Gut Microbes最新文献

{"title":"<i>Alcaligenes faecalis</i> promotes colitis to colorectal cancer transition through IgA+ B cell suppression and vinculin acetylation.","authors":"Jing Zheng, Chishun Zhou, Zizheng Li, Xin Jin, Yihua Zou, Shasha Bai, Huanjin Zheng, Weichao Ling, Yiru Zhao, Ying Wang, Rong Zhang, Zhongqiu Liu, Linlin Lu","doi":"10.1080/19490976.2025.2473511","DOIUrl":"10.1080/19490976.2025.2473511","url":null,"abstract":"<p><p>Lymphoid tissue-resident commensal bacteria (LRC), a subtype of gut microbiota essential for inflammation-associated carcinogenesis, predominantly attribute to colorectal cancer(CRC), whereas its role was largely unknown. Herein, we found <i>Alcaligenes faecalis</i> (<i>A. faecalis</i>), the main LRC embedded in Peyer's patches, was abundantly enriched in colitis, adenoma, and stage-dependently observed in CRC tissues. Interestingly, <i>A. faecalis</i> alone can not affect intestinal homeostasis, while during colitis, <i>A. faecalis</i> significantly translocated from Peyer's patches to colon, remarkably attenuated immune response abilities of B cells, T cells, and DC cells in PPs, consequently impeded IgA+ B cells homing. Meanwhile, during colitis, the ectopia of <i>A. faecalis</i> in colon tissues, promoted vinculin acetylation by <i>A. faecalis</i>-derived metabolite acetic acid, which impeded intestinal barrier via hindering the binding of vinculin to β-catenin. Our study revealed <i>A. faecalis</i> not only suppress mucosal immune responses via reducing IgA+ B cells in Peyer's patches but also disrupt intestinal barrier via increasing vinculin acetylation, ultimately promoting inflammation-to-cancer transition in CRC.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2473511"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11901412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine-learning assisted discovery unveils novel interplay between gut microbiota and host metabolic disturbance in diabetic kidney disease.","authors":"I-Wen Wu, Yu-Chieh Liao, Tsung-Hsien Tsai, Chieh-Hua Lin, Zhao-Qing Shen, Yun-Hsuan Chan, Chih-Wei Tu, Yi-Ju Chou, Chi-Jen Lo, Chi-Hsiao Yeh, Chun-Yu Chen, Heng-Chih Pan, Heng-Jung Hsu, Chin-Chan Lee, Mei-Ling Cheng, Wayne Huey-Herng Sheu, Chi-Chun Lai, Huey-Kang Sytwu, Ting-Fen Tsai","doi":"10.1080/19490976.2025.2473506","DOIUrl":"10.1080/19490976.2025.2473506","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a serious healthcare dilemma. Nonetheless, the interplay between the functional capacity of gut microbiota and their host remains elusive for DKD. This study aims to elucidate the functional capability of gut microbiota to affect kidney function of DKD patients. A total of 990 subjects were enrolled consisting of a control group (<i>n</i> = 455), a type 2 diabetes mellitus group (DM, <i>n</i> = 204), a DKD group (<i>n</i> = 182) and a chronic kidney disease group (CKD, <i>n</i> = 149). Full-length sequencing of 16S rRNA genes from stool DNA was conducted. Three findings are pinpointed. Firstly, new types of microbiota biomarkers have been created using a machine-learning (ML) method, namely relative abundance of a microbe, presence or absence of a microbe, and the hierarchy ratio between two different taxonomies. Four different panels of features were selected to be analyzed: (i) DM <i>vs</i>. Control, (ii) DKD <i>vs</i>. DM, (iii) DKD <i>vs</i>. CKD, and (iv) CKD <i>vs</i>. Control. These had accuracy rates between 0.72 and 0.78 and areas under curve between 0.79 and 0.86. Secondly, 13 gut microbiota biomarkers, which are strongly correlated with anthropometric, metabolic and/or renal indexes, concomitantly identified by the ML algorithm and the differential abundance method were highly discriminatory. Finally, the predicted functional capability of a DKD-specific biomarker, <i>Gemmiger</i> spp. is enriched in carbohydrate metabolism and branched-chain amino acid (BCAA) biosynthesis. Coincidentally, the circulating levels of various BCAAs (L-valine, L-leucine and L-isoleucine) and their precursor, L-glutamate, are significantly increased in DM and DKD patients, which suggests that, when hyperglycemia is present, there has been alterations in various interconnected pathways associated with glycolysis, pyruvate fermentation and BCAA biosynthesis. Our findings demonstrate that there is a link involving the gut-kidney axis in DKD patients. Furthermore, our findings highlight specific gut bacteria that can acts as useful biomarkers; these could have mechanistic and diagnostic implications.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2473506"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11901534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Life-course socioeconomic position and the gut microbiome in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).","authors":"Monica A Batalha, Madison N LeCroy, Juan Lin, Brandilyn A Peters, Qibin Qi, Zheng Wang, Tao Wang, Linda C Gallo, Gregory A Talavera, Amanda C McClain, Bharat Thyagarajan, Martha L Daviglus, Lifang Hou, Maria Llabre, Jianwen Cai, Robert C Kaplan, Carmen R Isasi","doi":"10.1080/19490976.2025.2479772","DOIUrl":"10.1080/19490976.2025.2479772","url":null,"abstract":"<p><p>Socioeconomic position (SEP) in childhood and beyond may influence the gut microbiome, with implications for disease risk. Studies evaluating the relationship between life-course SEP and the gut microbiome are sparse, particularly among Hispanic/Latino individuals, who have a high prevalence of low SEP. We use the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based cohort study conducted in four field centers in the United States (U.S.), to evaluate the association between life-course SEP and gut microbiome composition. Life-course SEP indicators included parental education (proxy of childhood SEP), current SEP (<i>n</i> = 2174), and childhood (<i>n</i> = 988) and current economic hardship (<i>n</i> = 994). Shotgun sequencing was performed on stool samples. Analysis of Compositions of Microbiomes was used to identify associations of life-course SEP indicators with gut microbiome species and functions. Parental education and current SEP were associated with the overall gut microbiome composition; however, parental education and current education explained more the gut microbiome variance than the current SEP. A lower parental education and current SEP were associated with a lower abundance of species from genus <i>Bacteroides</i>. In stratified analysis by nativity, we found similar findings mainly among foreign-born participants. Early-life SEP may have long-term effects on gut microbiome composition underscoring another biological mechanism linking early childhood factors to adult disease.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2479772"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657019","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}

