Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin
Abstract Vitamin B12 (VB12) deficiency, which may lead to hematologic and neurologic symptoms, has been associated with metformin use, but the underlying mechanism is unclear. Here we report the B. ovatus as an effective VB12 catcher which was enriched in the type 2 diabetes patients suffered from V...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | npj Biofilms and Microbiomes |
| Online Access: | https://doi.org/10.1038/s41522-023-00419-y |
| _version_ | 1797769666362343424 |
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| author | Manyun Chen Yan Shu Qing Li Zhiqiang Kang Tao Liu Honghao Zhou Weihua Huang Wei Zhang |
| author_facet | Manyun Chen Yan Shu Qing Li Zhiqiang Kang Tao Liu Honghao Zhou Weihua Huang Wei Zhang |
| author_sort | Manyun Chen |
| collection | DOAJ |
| description | Abstract Vitamin B12 (VB12) deficiency, which may lead to hematologic and neurologic symptoms, has been associated with metformin use, but the underlying mechanism is unclear. Here we report the B. ovatus as an effective VB12 catcher which was enriched in the type 2 diabetes patients suffered from VB12 deficiency after 3 to 6 months of metformin treatment. Colonization of B. ovatus increased the plasma levels of methylmalonic acid and homocysteine in high-fat diet (HFD)-fed mice treated with metformin, and compromised the efficacy of metformin against the HFD-induced metabolic disorders. Mechanistically, metformin increased the intracellular accumulation of VB12 in B. ovatus via btuB upregulation and promoted ATP production for energy-dependent translocation of VB12 transporters at the inner membrane, leading to an enhanced colonization of B. ovatus to compete for VB12 with hosts and subsequently an aggravated VB12 deficiency in the host. Our findings illustrate a previously unappreciated mechanism of metformin leads to host VB12 deficiency by acting directly on gut bacteria to increase their VB12 uptake and consumption, and suggest that inter-host-microbe competition for nutrients may broadly impact human health and drug safety. |
| first_indexed | 2024-03-12T21:11:20Z |
| format | Article |
| id | doaj.art-c54af40bbc954970b840ee25df3ce7c9 |
| institution | Directory Open Access Journal |
| issn | 2055-5008 |
| language | English |
| last_indexed | 2024-03-12T21:11:20Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Biofilms and Microbiomes |
| spelling | doaj.art-c54af40bbc954970b840ee25df3ce7c92023-07-30T11:09:08ZengNature Portfolionpj Biofilms and Microbiomes2055-50082023-07-019111510.1038/s41522-023-00419-yBacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalaminManyun Chen0Yan Shu1Qing Li2Zhiqiang Kang3Tao Liu4Honghao Zhou5Weihua Huang6Wei Zhang7Department of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityZhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou UniversityShenzhen Center for Chronic Disease Control and PreventionDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityDepartment of Clinical Pharmacology, Xiangya Hospital, Central South UniversityAbstract Vitamin B12 (VB12) deficiency, which may lead to hematologic and neurologic symptoms, has been associated with metformin use, but the underlying mechanism is unclear. Here we report the B. ovatus as an effective VB12 catcher which was enriched in the type 2 diabetes patients suffered from VB12 deficiency after 3 to 6 months of metformin treatment. Colonization of B. ovatus increased the plasma levels of methylmalonic acid and homocysteine in high-fat diet (HFD)-fed mice treated with metformin, and compromised the efficacy of metformin against the HFD-induced metabolic disorders. Mechanistically, metformin increased the intracellular accumulation of VB12 in B. ovatus via btuB upregulation and promoted ATP production for energy-dependent translocation of VB12 transporters at the inner membrane, leading to an enhanced colonization of B. ovatus to compete for VB12 with hosts and subsequently an aggravated VB12 deficiency in the host. Our findings illustrate a previously unappreciated mechanism of metformin leads to host VB12 deficiency by acting directly on gut bacteria to increase their VB12 uptake and consumption, and suggest that inter-host-microbe competition for nutrients may broadly impact human health and drug safety.https://doi.org/10.1038/s41522-023-00419-y |
| spellingShingle | Manyun Chen Yan Shu Qing Li Zhiqiang Kang Tao Liu Honghao Zhou Weihua Huang Wei Zhang Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin npj Biofilms and Microbiomes |
| title | Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin |
| title_full | Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin |
| title_fullStr | Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin |
| title_full_unstemmed | Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin |
| title_short | Bacteroides ovatus accelerates metformin-induced vitamin B12 deficiency in type 2 diabetes patients by accumulating cobalamin |
| title_sort | bacteroides ovatus accelerates metformin induced vitamin b12 deficiency in type 2 diabetes patients by accumulating cobalamin |
| url | https://doi.org/10.1038/s41522-023-00419-y |
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