The host immune system and the gut microbiota are regulated by the mitochondrial genetics
Increasing evidence suggests that alterations in the gut microbiota are associated with a variety of human diseases. Yet, the mechanisms by which the gut microbiota modulate disease risk remain unknown. Based on our results, our hypothesis is that both the gut microbiota and the immune system are modulated by the mitochondrial genome, in part through mitochondrial reactive oxygen species (mROS) production, forming a critical link between the gut microbiota and disease initiation and progression.
Our studies showed significant differences in gut microbiota in our conplastic mice which differ in their mtDNA lineages. Further, the transfer of the gut microbiota from a host of one mitochondrial genotype to a host of different mitochondrial genotypes shifted the gut microbiota composition toward that of the recipient animal. Moreover, we showed that host mROS levels modulated the composition of the gut microbiota.
Those conplastic mice also exhibit markedly different capacities to sustain melanoma tumor growth. Relative to control mtDNA (mtDNAB6) mice, the mice harboring NZB mtDNAs (mtDNANZB) have strong anti-tumor immune response while those with129 mtDNA (mtDNA129) are the opposite. We reduced mROS by expression of mitochondrial catalase (mCAT)Tg in eight tissue-specific experiments. Only in the hematopoietic cells the reduction of mROS changed the gut microbiota and obviated the anti-tumor effects on the mtDNANZB and mtDNAB6 mice. These observations suggest that melanoma severity, and gut microbiota are modulated by the mtDNA’s regulation of mROS production in host immune cells, pointing to new potential pathways for melanoma therapeutic development.