Identification of Causal Pathways among Gut Microbiota, Food Intake and Telomere Length: A Mendelian Randomization Study

Background Dietary habit plays an important role in the composition and function of gut microbiota which possibly manipulates host eating behavior. Gut microflora and nutritional imbalance are associated with telomere length (TL). However, the causality among them remains unclear. Methods Firstly, we calculate the significance threshold based on genetic correlations. Then we perform bi-directional Mendelian Randomization (MR) analyses among 82 food intakes (FIs) (UK Biobank, N=455,146), 95 gut microbial traits (Flemish Gut Flora Project, N=2,223) and TL (genome-wide meta-analysis from 15 cohorts, N=37,684) using summary-level data from large genome-wide association studies. Fixed-effect inverse variance weighting is the main analysis method and the other eight two-sample MR methods and three sensitivity analyses are performed. Finally, GO enrichment analyses are used to investigate the bio-function. Results Several bi-directional causal relationships among gut microbiota, FIs and TL are obtained by two-sample MR. Overall, we find suggestive evidence of three main causal pathways among them. Drinking more glasses of water per day is able to affect the habit of eating dried fruit through the host gut microbiota (Barnesiella). The change of one gut microbiota taxon (Collinsella) in the host causally influences another gut microbiota taxon (Lactonccus) through the diet habits (intake of oil-based spread). Additionally, the TL alters the habits of drinking ground coffee and further affects the gut microbiota (Acidaminococcaceae). GO enrichment analysis further confirmed the MR results. Conclusion TL has an impact on diet habits and gut microbiota and there are bi-directional relationships between diet habits and gut microbiota. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement HL was supported by the National Natural Science Foundation of China (Grant 82003557). FX was supported by the National Natural Science Foundation of China (Grant 82173625) and the Shandong Provincial Key Research and Development project (2018CXGC1210). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data. GWAS summary data for gut microbiota in FGFP can be download at . GWAS summary data for Food intake in UK biobank can be download at . GWAS summary data for telomere length can be download at . I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All the GWAS summary data are publically available. GWAS summary data for gut microbiota in FGFP can be download at . GWAS summary data for Food intake in UK biobank can be download at . GWAS summary data for telomere length can be download at .