{"title":"3'-Sialyllactose and <i>B. infantis</i> synergistically alleviate gut inflammation and barrier dysfunction by enriching cross-feeding bacteria for short-chain fatty acid biosynthesis.","authors":"Mingzhi Yang, Zipeng Jiang, Lutong Zhou, Nana Chen, Huan He, Wentao Li, Zhixin Yu, Siming Jiao, Deguang Song, Yizhen Wang, Mingliang Jin, Zeqing Lu","doi":"10.1080/19490976.2025.2486512","DOIUrl":"https://doi.org/10.1080/19490976.2025.2486512","url":null,"abstract":"<p><p>Ulcerative colitis (UC) poses significant threats to human health and quality of life worldwide, as it is a chronic inflammatory bowel disease. 3'-sialyllactose (3'-SL) is a key functional component of milk oligosaccharides. This study systematically evaluates the prebiotic effects of 3'-SL and its therapeutic potential in combination with <i>Bifidobacterium infantis</i> (<i>B. infantis</i>) for UC. The findings reveal that 3'-SL and <i>B. infantis</i> synergistically mitigate intestinal inflammation and barrier dysfunction by promoting the production of short-chain fatty acids (SCFAs) through cross-feeding mechanisms among gut microbiota. Individually, 3'-SL, <i>B. infantis</i>, and the synbiotic treatment all effectively alleviated UC symptoms, including reduced weight loss, improved disease activity scores, and prevention of colon shortening. Histopathological and immunofluorescence analyses further demonstrated that the synbiotic treatment significantly ameliorated colonic injury, enhanced barrier function, restored goblet cell counts, increased glycoprotein content in crypt goblet cells, and upregulated the expression of tight junction proteins (ZO-1, occludin, and claudin-1). Notably, the synbiotic treatment outperformed the individual components by better restoring gut microbiota balance, elevating SCFA levels, and modulating serum cytokine profiles, thereby reducing inflammation. These findings provide mechanistic insights into the protective effects of the synbiotic and underscore its therapeutic potential for UC and other intestinal inflammatory disorders.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2486512"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803220","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}

