The interplay between genetic factors, mitochondrial function, adiposity, and the gut microbiota has garnered significant attention in recent years due to its implications for metabolic health and disease risk. One such genetic factor of interest is the apolipoprotein E (APOE) gene, with the APOE4 allele being associated with a higher risk of neurodegenerative diseases and altered metabolic profiles. Additionally, mitochondrial transcription factor A (TFAM) plays a crucial role in maintaining mitochondrial DNA integrity and function, which are essential for cellular energy metabolism.

Our results reveal that individuals carrying the APOE4 allele exhibited a distinct microbial profile characterized by an enrichment of Barnesiella spp., Ruminococcus, and Verrucomicrobia taxa. The enrichment of these taxa in individuals with the APOE4 allele may reflect alterations in carbohydrate metabolism, SCFA production, or mucin turnover within the gut ecosystem. TFAM rs1937 was found to correlate with adiposity, suggesting a potential link between mitochondrial function and adipose tissue metabolism. Ruminococcaceae UCG-014, likely associated with fiber fermentation and short-chain fatty acid production, exhibited varying abundances across different TFAM genotypes. We also found differences in Sutterella, a member of the Alcaligenaceae family, indicating its potential involvement in gastrointestinal disorders and inflammatory bowel diseases. Additionally, the presence of the Eubacterium coprostanoligenes group, implicated in esterols metabolism, was also detected.

By addressing adiposity and microbiota composition in conjunction with genetic factors like APOE4 and TFAM , novel mechanisms can be elucidated in order to optimize metabolic health, enhance longevity, and reduce the burden of age-related diseases. These approaches represent a promising frontier in precision medicine and personalized healthcare.