Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species
Abstract Hepatic encephalopathy (HE) is the neuropsychiatric complication of liver cirrhosis (LC). The influence of gut microbiota on HE pathogenesis has been suggested but not precisely elucidated. Here, we investigate how the gut microbial profile changed in patients with HE to clarify the functio...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Health/LWW
2022-08-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1954 |
| _version_ | 1797758648235065344 |
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| author | Yoshimi Yukawa‐Muto Tomonori Kamiya Hideki Fujii Hiroshi Mori Atsushi Toyoda Ikuya Sato Yusuke Konishi Akiyoshi Hirayama Eiji Hara Shinji Fukuda Norifumi Kawada Naoko Ohtani |
| author_facet | Yoshimi Yukawa‐Muto Tomonori Kamiya Hideki Fujii Hiroshi Mori Atsushi Toyoda Ikuya Sato Yusuke Konishi Akiyoshi Hirayama Eiji Hara Shinji Fukuda Norifumi Kawada Naoko Ohtani |
| author_sort | Yoshimi Yukawa‐Muto |
| collection | DOAJ |
| description | Abstract Hepatic encephalopathy (HE) is the neuropsychiatric complication of liver cirrhosis (LC). The influence of gut microbiota on HE pathogenesis has been suggested but not precisely elucidated. Here, we investigate how the gut microbial profile changed in patients with HE to clarify the functional gut microbial species associated with HE. We focused on their responses to rifaximin (RFX), a nonabsorbable antibiotic used in HE therapy. Feces samples were collected from patients with decompensated LC (all HE), patients with compensated LC, and healthy controls, and fecal gut microbial profiles were compared using 16S ribosomal RNA gene amplicon and metagenomic sequencing. The linear discriminant analysis effect size was used to identify specific species. Urease‐positive Streptococcus salivarius, which can produce ammonia, was identified as the most significantly abundant gut microbiota in the HE group, and its ability to elevate the levels of blood ammonia as well as brain glutamine was experimentally verified in mice. Urease‐negative Ruminococcus gnavus was also identified as a significantly abundant species in patients with RFX‐nonresponsive HE after RFX administration. Interestingly, R. gnavus enhanced urease activity of recombinant urease itself, implying that R. gnavus could amplify ammonia production of surrounding urease‐positive microbiota. Furthermore, the sensitivity of S. salivarius and R. gnavus to RFX depended on conjugated secondary bile acid levels, suggesting a therapeutic potential of the combined use of secondary bile acid levels with RFX for enhancing the efficacy of RFX. This study identified specific gut bacterial species abundant in patients with HE and verified their functions linked to HE pathophysiology. Targeting these bacteria could be a potentially effective strategy to treat HE. |
| first_indexed | 2024-03-12T18:33:04Z |
| format | Article |
| id | doaj.art-8852857ddabc4cdc858b8f89e94f5086 |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T18:33:04Z |
| publishDate | 2022-08-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-8852857ddabc4cdc858b8f89e94f50862023-08-02T08:12:18ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2022-08-01682090210410.1002/hep4.1954Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial speciesYoshimi Yukawa‐Muto0Tomonori Kamiya1Hideki Fujii2Hiroshi Mori3Atsushi Toyoda4Ikuya Sato5Yusuke Konishi6Akiyoshi Hirayama7Eiji Hara8Shinji Fukuda9Norifumi Kawada10Naoko Ohtani11Department of Pathophysiology Graduate School of Medicine Osaka Metropolitan University (formerly, Osaka City University) Osaka JapanDepartment of Pathophysiology Graduate School of Medicine Osaka Metropolitan University (formerly, Osaka City University) Osaka JapanDepartment of Premier Preventive Medicine Graduate School of Medicine Osaka City University Osaka JapanAdvanced Genomics Center National Institute of Genetics Mishima JapanAdvanced Genomics Center National Institute of Genetics Mishima JapanMedical Affairs Department ASKA Pharmaceutical Co., Ltd. Tokyo JapanResearch Institute for Microbial Diseases Osaka University Suita JapanInstitute for Advanced Biosciences Keio University Tsuruoka JapanResearch Institute for Microbial Diseases Osaka University Suita JapanInstitute for Advanced Biosciences Keio University Tsuruoka JapanDepartment of Hepatology Graduate School of Medicine Osaka Metropolitan University (formerly, Osaka City University) Osaka JapanDepartment of Pathophysiology Graduate School of Medicine Osaka Metropolitan University (formerly, Osaka City University) Osaka JapanAbstract Hepatic encephalopathy (HE) is the neuropsychiatric complication of liver cirrhosis (LC). The influence of gut microbiota on HE pathogenesis has been suggested but not precisely elucidated. Here, we investigate how the gut microbial profile changed in patients with HE to clarify the functional gut microbial species associated with HE. We focused on their responses to rifaximin (RFX), a nonabsorbable antibiotic used in HE therapy. Feces samples were collected from patients with decompensated LC (all HE), patients with compensated LC, and healthy controls, and fecal gut microbial profiles were compared using 16S ribosomal RNA gene amplicon and metagenomic sequencing. The linear discriminant analysis effect size was used to identify specific species. Urease‐positive Streptococcus salivarius, which can produce ammonia, was identified as the most significantly abundant gut microbiota in the HE group, and its ability to elevate the levels of blood ammonia as well as brain glutamine was experimentally verified in mice. Urease‐negative Ruminococcus gnavus was also identified as a significantly abundant species in patients with RFX‐nonresponsive HE after RFX administration. Interestingly, R. gnavus enhanced urease activity of recombinant urease itself, implying that R. gnavus could amplify ammonia production of surrounding urease‐positive microbiota. Furthermore, the sensitivity of S. salivarius and R. gnavus to RFX depended on conjugated secondary bile acid levels, suggesting a therapeutic potential of the combined use of secondary bile acid levels with RFX for enhancing the efficacy of RFX. This study identified specific gut bacterial species abundant in patients with HE and verified their functions linked to HE pathophysiology. Targeting these bacteria could be a potentially effective strategy to treat HE.https://doi.org/10.1002/hep4.1954 |
| spellingShingle | Yoshimi Yukawa‐Muto Tomonori Kamiya Hideki Fujii Hiroshi Mori Atsushi Toyoda Ikuya Sato Yusuke Konishi Akiyoshi Hirayama Eiji Hara Shinji Fukuda Norifumi Kawada Naoko Ohtani Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species Hepatology Communications |
| title | Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species |
| title_full | Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species |
| title_fullStr | Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species |
| title_full_unstemmed | Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species |
| title_short | Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species |
| title_sort | distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species |
| url | https://doi.org/10.1002/hep4.1954 |
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