Genetically informed causal links between gut microbiota and bone mass: pleiotropy and metabolic mediation
The interplay among host genetic architecture, gut microbiota, metabolites and bone metabolism remains poorly understood. This study aims to comprehensively investigate the shared genetic factors, causal relationships, and the involvement of blood metabolites between gut microbiota and bone mass, based on datasets from European populations. Here, we estimate the polygenic SNP heritability for 1104 gut microbiota taxa, only 96 (8.7%) showed significant polygenic heritability. We identify 14 distinct gut microbiota taxa with pleiotropic effects on estimated heel bone mineral density (eBMD), 11 of them are found to have a causal association with eBMD. Following sensitivity and validation analyses, we find that the gut microbiota taxa family Bifidobacteriaceae; genus Bifidobacterium and species Bifidobacterium adolescentis exert causal effects leading to decreased eBMD. Mediation analyses indicate that the impact of these taxa on eBMD may be driven by their influence on circulating stearidonate (18:4n-3) levels via n-3 pathway, with mediating proportion from 77.53% to 87.24%. In conclusion, the genetically informed negative association between bifidobacterial taxa and bone mass may reflect the host-microbe interactions at LCT/MCM6 locus and represent an adaptive microbial response to lactose intolerance, thus, it could potentially be mitigated through supplementation with bifidobacterial probiotics and n-3 polyunsaturated fatty acids.
Authors
- Ching‐Lung Cheung (ORCID: https://orcid.org/0000-0002-6233-9144)
- Pianpian Zhao (ORCID: https://orcid.org/0009-0009-1676-1748)
- Peng-Lin Guan (ORCID: https://orcid.org/0009-0002-5603-2012)
- Fusheng Zhou (ORCID: https://orcid.org/0000-0003-4195-2801)
- Chun-Fu Yu
- Cai-Rui Liu
- Wei Xu (ORCID: https://orcid.org/0000-0003-4208-7477)
- Hou‐Feng Zheng (ORCID: https://orcid.org/0000-0001-5681-8598)
- Mengyuan Yang (ORCID: https://orcid.org/0000-0001-5235-5733)
- Xiaoli Rong (ORCID: https://orcid.org/0000-0002-1030-509X)
- Shuyang Xie (ORCID: https://orcid.org/0000-0002-8090-2180)
- Yu Qian (ORCID: https://orcid.org/0000-0003-1327-9891)
- Yi-Hu Fang
- Wei Peng (ORCID: https://orcid.org/0000-0002-0868-0974)
- Mingyu Han (ORCID: https://orcid.org/0000-0002-8140-0537)
- Jiangwei Xia
- Cheng‐Da Yuan (ORCID: https://orcid.org/0009-0001-0009-812X)
Institutions
- Shangrao Normal University (CN)
- Binzhou Medical University (CN)
- Anhui University (CN)
- Shandong University of Aeronautics (CN)
- Capital Medical University (CN)
- Anhui Medical University (CN)
- Westlake University (CN)
- Soochow University (CN)
- First Affiliated Hospital of Jiangxi Medical College (CN)
- Second Affiliated Hospital of Soochow University (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Stanford Medicine (US)
- Hangzhou Hospital of Traditional Chinese Medicine (CN)
- Zhejiang University (CN)
- University of Hong Kong (HK)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-66881-8
- Citations
- 1
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Westlake University
- National Natural Science Foundation of China