{"title":"Mucus-penetrating microbiota drive chronic low-grade intestinal inflammation and metabolic dysregulation.","authors":"Melissa C Kordahi, Noëmie Daniel, Andrew T Gewirtz, Benoit Chassaing","doi":"10.1080/19490976.2025.2455790","DOIUrl":"10.1080/19490976.2025.2455790","url":null,"abstract":"<p><p>Metabolic syndrome is, in humans, associated with alterations in the composition and localization of the intestinal microbiota, including encroachment of bacteria within the colon's inner mucus layer. Possible promoters of these events include dietary emulsifiers, such as carboxymethylcellulose (CMC) and polysorbate-80 (P80), which, in mice, result in altered microbiota composition, encroachment, low-grade inflammation and metabolic syndrome. While assessments of gut microbiota composition have largely focused on fecal/luminal samples, we hypothesize an outsized role for changes in mucus microbiota in driving low-grade inflammation and its consequences. In support of this notion, we herein report that both CMC and P80 led to stark changes in the mucus microbiome, markedly distinct from those observed in feces. Moreover, transfer of mucus microbiota from CMC- and P80-fed mice to germfree mice resulted in microbiota encroachment, low-grade inflammation, and various features of metabolic syndrome. Thus, we conclude that mucus-associated bacteria are pivotal determinants of intestinal inflammatory tone and host metabolism.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2455790"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbes metabolize strawberry phytochemicals and mediate their beneficial effects on vascular inflammation.","authors":"Chrissa Petersen, Adhini Kuppuswamy Satheesh Babu, Ceres Mattos Della Lucia, Henry A Paz, Lisard Iglesias-Carres, Ying Zhong, Thunder Jalili, J David Symons, Kartik Shankar, Andrew P Neilson, Umesh D Wankhade, Pon Velayutham Anandh Babu","doi":"10.1080/19490976.2024.2446375","DOIUrl":"https://doi.org/10.1080/19490976.2024.2446375","url":null,"abstract":"<p><p>Evidence suggests that a healthy gut microbiome is essential for metabolizing dietary phytochemicals. However, the microbiome's role in metabolite production and the influence of gut dysbiosis on this process remain unclear. Further, studies on the relationship among gut microbes, metabolites, and biological activities of phytochemicals are limited. We addressed this knowledge gap using strawberry phytochemicals as a model. C57BL/6J mice were fed a standard diet [C]; strawberry-supplemented diet (~2 human servings) [CS]; strawberry-supplemented diet and treated with antibiotics (to deplete gut microbes) [CSA]; high-fat diet (HFD) [HF]; strawberry-supplemented HFD [HS]; and strawberry-supplemented HFD and treated with antibiotics [HSA] for 12 weeks. First, antibiotic treatment suppressed the production of selected metabolites (CSA <i>vs</i>. CS), and <i>p</i>-coumaric acid was identified as a strawberry-derived microbial metabolite. Second, HFD-induced dysbiosis negatively affected metabolite production (HS <i>vs</i>. HF), and hippuric acid was identified as a microbial metabolite in HFD conditions. Third, dietary strawberries improved HFD-induced vascular inflammation (HS <i>vs</i>. HF). However, antibiotic treatment reduced metabolite production and abolished the vascular effects of strawberries (HSA <i>vs</i>. HS), indicating the importance of gut microbes in mediating the vascular benefits of strawberries <i>via</i> metabolites. Fourth, strawberry supplementation decreased <i>Coprobacillus</i> that was positively associated with vascular inflammation, whereas it increased <i>Lachnospiraceae</i> that was negatively associated with vascular inflammation and positively associated with hippuric acid. Fifth, hippuric acid was negatively associated with vascular inflammation. Our study fills in some pieces of the giant puzzle regarding the influence of gut microbes on the biological activities of phytochemicals. HFD-induced gut dysbiosis negatively impacts metabolite production and a strong association exists among gut microbes, strawberry-derived microbial metabolites, and the vascular benefits of dietary strawberries. Further, our study provides significant proof of concept to warrant future research on the use of strawberries as a nutritional strategy to prevent vascular complications.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2446375"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931580","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}

{"title":"<i>Clostridioides difficile</i> binary toxin CDT induces biofilm-like persisting microcolonies.","authors":"Jazmin Meza-Torres, Jean-Yves Tinevez, Aline Crouzols, Héloïse Mary, Minhee Kim, Lise Hunault, Susan Chamorro-Rodriguez, Emilie Lejal, Pamela Altamirano-Silva, Déborah Groussard, Samy Gobaa, Johann Peltier, Benoit Chassaing, Bruno Dupuy","doi":"10.1080/19490976.2024.2444411","DOIUrl":"https://doi.org/10.1080/19490976.2024.2444411","url":null,"abstract":"<p><p>Clinical symptoms of <i>Clostridioides difficile</i> infection (CDI) range from diarrhea to pseudomembranous colitis. A major challenge in managing CDI is the high rate of relapse. Several studies correlate the production of CDT binary toxin by clinical strains of <i>C. difficile</i> with higher relapse rates. Although the mechanism of action of CDT on host cells is known, its exact contribution to CDI is still unclear. To understand the physiological role of CDT during CDI, we established two hypoxic relevant intestinal models, Transwell and Microfluidic Intestine-on-Chip systems. Both were challenged with the epidemic strain UK1 CDT⁺ and its isogenic CDT^- mutant. We report that CDT induces mucin-associated microcolonies that increase <i>C. difficile</i> colonization and display biofilm-like properties by enhancing <i>C. difficile</i> resistance to vancomycin. Importantly, biofilm-like microcolonies were also observed in the cecum and colon of infected mice. Hence, our study shows that CDT induces biofilm-like microcolonies, increasing <i>C. difficile</i> persistence and risk of relapse.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2444411"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885583","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}

