Nguyen, H. V. M. | bioRxiv Science

bioRxiv2024

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

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-HETB/W rat. Alpha-diversity, measuring richness and evenness of gut microbiome composition, did not change with age or mitochondrial-haplotype. However, beta-diversity, a measure of microbial differences among samples, was significantly modulated by age in male and female rats in both mitochondrial-haplotypes. 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 hosts 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 and supports previous studies suggesting a bidirectional interaction between the gut microbiome and host mitochondria. HighlightsMost age-related changes in microbial species occurred in one sex but not the other Mitochondrial-haplotype altered the microbiome and was generally sex dependent Microbiome associated metabolites differed by age, sex, and mitochondria-haplotype

microbiology↗

bioRxiv2024

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High Fat, High Fructose, High Cholesterol Diet Mouse Model

Chronic inflammation is a key player in metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Necroptosis, an inflammatory cell death pathway, is elevated in MAFLD patients and mouse models, yet its role is unclear due to diverse mouse models and inhibition strategies. In our study, we inhibited necroptosis by targeting mixed lineage kinase domain like pseudokinase (MLKL), the terminal effector of necroptosis, in a high-fat, high-fructose, high-cholesterol (HFHFrHC) mouse model of diet-induced MAFLD mouse model. Despite HFHFrHC diet upregulating MLKL (2.5-fold), WT mice livers showed no increase in necroptosis markers or associated proinflammatory cytokines. Surprisingly, Mlkl-/-mice experienced exacerbated liver inflammation without protection from diet-induced liver damage, steatosis, or fibrosis. In contrast, Mlkl+/- mice showed significant reduction in these parameters that was associated with elevated Ppar and Ppar{gamma} levels. Both Mlkl-/-and Mlkl+/- mice on HFHFrHC diet resisted diet-induced obesity, attributed to increased beiging, enhanced oxygen consumption and energy expenditure due to adipose tissue, and exhibited improved insulin sensitivity. These findings highlight the tissue specific effects of MLKL on the liver and adipose tissue, and suggest a dose-dependent effect of MLKL on liver pathology.

biochemistry↗