Pub Date : 2024-01-01Epub Date: 2024-01-30DOI: 10.1080/19490976.2023.2301147
Lise Hunault, Emile Auria, Patrick England, Julien Deschamps, Romain Briandet, Vanessa Kremer, Bruno Iannascoli, Léo Vidal-Maison, Chunguang Guo, Lynn Macdonald, Séverine Péchiné, Cécile Denève-Larrazet, Bruno Dupuy, Guy Gorochov, Pierre Bruhns, Delphine Sterlin
Clostridioides difficile (C. difficile), a gram-positive anaerobic and spore-forming bacterium, is the leading cause of nosocomial antibiotic-associated diarrhea in adults which is characterized by high levels of recurrence and mortality. Surface (S)-layer Protein A (SlpA), the most abundantly expressed protein on the bacterial surface, plays a crucial role in the early stages of infection although the nature of its involvement in C. difficile physiology is yet to be fully understood. Anti-S-layer antibodies have been identified in the sera of convalescent patients and have been correlated with improved outcomes of C. difficile infection (CDI). However, the precise mechanisms by which anti-S-layer antibodies confer protection to the host remain unknown. In this study, we report the first monoclonal antibodies (mAbs) targeting the S-layer of reference strain 630. Characterization of these mAbs unraveled important roles for the S-layer protein in growth, toxin secretion, and biofilm formation by C. difficile, with differential and even opposite effects of various anti-SlpA mAbs on these functions. Moreover, one anti-SlpA mAb impaired C. difficile growth and conferred sensitivity to lysozyme-induced lysis. The results of this study show that anti-S-layer antibody responses can be beneficial or harmful for the course of CDI and provide important insights for the development of adequate S-layer-targeting therapeutics.
艰难梭状芽孢杆菌(C. difficile)是一种革兰氏阳性厌氧芽孢杆菌,是引起成人院内抗生素相关性腹泻的主要原因,其特点是复发率和死亡率高。表面(S)层蛋白 A(SlpA)是细菌表面表达最丰富的蛋白质,在感染的早期阶段起着至关重要的作用,但它参与艰难梭菌生理学的性质尚不完全清楚。在康复患者的血清中发现了抗 S 层抗体,这种抗体与艰难梭菌感染(CDI)疗效的改善有关。然而,抗 S 层抗体为宿主提供保护的确切机制仍然未知。在这项研究中,我们首次报道了针对参考菌株 630 的 S 层的单克隆抗体(mAbs)。这些 mAbs 的特性揭示了 S 层蛋白在艰难梭菌的生长、毒素分泌和生物膜形成中的重要作用,不同的抗 SlpA mAbs 对这些功能的影响不同,甚至相反。此外,一种抗 SlpA mAb 会阻碍艰难梭菌的生长,并使其对溶菌酶诱导的裂解敏感。这项研究结果表明,抗S层抗体反应对艰难梭菌感染的病程有利或有害,并为开发适当的S层靶向疗法提供了重要启示。
{"title":"Anti-S-layer monoclonal antibodies impact <i>Clostridioides difficile</i> physiology.","authors":"Lise Hunault, Emile Auria, Patrick England, Julien Deschamps, Romain Briandet, Vanessa Kremer, Bruno Iannascoli, Léo Vidal-Maison, Chunguang Guo, Lynn Macdonald, Séverine Péchiné, Cécile Denève-Larrazet, Bruno Dupuy, Guy Gorochov, Pierre Bruhns, Delphine Sterlin","doi":"10.1080/19490976.2023.2301147","DOIUrl":"10.1080/19490976.2023.2301147","url":null,"abstract":"<p><p><i>Clostridioides difficile</i> (<i>C. difficile</i>), a gram-positive anaerobic and spore-forming bacterium, is the leading cause of nosocomial antibiotic-associated diarrhea in adults which is characterized by high levels of recurrence and mortality. Surface (S)-layer Protein A (SlpA), the most abundantly expressed protein on the bacterial surface, plays a crucial role in the early stages of infection although the nature of its involvement in <i>C. difficile</i> physiology is yet to be fully understood. Anti-S-layer antibodies have been identified in the sera of convalescent patients and have been correlated with improved outcomes of <i>C. difficile</i> infection (CDI). However, the precise mechanisms by which anti-S-layer antibodies confer protection to the host remain unknown. In this study, we report the first monoclonal antibodies (mAbs) targeting the S-layer of reference strain 630. Characterization of these mAbs unraveled important roles for the S-layer protein in growth, toxin secretion, and biofilm formation by <i>C. difficile</i>, with differential and even opposite effects of various anti-SlpA mAbs on these functions. Moreover, one anti-SlpA mAb impaired <i>C. difficile</i> growth and conferred sensitivity to lysozyme-induced lysis. The results of this study show that anti-S-layer antibody responses can be beneficial or harmful for the course of CDI and provide important insights for the development of adequate S-layer-targeting therapeutics.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10829821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575461","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}
Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify Phocaeicola vulgatus (P. vulgatus) as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of P. vulgatus mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by P. vulgatus, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of P. vulgatus in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.
