Ozcan, E. | Search bioRxiv

bioRxiv2024

The maternal microbiome modifies adverse effects of protein undernutrition on offspring neurobehavioral impairment in mice

Protein undernutrition is a global risk factor for impaired growth and neurobehavioral development in children. However, the critical periods, environmental interactions, and maternal versus neonatal influences on programming lasting behavioral abnormalities are poorly understood. In a mouse model of fetal growth restriction, limiting maternal protein intake particularly during pregnancy leads to cognitive and anxiety-like behavioral abnormalities in adult offspring, indicating a critical role for the gestational period. By cross-fostering newborn mice to dams previously exposed to either low protein or standard diet, we find that the adult behavioral impairments require diet-induced conditioning of both fetal development and maternal peripartum physiology, rather than either alone. This suggests that protein undernutrition during pregnancy directly disrupts fetal neurodevelopment and indirectly alters maternal state in ways that interact postnatally to precipitate behavioral deficits. Consistent with this, maternal protein restriction during pregnancy reduces the diversity of the maternal gut microbiome, modulates maternal serum metabolomic profiles, and yields widespread alterations in fetal brain transcriptomic and metabolomic profiles, including subsets of microbiome-dependent metabolites. Depletion of the maternal microbiome in protein-restricted dams further alters fetal brain gene expression and exacerbates neurocognitive behavior in adult offspring, suggesting that the maternal microbiome modifies the impact of gestational protein undernutrition on risk for neurobehavioral impairment in the offspring. To explore the potential for microbiome-targeted interventions, we find that maternal treatment with short chain fatty acids or a cocktail of 10 diet- and microbiome-dependent metabolites each yield differential effects on fetal development and/or postnatal behavior. Results from this study highlight impactful prenatal influences of maternal protein undernutrition on fetal neurodevelopment and adverse neurobehavioral trajectories in offspring, which are mitigated by microbiome-targeted interventions during pregnancy.

animal behavior and cognition↗

bioRxiv2024

Complex carbohydrate utilization by gut bacteria modulates host food preference

The gut microbiota interacts directly with dietary nutrients and has the ability to modify host feeding behavior, but the underlying mechanisms remain poorly understood. Select gut bacteria digest complex carbohydrates that are non-digestible by the host and liberate metabolites that serve as additional energy sources and pleiotropic signaling molecules. Here we use a gnotobiotic mouse model to examine how differential fructose polysaccharide metabolism by commensal gut bacteria influences host preference for diets containing these carbohydrates. Bacteroides thetaiotaomicron and Bacteroides ovatus selectively ferment fructans with different glycosidic linkages: B. thetaiotaomicron ferments levan with {beta}2-6 linkages, whereas B. ovatus ferments inulin with {beta}2-1 linkages. Since inulin and levan are both fructose polymers, inulin and levan diet have similar perceptual salience to mice. We find that mice colonized with B. thetaiotaomicron prefer the non-fermentable inulin diet, while mice colonized with B. ovatus prefer the non-fermentable levan diet. Knockout of bacterial fructan utilization genes abrogates this preference, whereas swapping the fermentation ability of B. thetaiotaomicron to inulin confers host preference for the levan diet. Bacterial fructan fermentation and host behavioral preference for the non-fermentable fructan are associated with increased neuronal activation in the arcuate nucleus of the hypothalamus, a key brain region for appetite regulation. These results reveal that selective nutrient metabolism by gut bacteria contributes to host associative learning of dietary preference, and further informs fundamental understanding of the biological determinants of food choice.

microbiology↗