Analysis of strain, sex, and diet-dependent modulation of gut microbiota reveals candidate keystone organisms driving microbial diversity in response to American and ketogenic diets

Authors: SALVADOR, ANNA - Texas A&M University; HUDA, NAZMUL - University Of California, Davis; ARENDS, DANNY - Texas A&M University; ELSADDI, AHMED - Texas A&M University; GACASAN, ANTHONY - Texas A&M University; BROCKMANN, GUDRUN - University Of Humbolt; VALDAR, WILLIAM - University Of North Carolina; Bennett, Brian; THREADGILL, DAVID - Texas A&M University

Submitted to: Microbiome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/1/2023
Publication Date: 10/3/2023
Citation: Salvador, A.C., Huda, N.M., Arends, D., Elsaddi, A.M., Gacasan, A.C., Brockmann, G.A., Valdar, W., Bennett, B.J., Threadgill, D.W. 2023. Analysis of strain, sex, and diet-dependent modulation of gut microbiota reveals candidate keystone organisms driving microbial diversity in response to American and ketogenic diets. Microbiome. 11(220). https://doi.org/10.1186/s40168-023-01588-w.
DOI: https://doi.org/10.1186/s40168-023-01588-w

Interpretive Summary: Host genetics, diet, and sex modulate gut microbiota composition. The magnitude of these effects and interactions among them is important to understanding inter-individual variability in gut microbiota. Here, we searched for genetic variants underlying differences in the gut microbiome in response to American and ketogenic diets between two mouse strains, C57BL/6J (B6) and FVB/NJ (FVB). We identified 14 genotype-specific loci, 6 genotype and diet-specific loci, and 3 genotype and sex-specific loci that modulate microbial composition. We also identified a bidirectional relationship between microbial diversity and abundances of Bilophila and Lachnospiraceae. Irrespective of genetic background, diet has a profound ability to modulate gut microbiota. Sex, while important to the analyses, was not as strong of a predictor for microbial abundances. These results demonstrate that precision nutrition will be advanced through the integration of genetic variation, microbiota variation, and sex.

Technical Abstract: The microbiome is modulated by a combination of host genetics, diet, and sex effects. The magnitude of these effects and interactions among them is important to understanding inter-individual variability in gut microbiota. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed along with several QTL for metabolic traits. In the current study, we searched for genetic variants underlying differences in the gut microbiome in response to American and ketogenic diets between C57BL/6J (B6) and FVB/NJ (FVB) mouse strains. Genetic mapping of microbial traits revealed 14 loci that were genotype specific, 6 loci that were genotype and diet specific, and 3 loci that were genotype and sex specific. For many microbial traits, irrespective to which quantitative trait loci model was used, diet or the interaction between diet and a genotype were the strongest predictors of the abundance of each microbial trait. Conditioned linkage analysis suggests that there is a bidirectional relationship between microbial diversity and abundances of Bilophila and Lachnospiraceae. Irrespective to genetic background, diet has a profound ability to modulate gut microbiota. Sex, while important to the analyses, was not as strong of a predictor for microbial abundances. These results demonstrate the importance of characterizing the magnitude of the effects that sex, diet, and genetic background have on inter-individual differences in gut microbiota. Precision nutrition will be advanced through integration of genetic variation, microbiota variation, and sex in response to diets varied in carbohydrate composition.