{"title":"<i>Phocaeicola vulgatus</i> alleviates diet-induced metabolic dysfunction-associated steatotic liver disease progression by downregulating histone acetylation level via 3-HPAA.","authors":"Shengxi Jin, Peng Chen, Jing Yang, Duguang Li, Xiaolong Liu, Yiyin Zhang, Qiming Xia, Yiling Li, Guoqiao Chen, Yixuan Li, Yifan Tong, Weihua Yu, Xiaoxiao Fan, Hui Lin","doi":"10.1080/19490976.2024.2309683","DOIUrl":"10.1080/19490976.2024.2309683","url":null,"abstract":"<p><p>Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify <i>Phocaeicola vulgatus (P. vulgatus)</i> as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of <i>P. vulgatus</i> mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by <i>P. vulgatus</i>, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of <i>P. vulgatus</i> in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10854360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139681020","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}
Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (S)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (S)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (S)-ketamine treatments improved the abnormal composition of the gut microbiome (β-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut - brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (S)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (S)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (S)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota - brain axis, primarily through the enhancement of hippocampal BDNF - TrkB signaling by butyrate.
{"title":"Repeated (<i>S</i>)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota-brain axis.","authors":"Yubin Jiang, Xingming Wang, Jiawei Chen, Yibao Zhang, Kenji Hashimoto, Jian-Jun Yang, Zhiqiang Zhou","doi":"10.1080/19490976.2024.2310603","DOIUrl":"10.1080/19490976.2024.2310603","url":null,"abstract":"<p><p>Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (<i>S</i>)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (<i>S</i>)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (<i>S</i>)-ketamine treatments improved the abnormal composition of the gut microbiome (β-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut - brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (<i>S</i>)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (<i>S</i>)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (<i>S</i>)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota - brain axis, primarily through the enhancement of hippocampal BDNF - TrkB signaling by butyrate.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10860353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706573","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}
Pub Date : 2024-01-01Epub Date: 2024-02-27DOI: 10.1080/19490976.2024.2320280
Mariana Santos Cruz, Joseph Tintelnot, Nicola Gagliani
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. This is due to the fact that most cases are only diagnosed at an advanced and palliative disease stage, and there is a high incidence of therapy resistance. Despite ongoing efforts, to date, the mechanisms underlying PDAC oncogenesis and its poor responses to treatment are still largely unclear. As the study of the microbiome in cancer progresses, growing evidence suggests that bacteria or fungi might be key players both in PDAC oncogenesis as well as in its resistance to chemo- and immunotherapy, for instance through modulation of the tumor microenvironment and reshaping of the host immune response. Here, we review how the microbiota exerts these effects directly or indirectly via microbial-derived metabolites. Finally, we further discuss the potential of modulating the microbiota composition as a therapy in PDAC.
