Biology subjects

Hamaker, B. R.

Publications and source records attributed to Hamaker, B. R..

3 recordsLinked to original sources

bioRxiv2023

Moderating carbohydrate digestion rate promotes metabolic flexibility in mice

Superior metabolic flexibility, or the ability to efficiently switch between oxidation of carbohydrate and fat, is inversely associated with obesity and type 2 diabetes. This study examined the impact of dietary carbohydrate digestion rate on metabolic substrate utilization and metabolic flexibility. We employed percent relative cumulative frequency (PRCF) analyses coupled with a new application of modeling using the Mixed Weibull Cumulative Distribution function to examine respiratory exchange ratio (RER) data from wild-type mice and mice lacking the mucosal maltase-glucoamylase enzyme (Mgam, null) under different dietary carbohydrate conditions. We further devised a Metabolic Flexibility Factor (MFF) to quantitate metabolic flexibility, with higher MFF indicating higher metabolic flexibility. The collective results indicated that a diet high in slowly digestible starch exhibited higher metabolic flexibility (MFF) than diets high in resistant starch, sucrose, or fat. These findings show a new-found benefit of consuming slowly digestible carbohydrates for improved metabolic health.

physiology↗

bioRxiv2022

SUBTLE DIFFERENCES IN FINE POLYSACCHARIDE STRUCTURES GOVERN SELECTION AND SUCCESSION OF HUMAN GUT MICROBIOTA

Dietary fibers are fermented in the human gut and are known to modulate microbiome composition and metabolic function, but few studies have explored to what extent the small variations in complex fiber structures impact community assembly, microbial division of labor, and organismal metabolic responses across individuals microbiome structures. To test the hypothesis that subtle linkage variations in chemical structures of polysaccharides afford different ecological niches for distinct communities and metabolism, we employed a 7-day in vitro sequential batch fermentation with fecal inocula from individual donors and measured microbial responses using an integrated multi-omics approach. We fermented two sorghum arabinoxylans (SAXs) as model complex polysaccharides, with fecal microbiota from three donors and an artificially high diversity mix of all three. Although differences in sugar linkage profiles across SAXs were subtle, surprisingly, consortia fermenting different AXs revealed distinct species-level genomic diversity and metabolic outcomes with nearly-identical strains on each polysaccharide across inocula. Carbohydrate active enzyme (CAZyme) genes in metagenomes revealed broad AX-related hydrolytic potentials; however, CAZyme genes enriched in different AX-fermenting consortia were specific to SAX type and displayed various catabolic domain fusions with diverse accessory motifs, suggesting they may be functionally degenerate and this degeneracy may relate to fine substrate structure. These results suggest that fine polysaccharide structure exerts deterministic selection effect for distinct fermenting consortia, which are present amongst unrelated individuals.

microbiology↗

bioRxiv2022

A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice

Parkinsons disease (PD) is a movement disorder characterized by neuroinflammation, -synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, though mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in -synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces -synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.

physiology↗