Mitochondrial Influence on the Microbiome: A Role for Reactive Oxygen Species (ROS)
Tal Yardeni1, Ceylan Tanes2, Kyle Bittinger2, Lisa M. Mattei2, Deborah G. Murdock1, Douglas C. Wallace1,3
1Center for Mitochondrial and Epigenomic Medicine, 2Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia; 3Department of Pathology and Laboratory Medicine, University of Pennsylvania
Changes in the gut microbiome and the mitochondrial genotype have both been correlated with a variety of clinical phenotypes including diabetes mellitus, autism, and Parkinson disease. What then causes these diseases, the microbiome or the mitochondrial genotype? We hypothesized that the mitochondrial genotype controls both the phenotype and the microbiome.
To address this hypothesis, we analyzed the gut microbiota in mouse models harboring mtDNA and/or nDNA variants in mitochondrial genes. Our data showed that mice with different mitochondrial genotypes developed characteristic microbiota. For example, a pathogenic mutation in the mtDNA (ND6 P25L) is associated with significantly different microbiota. Additionally, we found that mismatch in nuclear and mitochondrial background resulted in altered microbiome diversity. Specifically, in C57BL/6J mice homoplasmic for 129 or NZB mtDNAs, the microbiome diversity was lower in NZB mice. Also, the Bacteroidetes/Firmicutes ratio directly correlated with the percentage of NZB mtDNAs.
Mitochondrial physiology was linked to microbiota composition by studying mice that differed in the expression of the mitochondrial antioxidant gene for the nicotinamide nucleotide transhydrogenase (NNT). The Nnt+/+ and Nnt-/- mice had markedly different gut microbiomes. To confirm that the Nnt genotype causes these differences, we fostered newborn pups with the Nnt+/+ and Nnt-/- genotypes on mothers with the reciprocal Nnt genotype. Within 2 months, the Nnt genotype of the pups restructured the microbiota from that of the nursing mother back toward the characteristics of the pup's Nnt genotype. When the Nnt-/- mutation was combined with the mitochondrially-targeted human catalase (mCAT), the microbiome of the Nnt-/- mice with the mCAT was markedly different from cohoused Nnt-/- littermates without mCAT.
These data indicate that the mitochondrial genotype can control both the mammalian clinical phenotype and the gut microbiome. Moreover, mitochondrially-generated ROS may be one of the factors that modulates the gut microbiome.