Age-specific Effects Of Maternal Gut Biome Influence Sex Dependent Changes In Offspring Weight, Behavior, And Depression

Background: The gut-brain axis has recently become key in understanding stroke pathogenesis. The bidirectional communication between the gut and the brain are highly involved in the immune response to stroke. The effect of the aged biome, naturally occurring dysbiosis through the process of inflammaging, may have significant impact on offspring in terms of stroke risk factors. Method: Young (3-month) female wildtype C57B/6 mice were subjected to antibiotic treatment to clear their native gut biome and were then treated with fecal microbiome transplants from 3-month (M) control, 14M menopausal, and 18M reproductively senescent female mice, and were bred in our facility. Subsequent pups obtained were aged to 9 months followed by a battery of behavioral tests (novel object recognition (NORT), Y-maze, tail suspension, and open field test) and body weight measurements. Feces was collected periodically for 16s rRNA sequencing analysis. Results: Aged biome affected the female fecundity significantly (p=0.028, n=7/12) and the pup biome showed a significant sex specific difference in composition through 16s sequencing (p=0.009, n=7). Female pup from 14- or 18M biome mothers had consistently higher body weight from 21 days to 9 months of age compared to controls (p=0.183, n=6/9/13). Male pups from 18M biome dams showed significantly low body weight 2 months post birth (p=0.048, n= 7/10). Mothers that received 14M biome had overweight male offspring at 9 months of age (p=0.017. Cognitive assessment through NORT showed that female pups from mothers colonized with 14M biome had a significantly lower discrimination index compared to controls (p=0.045, n=6/9). Only male pups from 14M biome mothers showed a deficit in spatial cognition (p=0.018). Both males and females exhibited an early depressive phenotype compared to controls at 2 months of age (p=0.028), with female pups also exhibiting this phenotype at 9 months (p=0.018). Conclusion: Age of the maternal biome has a significant effect on its offspring’s health, specifically body weight, cognition, and depressive phenotype in a sex and time dependent manner. These effects correlate positively with stroke risk factors highlighting the importance of the microbiome as an epigenetic regulator of offspring health.