Biology subjects

Hsiao, E. Y.

Publications and source records attributed to Hsiao, E. Y..

10 recordsLinked to original sources

bioRxiv2026

Consumption of processed foods impairs memory function through dietary advanced glycation end-products

Consumption of processed foods is associated with dementia, obesity, and other negative health outcomes. Sustained heat treatment, a common food processing approach to enhance flavor, induces the chemical Maillard reaction that promotes the formation of dietary advanced glycation end-products (AGEs). The neurocognitive impacts of consuming dietary AGEs are poorly understood. Here we modeled an AGE-rich diet through heat treatment fed to rats during adolescence, a critical period of neural development, to mechanistically evaluate the long-term impact of early life dietary AGEs on behavioral and neural processes. Consuming the AGE-rich diet impaired hippocampal-dependent memory function and altered the gut microbiome without inducing obesity or nonspecific behavioral deficits. AGE-induced memory deficits were coupled with impaired hippocampal glutamatergic synaptic neurotransmission and altered expression in the synapse-pruning complement system. Hippocampal synaptic deficits likely result from direct AGE-complement interactions, as our extended studies reveal competitive antagonist action of AGEs on complement receptors. Memory impairments were prevented by administration of the AGE-inhibitor, alagebrium, and by supplementation with an AGE-inhibiting bacterial taxon, Lactococcus lactis, which was depleted in the heat-treated diet. These findings reveal a functional connection between early life dietary AGEs, the microbiome, and memory impairments, thus illuminating mechanisms through which food processing negatively impacts neurocognition.

neuroscience↗

bioRxiv2024

Dietary fiber content in clinical ketogenic diets modifies the gut microbiome and seizure resistance in mice

The gut microbiome is emerging as an important modulator of the anti-seizure effects of the classic ketogenic diet. However, many variations of the ketogenic diet are used clinically to treat refractory epilepsy, and how different dietary formulations differentially modify the gut microbiome in ways that impact seizure outcome is poorly understood. We find that clinically prescribed ketogenic infant formulas vary in macronutrient ratio, fat source, and fiber content and also in their ability to promote resistance to 6-Hz psychomotor seizures in mice. By screening specific dietary variables for their effects on a model human infant microbial community, we observe that dietary fiber, rather than fat ratio or source, drives substantial metagenomic shifts. Addition of dietary fiber to a fiber-deficient ketogenic formula restores seizure resistance, and supplementing protective ketogenic formulas with excess dietary fiber further potentiates seizure resistance. By screening 13 fiber sources and types, we identify distinct subsets of metagenomic responses in the model human infant microbial community that correspond with increased seizure resistance in mice. In particular, supplementation with seizure-protective fibers enriches microbial representation of genes related to queuosine biosynthesis and preQ0 biosynthesis and decreases representation of microbial genes related to sucrose degradation, which is also seen in seizure-protected mice that are fed fiber-containing ketogenic infant formulas. Overall, this study reveals that different formulations of clinical ketogenic diets, and dietary fiber content in particular, differentially impact seizure outcome in mice, likely through modification of the gut microbiome. Understanding interactions between dietary components of the ketogenic diet, the gut microbiome, and host susceptibility to seizures could inform novel microbiome-guided approaches to treat refractory epilepsy.

microbiology↗

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↗

bioRxiv2023

The maternal microbiome promotes placental development in mice

The maternal microbiome is an important regulator of gestational health, but how it impacts the placenta as the interface between mother and fetus remains unexplored. Here we show that the maternal gut microbiota supports placental development in mice. Depletion of the maternal gut microbiota restricts placental growth and impairs feto-placental vascularization. The maternal gut microbiota modulates metabolites in the maternal and fetal circulation. Short-chain fatty acids (SCFAs) stimulate angiogenesis-related tube formation by endothelial cells and prevent abnormalities in placental vascularization in microbiota-deficient mice. Furthermore, in a model of maternal malnutrition, gestational supplementation with SCFAs prevents placental growth restriction and vascular insufficiency. These findings highlight the importance of host-microbial symbioses during pregnancy and reveal that the maternal gut microbiome promotes placental growth and vascularization in mice.

microbiology↗

bioRxiv2022

Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote symptoms of Parkinson's disease

Gastrointestinal (GI) disruptions, such as inflammatory bowel disease (IBD), are common prodromal symptoms of Parkinsons disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD symptoms in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male, but not female, mice promotes -synuclein aggregation in the substantia nigra, elevated -synuclein loads in microglia, loss of dopaminergic neurons, and motor impairment. This male bias in gene-environment interaction is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S, revealing that XY chromosomes, not testicular hormones, mediate the male bias in the gut-brain-driven risk for endophenotypes of PD. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by the accumulation of -synuclein in the colon, increases in -synuclein-positive macrophages in the colonic lamina propria, and elevations in -synuclein loads within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD symptoms in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of -synuclein in myeloid cells within the gut and brain.

physiology↗

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↗

bioRxiv2020

The gut microbiome regulates memory function

Emerging evidence highlights a critical relationship between gut microbiota and neurocognitive development. Excessive consumption of sugar and other unhealthy dietary factors during early life developmental periods yields changes in the gut microbiome as well as neurocognitive impairments. However, it is unclear whether these two outcomes are functionally connected. Here we explore whether excessive early life consumption of added sugars negatively impacts memory function via the gut microbiome. Rats were given free access to a sugar-sweetened beverage (SSB) during the adolescent stage of development. Memory function and anxiety-like behavior were assessed during adulthood and gut bacterial and brain transcriptome analyses were conducted. Taxa-specific microbial enrichment experiments examined the functional relationship between sugar-induced microbiome changes and neurocognitive and brain transcriptome outcomes. Chronic early life sugar consumption impaired adult hippocampal-dependent memory function without affecting body weight or anxiety-like behavior. Adolescent SSB consumption during adolescence also altered the gut microbiome, including elevated abundance of two species in the genus Parabacteroides (P. distasonis and P. johnsonii) that were negatively correlated with hippocampal function. Transferred enrichment of these specific bacterial taxa in adolescent rats impaired hippocampal-dependent memory during adulthood. Hippocampus transcriptome analyses revealed that early life sugar consumption altered gene expression in intracellular kinase and synaptic neurotransmitter signaling pathways, whereas Parabacteroides microbial enrichment altered gene expression in pathways associated with metabolic function, neurodegenerative disease, and dopaminergic signaling. Collectively these results identify a role for microbiota "dysbiosis" in mediating the detrimental effects of early life unhealthy dietary factors on hippocampal-dependent memory function.

neuroscience↗