{"title":"Roles of microbiota in pancreatic cancer development and treatment.","authors":"Mariana Santos Cruz, Joseph Tintelnot, Nicola Gagliani","doi":"10.1080/19490976.2024.2320280","DOIUrl":"10.1080/19490976.2024.2320280","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. This is due to the fact that most cases are only diagnosed at an advanced and palliative disease stage, and there is a high incidence of therapy resistance. Despite ongoing efforts, to date, the mechanisms underlying PDAC oncogenesis and its poor responses to treatment are still largely unclear. As the study of the microbiome in cancer progresses, growing evidence suggests that bacteria or fungi might be key players both in PDAC oncogenesis as well as in its resistance to chemo- and immunotherapy, for instance through modulation of the tumor microenvironment and reshaping of the host immune response. Here, we review how the microbiota exerts these effects directly or indirectly via microbial-derived metabolites. Finally, we further discuss the potential of modulating the microbiota composition as a therapy in PDAC.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971702","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}
Pub Date : 2024-01-01Epub Date: 2024-02-29DOI: 10.1080/19490976.2024.2323235
Joana Pereira-Marques, Rui M Ferreira, Ceu Figueiredo
The high background of host RNA poses a major challenge to metatranscriptome analysis of human samples. Hence, metatranscriptomics has been mainly applied to microbe-rich samples, while its application in human tissues with low ratio of microbial to host cells has yet to be explored. Since there is no computational workflow specifically designed for the taxonomic and functional analysis of this type of samples, we propose an effective metatranscriptomics strategy to accurately characterize the microbiome in human tissues with a low ratio of microbial to host content. We experimentally generated synthetic samples with well-characterized bacterial and host cell compositions, and mimicking human samples with high and low microbial loads. These synthetic samples were used for optimizing and establishing the workflow in a controlled setting. Our results show that the integration of the taxonomic analysis of optimized Kraken 2/Bracken with the functional analysis of HUMAnN 3 in samples with low microbial content, enables the accurate identification of a large number of microbial species with a low false-positive rate, while improving the detection of microbial functions. The effectiveness of our metatranscriptomics workflow was demonstrated in synthetic samples, simulated datasets, and most importantly, human gastric tissue specimens, thus providing a proof of concept for its applicability on mucosal tissues of the gastrointestinal tract. The use of an accurate and reliable metatranscriptomics approach for human tissues with low microbial content will expand our understanding of the functional activity of the mucosal microbiome, uncovering critical interactions between the microbiome and the host in health and disease.
{"title":"A metatranscriptomics strategy for efficient characterization of the microbiome in human tissues with low microbial biomass.","authors":"Joana Pereira-Marques, Rui M Ferreira, Ceu Figueiredo","doi":"10.1080/19490976.2024.2323235","DOIUrl":"10.1080/19490976.2024.2323235","url":null,"abstract":"<p><p>The high background of host RNA poses a major challenge to metatranscriptome analysis of human samples. Hence, metatranscriptomics has been mainly applied to microbe-rich samples, while its application in human tissues with low ratio of microbial to host cells has yet to be explored. Since there is no computational workflow specifically designed for the taxonomic and functional analysis of this type of samples, we propose an effective metatranscriptomics strategy to accurately characterize the microbiome in human tissues with a low ratio of microbial to host content. We experimentally generated synthetic samples with well-characterized bacterial and host cell compositions, and mimicking human samples with high and low microbial loads. These synthetic samples were used for optimizing and establishing the workflow in a controlled setting. Our results show that the integration of the taxonomic analysis of optimized Kraken 2/Bracken with the functional analysis of HUMAnN 3 in samples with low microbial content, enables the accurate identification of a large number of microbial species with a low false-positive rate, while improving the detection of microbial functions. The effectiveness of our metatranscriptomics workflow was demonstrated in synthetic samples, simulated datasets, and most importantly, human gastric tissue specimens, thus providing a proof of concept for its applicability on mucosal tissues of the gastrointestinal tract. The use of an accurate and reliable metatranscriptomics approach for human tissues with low microbial content will expand our understanding of the functional activity of the mucosal microbiome, uncovering critical interactions between the microbiome and the host in health and disease.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10913719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996082","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}
Rapid and accurate clinical staging of pediatric patients with inflammatory bowel disease (IBD) is crucial to determine the appropriate therapeutic approach. This study aimed to identify effective, convenient biomarkers for staging IBD in pediatric patients. We recruited cohorts of pediatric patients with varying severities of IBD to compare the features of the intestinal microbiota and metabolites between the active and remitting disease stages. Metabolites with potential for staging were targeted for further assessment in both patients and colitis model mice. The performance of these markers was determined using machine learning and was validated in a separate patient cohort. Pediatric patients with IBD exhibited distinct gut microbiota structures at different stages of disease activity. The enterotypes of patients with remitting and active disease were Bacteroides-dominant and Escherichia-Shigella-dominant, respectively. The bile secretion pathway showed the most significant differences between the two stages. Fecal and serum bile acid (BA) levels were strongly related to disease activity in both children and mice. The ratio of primary BAs to secondary BAs in serum was developed as a novel comprehensive index, showing excellent diagnostic performance in stratifying IBD activity (0.84 area under the receiver operating characteristic curve in the primary cohort; 77% accuracy in the validation cohort). In conclusion, we report profound insights into the interactions between the gut microbiota and metabolites in pediatric IBD. Serum BAs have potential as biomarkers for classifying disease activity, and may facilitate the personalization of treatment for IBD.