{"title":"<i>Staphylococcus warneri</i> dampens SUMOylation and promotes intestinal inflammation.","authors":"Léa Loison, Marion Huré, Benjamin Lefranc, Jérôme Leprince, Christine Bôle-Feysot, Moïse Coëffier, David Ribet","doi":"10.1080/19490976.2024.2446392","DOIUrl":"https://doi.org/10.1080/19490976.2024.2446392","url":null,"abstract":"<p><p>Gut bacteria play key roles in intestinal physiology, via the secretion of diversified bacterial effectors. Many of these effectors remodel the host proteome, either by altering transcription or by regulating protein post-translational modifications. SUMOylation, a ubiquitin-like post-translational modification playing key roles in intestinal physiology, is a target of gut bacteria. Mutualistic gut bacteria can promote SUMOylation, via the production of short- or branched-chain fatty acids (SCFA/BCFA). In contrast, several pathogenic bacteria were shown to dampen SUMOylation in order to promote infection. Here, we demonstrate that <i>Staphylococcus warneri</i>, a natural member of the human gut microbiota, decreases SUMOylation in intestinal cells. We identify that Warnericin RK, a hemolytic toxin secreted by <i>S. warneri</i>, targets key components of the host SUMOylation machinery, leading to the loss of SUMO-conjugated proteins. We further demonstrate that Warnericin RK promotes inflammation in intestinal and immune cells using both SUMO-dependent and SUMO-independent mechanisms. We finally show that Warnericin RK regulates the expression of genes involved in intestinal tight junctions. Together, these results highlight the diversity of mechanisms used by bacteria from the gut microbiota to manipulate host SUMOylation. They further highlight that changes in gut microbiota composition may impact intestinal inflammation, by altering the equilibrium between bacterial effectors promoting or dampening SUMOylation.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2446392"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004536","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}

{"title":"Hypoglycemic effect of <i>C. butyricum</i>-pMTL007-GLP-1 engineered probiotics on type 2 diabetes mellitus.","authors":"Dexi Zhou, Shengjie Li, Gang Hu, Yufan Wang, Zhanghua Qi, Xuan Xu, Jing Wei, Qiong Liu, Tingtao Chen","doi":"10.1080/19490976.2024.2447814","DOIUrl":"https://doi.org/10.1080/19490976.2024.2447814","url":null,"abstract":"<p><p>Diabetes mellitus (DM) is a complex metabolic disease characterized by hyperglycemia. Recently, the incidence of diabetes has increased exponentially, and it is estimated to become the seventh leading cause of global mortality by 2030. Glucagon-like peptide-1 (GLP-1), a hormone derived from the intestine, has been demonstrated to exert remarkable hypoglycemic effects. However, its limitation lies in its short plasma half-life, necessitating the continuous intravenous injection of GLP-1 drugs to achieve efficacy. Here, we engineered <i>Clostridium butyricum</i> to continuously express and deliver GLP-1 (denoted as Cb-GLP-1), and assessed its therapeutic efficacy in type 2 diabetes mellitus (T2DM) mice. We demonstrated that administration of Cb-GLP-1 effectively lowered blood glucose levels, regulated dyslipidemia, and ameliorated hepatic impairment in T2DM mice. Furthermore, Cb-GLP-1 treatment facilitated insulin secretion by retarding islet cell apoptosis and activating the glucagon-like peptide 1 receptor/adenylate cyclase/protein kinase A (GLP-1 R/AC/PKA) signaling pathway. Gut microbiota analysis revealed that Cb-GLP-1 restored gut homeostasis disrupted in T2DM mice, as indicated by the decreased abundance of <i>Lactobacillus</i> and <i>Providencia</i> genera in response to Cb-GLP-1 treatment. Collectively, the intestinal microbiota regulation and hypoglycemic effect of the engineered strain Cb-GLP-1 presents a promising approach for diabetes management.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2447814"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914573","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}

{"title":"Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine.","authors":"Izabella Sall, Randi Foxall, Lindsey Felth, Soren Maret, Zachary Rosa, Anirudh Gaur, Jennifer Calawa, Nadia Pavlik, Jennifer L Whistler, Cheryl A Whistler","doi":"10.1080/19490976.2024.2446423","DOIUrl":"10.1080/19490976.2024.2446423","url":null,"abstract":"<p><p>The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance, which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2446423"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}