Research Paper|Volume 17, Issue 2|pp 524—549

Age, sex, and mitochondrial-haplotype influence gut microbiome composition and metabolites in a genetically diverse rat model

Hoang Van M. Nguyen¹, Eleana Cabello², David Dyer², Chloe Fender³, Manuel Garcia-Jaramillo³, Norman G. Hord⁴, Steven Austad⁵, Arlan Richardson^6,^7,⁸, Archana Unnikrishnan^7,⁹

¹Department of Nutritional Sciences, College of Allied Health, University of Oklahoma Health Sciences, Oklahoma City, OK 73117, USA
²Department of Microbiology and Immunology, College of Medicine, University of Oklahoma Health Sciences, Oklahoma City, OK 73117, USA
³Environmental and Molecular Toxicology, College of Agricultural Sciences, Oregon State University, Corvallis, OR 97331, USA
⁴Department of Nutritional Sciences, College of Education and Human Sciences, Oklahoma State University, Stillwater, OK 74075, USA
⁵Department of Biology, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, AL 35205, USA
⁶Department of Biochemistry and Physiology, College of Medicine, University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
⁷Oklahoma Center for GeroScience and Healthy Brain Aging, University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
⁸Oklahoma Veteran Affairs Medical Center, Oklahoma City, OK 73104, USA
⁹Harold Hamm Diabetes Center, OU Health, Oklahoma City, OK 73104, USA

Received: October 28, 2024Accepted: February 3, 2025Published: February 27, 2025

https://doi.org/10.18632/aging.206211

Copyright: © 2025 Nguyen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

We evaluated the impact of sex and mitochondrial-haplotype on the age-related changes in the fecal gut microbiome of the genetically heterogeneous rodent model, the OKC-HET^B/W rat. The age-related changes in the microbiome differed markedly between male and female rats. Five microbial species changed significantly with age in male rats compared to nine microbial species in female rats. Only three of these microbes changed with age in both male and female rats. The mitochondrial-haplotype of the rats also affected how aging altered the microbiome. Interestingly, most of the microbial species that changed significantly with age were mitochondrial-haplotype and sex specific, i.e., changing in one sex and not the other. We also discovered that sex and mitochondrial-haplotype significantly affected the age-related variations in content of fecal short-chain fatty acids and plasma metabolites that influence or are regulated by the microbiome, e.g., tryptophan derived metabolites and bile acids. This study demonstrates that the host’s sex plays a significant role in how the gut microbiome evolves with age, even within a genetically diverse background. Importantly, this is the first study to show that the mitochondrial-haplotype of a host impacts the age-related changes in the microbiome.