{"title":"Bile acid profiling as an effective biomarker for staging in pediatric inflammatory bowel disease.","authors":"Wei Chen, Daosheng Wang, Xing Deng, Hong Zhang, Danfeng Dong, Tongxuan Su, Qiuya Lu, Cen Jiang, Qi Ni, Yingchao Cui, Qianli Zhao, Xuefeng Wang, Yuan Xiao, Yibing Peng","doi":"10.1080/19490976.2024.2323231","DOIUrl":"10.1080/19490976.2024.2323231","url":null,"abstract":"<p><p>Rapid and accurate clinical staging of pediatric patients with inflammatory bowel disease (IBD) is crucial to determine the appropriate therapeutic approach. This study aimed to identify effective, convenient biomarkers for staging IBD in pediatric patients. We recruited cohorts of pediatric patients with varying severities of IBD to compare the features of the intestinal microbiota and metabolites between the active and remitting disease stages. Metabolites with potential for staging were targeted for further assessment in both patients and colitis model mice. The performance of these markers was determined using machine learning and was validated in a separate patient cohort. Pediatric patients with IBD exhibited distinct gut microbiota structures at different stages of disease activity. The enterotypes of patients with remitting and active disease were <i>Bacteroides-dominant</i> and <i>Escherichia-Shigella-dominant</i>, respectively. The bile secretion pathway showed the most significant differences between the two stages. Fecal and serum bile acid (BA) levels were strongly related to disease activity in both children and mice. The ratio of primary BAs to secondary BAs in serum was developed as a novel comprehensive index, showing excellent diagnostic performance in stratifying IBD activity (0.84 area under the receiver operating characteristic curve in the primary cohort; 77% accuracy in the validation cohort). In conclusion, we report profound insights into the interactions between the gut microbiota and metabolites in pediatric IBD. Serum BAs have potential as biomarkers for classifying disease activity, and may facilitate the personalization of treatment for IBD.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10913721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021579","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}
In the development of Type 1 diabetes (T1D), there are critical states just before drastic changes, and identifying these pre-disease states may predict T1D or provide crucial early-warning signals. Unlike gene expression data, gut microbiome data can be collected noninvasively from stool samples. Gut microbiome sequencing data contain different levels of phylogenetic information that can be utilized to detect the tipping point or critical state in a reliable manner, thereby providing accurate and effective early-warning signals. However, it is still difficult to detect the critical state of T1D based on gut microbiome data due to generally non-significant differences between healthy and critical states. To address this problem, we proposed a new method - microbiome network flow entropy (mNFE) based on a single sample from each individual - for detecting the critical state before seroconversion and abrupt transitions of T1D at various taxonomic levels. The numerical simulation validated the robustness of mNFE under different noise levels. Furthermore, based on real datasets, mNFE successfully identified the critical states and their dynamic network biomarkers (DNBs) at different taxonomic levels. In addition, we found some high-frequency species, which are closely related to the unique clinical characteristics of autoantibodies at the four levels, and identified some non-differential 'dark species' play important roles during the T1D progression. mNFE can robustly and effectively detect the pre-disease states at various taxonomic levels and identify the corresponding DNBs with only a single sample for each individual. Therefore, our mNFE method provides a new approach not only for T1D pre-disease diagnosis or preventative treatment but also for preventative medicine of other diseases by gut microbiome.
