Biology subjects

Paramo, J.

Publications and source records attributed to Paramo, J..

5 recordsLinked to original sources

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↗

bioRxiv2023

Vagal interoception of microbial metabolites from the small intestinal lumen

The vagus nerve is proposed to enable communication between the gut microbiome and brain, but activity-based evidence is lacking. Herein, we assess the extent of gut microbial influences on afferent vagal activity and metabolite signaling mechanisms involved. We find that mice reared without microbiota (germ-free, GF) exhibit decreased vagal afferent tone relative to conventionally colonized mice (specific pathogen-free, SPF), which is reversed by colonization with SPF microbiota. Perfusing non-absorbable antibiotics (ABX) into the small intestine of SPF mice, but not GF mice, acutely decreases vagal activity, which is restored upon re-perfusion with bulk lumenal contents or sterile filtrates from the small intestine and cecum of SPF, but not GF, mice. Of several candidates identified by metabolomic profiling, microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate stimulate vagal activity with varied response kinetics, which is blocked by co-perfusion of pharmacological antagonists of FFAR2, TGR5, and TRPA1, respectively, into the small intestine. At the single-unit level, serial perfusion of each metabolite class elicits more singly responsive neurons than dually responsive neurons, suggesting distinct neuronal detection of different microbiome- and macronutrient-dependent metabolites. Finally, microbial metabolite-induced increases in vagal activity correspond with activation of neurons in the nucleus of the solitary tract, which is also blocked by co-administration of their respective receptor antagonists. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate chemosensory vagal afferent neurons, thereby enabling microbial modulation of interoceptive signals for gut-brain communication. HIGHLIGHTSO_LIMicrobiota colonization status modulates afferent vagal nerve activity C_LIO_LIGut microbes differentially regulate metabolites in the small intestine and cecum C_LIO_LISelect microbial metabolites stimulate vagal afferents with varied response kinetics C_LIO_LISelect microbial metabolites activate vagal afferent neurons and brainstem neurons via receptor-dependent signaling C_LI

neuroscience↗

bioRxiv2023

Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice

The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human drug-resistant epilepsy is unclear. Herein, we find that the clinical KD shifts the function of the gut microbiome in children with refractory epilepsy. Colonizing mice with KD-associated human gut microbes confers increased resistance to 6-Hz psychomotor seizures, as compared to colonization with gut microbes from matched pre-treatment controls. Parallel analysis of human donor and mouse recipient metagenomic and metabolomic profiles identifies subsets of shared functional features that are seen in response to KD treatment in humans and preserved upon transfer to mice fed a standard diet. These include enriched representation of microbial genes and metabolites related to anaplerosis, fatty acid beta-oxidation, and amino acid metabolism. Mice colonized with KD-associated human gut microbes further exhibit altered hippocampal and frontal cortical transcriptomic profiles relative to colonized pre-treatment controls, including differential expression of genes related to ATP synthesis, glutathione metabolism, oxidative phosphorylation, and translation. Integrative co-occurrence network analysis of the metagenomic, metabolomic, and brain transcriptomic datasets identifies features that are shared between human and mouse networks, and select microbial functional pathways and metabolites that are candidate primary drivers of hippocampal expression signatures related to epilepsy. Together, these findings reveal key microbial functions and biological pathways that are altered by clinical KD therapies for pediatric refractory epilepsy and further linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.

microbiology↗

bioRxiv2022

Turicibacter modifies host bile acids and lipids in a strain-specific manner

Bacteria from the Turicibacter genus are prominent members of the mammalian gut microbiota and are associated with alterations in dietary fat and body weight, but the specific connections between these symbionts and host physiology are poorly understood. We genomically and phenotypically characterized a diverse set of mouse-and human-derived Turicibacter strains, and found they group into three clades that differ in their transformations of bile acids. We identified Turicibacter bile salt hydrolases that confer strain-specific differences in bile deconjugation. Colonization with individual Turicibacter strains led to changes in host bile acid profiles, generally aligning with those produced in vitro. Further, colonizing mice with another bacterium expressing bile-modifying genes from these strains decreased serum cholesterol and triglycerides, as well as adipose tissue mass. This work identifies genes that enable diverse Turicibacter strains to differentially modify host bile acids and lipid metabolism, and positions multiple Turicibacter strains as candidates for altering host fat biology. MAIN TEXT

microbiology↗