerative colitis (UC), therapeutic strategies aim to reshape microbial balance and reduce inflammation. It is unclear that how this bidirectional regulation between microbe-immune system is achieved and what is a possible nexus point for this regulation. Here, we demonstrated that palmatine (PAL) alleviates colitis by modulating interference competition between two microbes through the mediation of microbial tyrosine metabolites. Specifically, PAL directly inhibits B. acidifaciens while indirectly promoting the growth of B. stercorirosoris in mice with DSS-induced colitis. Notably, p-cresol (PC), a crucial microbial metabolite produced by B. acidifaciens, exacerbates colitis by promoting Th17 cells activation and inhibiting the growth of B. stercorirosoris. Furthermore, the immediate reduction in p-hydroxyphenylacetic acid, which is metabolized by B. stercorirosoris, contributes to the aggravation of colitis. Mechanistically, PC significantly inhibited the glycolysis of B. stercorirosoris, with downregulation of gene expression associated with glycolysis. In addition, we found that the inhibitory function of PC was offset by the addition of large amounts of polysaccharide and glucose in the medium of B. stercorirosoris. In summary, this study uncovers the mechanism by which palmatine‒microbiome‒host crosstalk cooperatively alleviate colitis through PC-mediated the bidirectional regulation. These findings propose that microbial metabolites function as regulators of microbiota‒host interactions, offering potential interventions for the treatment or prevention of dysbiosis-driven diseases.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"29 1","pages":"2596405"},"PeriodicalIF":12.2,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704317","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}
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