{"title":"mNFE: microbiome network flow entropy for detecting pre-disease states of type 1 diabetes.","authors":"Rong Gao, Peiluan Li, Yueqiong Ni, Xueqing Peng, Jing Ren, Luonan Chen","doi":"10.1080/19490976.2024.2327349","DOIUrl":"10.1080/19490976.2024.2327349","url":null,"abstract":"<p><p>In the development of Type 1 diabetes (T1D), there are critical states just before drastic changes, and identifying these pre-disease states may predict T1D or provide crucial early-warning signals. Unlike gene expression data, gut microbiome data can be collected noninvasively from stool samples. Gut microbiome sequencing data contain different levels of phylogenetic information that can be utilized to detect the tipping point or critical state in a reliable manner, thereby providing accurate and effective early-warning signals. However, it is still difficult to detect the critical state of T1D based on gut microbiome data due to generally non-significant differences between healthy and critical states. To address this problem, we proposed a new method - microbiome network flow entropy (mNFE) based on a single sample from each individual - for detecting the critical state before seroconversion and abrupt transitions of T1D at various taxonomic levels. The numerical simulation validated the robustness of mNFE under different noise levels. Furthermore, based on real datasets, mNFE successfully identified the critical states and their dynamic network biomarkers (DNBs) at different taxonomic levels. In addition, we found some high-frequency species, which are closely related to the unique clinical characteristics of autoantibodies at the four levels, and identified some non-differential 'dark species' play important roles during the T1D progression. mNFE can robustly and effectively detect the pre-disease states at various taxonomic levels and identify the corresponding DNBs with only a single sample for each individual. Therefore, our mNFE method provides a new approach not only for T1D pre-disease diagnosis or preventative treatment but also for preventative medicine of other diseases by gut microbiome.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10962612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140184257","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}
Pub Date : 2024-01-01Epub Date: 2024-03-28DOI: 10.1080/19490976.2024.2333463
Yijie Guo, Sho Kitamoto, Gustavo Caballero-Flores, Yeji Kim, Daisuke Watanabe, Kohei Sugihara, Gabriel Núñez, Christopher J Alteri, Naohiro Inohara, Nobuhiko Kamada
The ectopic gut colonization by orally derived pathobionts has been implicated in the pathogenesis of various gastrointestinal diseases, including inflammatory bowel disease (IBD). For example, gut colonization by orally derived Klebsiella spp. has been linked to IBD in mice and humans. However, the mechanisms whereby oral pathobionts colonize extra-oral niches, such as the gut mucosa, remain largely unknown. Here, we performed a high-density transposon (Tn) screening to identify genes required for the adaptation of an oral Klebsiella strain to different mucosal sites - the oral and gut mucosae - at the steady state and during inflammation. We find that K. aerogenes, an oral pathobiont associated with both oral and gut inflammation in mice, harbors a newly identified genomic locus named "locus of colonization in the inflamed gut (LIG)" that encodes genes related to iron acquisition (Sit and Chu) and host adhesion (chaperon usher pili [CUP] system). The LIG locus is highly conserved among K. aerogenes strains, and these genes are also present in several other Klebsiella species. The Tn screening revealed that the LIG locus is required for the adaptation of K. aerogenes in its ectopic niche. In particular, we determined K. aerogenes employs a CUP system (CUP1) present in the LIG locus for colonization in the inflamed gut, but not in the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche compared to their native niche.
口服致病菌的异位肠道定植与包括炎症性肠病(IBD)在内的多种胃肠道疾病的发病机制有关。例如,口服克雷伯氏菌属的肠道定植与小鼠和人类的 IBD 有关。然而,口腔致病菌在口腔外壁龛(如肠道粘膜)定植的机制在很大程度上仍然未知。在这里,我们进行了一次高密度转座子(Tn)筛选,以确定口腔克雷伯氏菌菌株在稳定状态和炎症期间适应不同粘膜部位(口腔和肠道粘膜)所需的基因。我们发现,与小鼠口腔和肠道炎症相关的一种口腔致病菌--产气克雷伯氏菌携带一个新发现的基因组位点,该位点被命名为 "炎症肠道定殖位点(LIG)",它编码与铁获取(Sit 和 Chu)和宿主粘附(伴侣纤毛[CUP]系统)相关的基因。LIG 基因座在产气克雷伯氏菌菌株中高度保守,这些基因也存在于其他几个克雷伯氏菌物种中。Tn 筛选结果表明,LIG 基因座是产气荚膜克雷伯氏菌适应异位生态位所必需的。特别是,我们确定产气荚膜克雷伯菌利用 LIG 基因座中的 CUP 系统(CUP1)在发炎的肠道中定植,但不在口腔粘膜中定植。因此,口腔致病菌在其异位定殖的肠道生态位中可能利用了与其原生生态位不同的适应机制。
{"title":"Oral pathobiont <i>Klebsiella</i> chaperon usher pili provide site-specific adaptation for the inflamed gut mucosa.","authors":"Yijie Guo, Sho Kitamoto, Gustavo Caballero-Flores, Yeji Kim, Daisuke Watanabe, Kohei Sugihara, Gabriel Núñez, Christopher J Alteri, Naohiro Inohara, Nobuhiko Kamada","doi":"10.1080/19490976.2024.2333463","DOIUrl":"10.1080/19490976.2024.2333463","url":null,"abstract":"<p><p>The ectopic gut colonization by orally derived pathobionts has been implicated in the pathogenesis of various gastrointestinal diseases, including inflammatory bowel disease (IBD). For example, gut colonization by orally derived <i>Klebsiella</i> spp. has been linked to IBD in mice and humans. However, the mechanisms whereby oral pathobionts colonize extra-oral niches, such as the gut mucosa, remain largely unknown. Here, we performed a high-density transposon (Tn) screening to identify genes required for the adaptation of an oral <i>Klebsiella</i> strain to different mucosal sites - the oral and gut mucosae - at the steady state and during inflammation. We find that <i>K. aerogenes</i>, an oral pathobiont associated with both oral and gut inflammation in mice, harbors a newly identified genomic locus named \"locus of colonization in the inflamed gut (LIG)\" that encodes genes related to iron acquisition (Sit and Chu) and host adhesion (chaperon usher pili [CUP] system). The LIG locus is highly conserved among <i>K. aerogenes</i> strains, and these genes are also present in several other <i>Klebsiella</i> species. The Tn screening revealed that the LIG locus is required for the adaptation of <i>K. aerogenes</i> in its ectopic niche. In particular, we determined <i>K. aerogenes</i> employs a CUP system (CUP1) present in the LIG locus for colonization in the inflamed gut, but not in the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche compared to their native niche.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305413","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}
Pub Date : 2024-01-01Epub Date: 2024-03-28DOI: 10.1080/19490976.2024.2331434
Bin Jiao, Ziyu Ouyang, Qianqian Liu, Tianyan Xu, Meidan Wan, Guangrong Ma, Lu Zhou, Jifeng Guo, Junling Wang, Beisha Tang, Zhixiang Zhao, Lu Shen
The role of microbiota-gut-brain axis in modulating longevity remains undetermined. Here, we performed a multiomics analysis of gut metagenomics, gut metabolomics, and brain functional near-infrared spectroscopy (fNIRS) in a cohort of 164 participants, including 83 nonagenarians (NAs) and 81 non-nonagenarians (NNAs) matched with their spouses and offspring. We found that 438 metabolites were significantly different between the two groups; among them, neuroactive compounds and anti-inflammatory substances were enriched in NAs. In addition, increased levels of neuroactive metabolites in NAs were significantly associated with NA-enriched species that had three corresponding biosynthetic potentials: Enterocloster asparagiformis, Hungatella hathewayi and Oxalobacter formigenes. Further analysis showed that the altered gut microbes and metabolites were linked to the enhanced brain connectivity in NAs, including the left dorsolateral prefrontal cortex (DLPFC)-left premotor cortex (PMC), left DLPFC-right primary motor area (M1), and right inferior frontal gyrus (IFG)-right M1. Finally, we found that neuroactive metabolites, altered microbe and enhanced brain connectivity contributed to the cognitive preservation in NAs. Our findings provide a comprehensive understanding of the microbiota-gut-brain axis in a long-lived population and insights into the establishment of a microbiome and metabolite homeostasis that can benefit human longevity and cognition by enhancing functional brain connectivity.
{"title":"Integrated analysis of gut metabolome, microbiome, and brain function reveal the role of gut-brain axis in longevity.","authors":"Bin Jiao, Ziyu Ouyang, Qianqian Liu, Tianyan Xu, Meidan Wan, Guangrong Ma, Lu Zhou, Jifeng Guo, Junling Wang, Beisha Tang, Zhixiang Zhao, Lu Shen","doi":"10.1080/19490976.2024.2331434","DOIUrl":"10.1080/19490976.2024.2331434","url":null,"abstract":"<p><p>The role of microbiota-gut-brain axis in modulating longevity remains undetermined. Here, we performed a multiomics analysis of gut metagenomics, gut metabolomics, and brain functional near-infrared spectroscopy (fNIRS) in a cohort of 164 participants, including 83 nonagenarians (NAs) and 81 non-nonagenarians (NNAs) matched with their spouses and offspring. We found that 438 metabolites were significantly different between the two groups; among them, neuroactive compounds and anti-inflammatory substances were enriched in NAs. In addition, increased levels of neuroactive metabolites in NAs were significantly associated with NA-enriched species that had three corresponding biosynthetic potentials: <i>Enterocloster asparagiformis</i>, <i>Hungatella hathewayi</i> and <i>Oxalobacter formigenes</i>. Further analysis showed that the altered gut microbes and metabolites were linked to the enhanced brain connectivity in NAs, including the left dorsolateral prefrontal cortex (DLPFC)-left premotor cortex (PMC), left DLPFC-right primary motor area (M1), and right inferior frontal gyrus (IFG)-right M1. Finally, we found that neuroactive metabolites, altered microbe and enhanced brain connectivity contributed to the cognitive preservation in NAs. Our findings provide a comprehensive understanding of the microbiota-gut-brain axis in a long-lived population and insights into the establishment of a microbiome and metabolite homeostasis that can benefit human longevity and cognition by enhancing functional brain connectivity.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318168","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}
Ulcerative colitis (UC) is a challenging form of inflammatory bowel disease, and its etiology is intricately linked to disturbances in the gut microbiome. To identify the potential alleviators of UC, we employed an integrative analysis combining microbial community modeling with advanced machine learning techniques. Using metagenomics data sourced from the Integrated Human Microbiome Project, we constructed individualized microbiome community models for each participant. Our analysis highlighted a significant decline in both α and β-diversity of strain-level microbial populations in UC subjects compared to controls. Distinct differences were also observed in the predicted fecal metabolite profiles and strain-to-metabolite contributions between the two groups. Using tree-based machine learning models, we successfully identified specific microbial strains and their associated metabolites as potential alleviators of UC. Notably, our experimental validation using a dextran sulfate sodium-induced UC mouse model demonstrated that the administration of Parabacteroides merdae ATCC 43,184 and N-acetyl-D-mannosamine provided notable relief from colitis symptoms. In summary, our study underscores the potential of an integrative approach to identify novel therapeutic avenues for UC, paving the way for future targeted interventions.
{"title":"Integrative analysis with microbial modelling and machine learning uncovers potential alleviators for ulcerative colitis.","authors":"Jinlin Zhu, Jialin Yin, Jing Chen, Mingyi Hu, Wenwei Lu, Hongchao Wang, Hao Zhang, Wei Chen","doi":"10.1080/19490976.2024.2336877","DOIUrl":"10.1080/19490976.2024.2336877","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is a challenging form of inflammatory bowel disease, and its etiology is intricately linked to disturbances in the gut microbiome. To identify the potential alleviators of UC, we employed an integrative analysis combining microbial community modeling with advanced machine learning techniques. Using metagenomics data sourced from the Integrated Human Microbiome Project, we constructed individualized microbiome community models for each participant. Our analysis highlighted a significant decline in both α and β-diversity of strain-level microbial populations in UC subjects compared to controls. Distinct differences were also observed in the predicted fecal metabolite profiles and strain-to-metabolite contributions between the two groups. Using tree-based machine learning models, we successfully identified specific microbial strains and their associated metabolites as potential alleviators of UC. Notably, our experimental validation using a dextran sulfate sodium-induced UC mouse model demonstrated that the administration of <i>Parabacteroides merdae</i> ATCC 43,184 and N-acetyl-D-mannosamine provided notable relief from colitis symptoms. In summary, our study underscores the potential of an integrative approach to identify novel therapeutic avenues for UC, paving the way for future targeted interventions.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10989691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335371","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}