Biology subjects

Spencer, S. P.

Publications and source records attributed to Spencer, S. P..

6 recordsLinked to original sources

bioRxiv2026

Fermentation-Derived Metabolites Shape Host Biology to Attenuate Severity of Inflammatory and Metabolic Disease

Fermented foods are among the few dietary interventions shown to increase gut microbiome diversity and reduce systemic inflammation in healthy adults, yet the underlying mechanisms remain poorly defined. Metabolites produced during food fermentation, termed fermentation-derived metabolites (FDMs), represent a largely uncharacterized pool of bioactive compounds that may directly mediate the physiological effects of fermented food consumption. Here, we characterize the metabolite landscape of ten vegetable-based fermented foods using metabolomics, identifying conserved enrichment of aromatic and branched-chain amino acid derivatives across diverse substrates. Using sauerkraut as a chemically representative model system, we show that metabolite extracts from wild green sauerkraut (wGS-FDMs) remodel intestinal and systemic immune populations and shift gut microbiome composition in healthy mice. wGS-FDMs suppressed NF-{kappa}B activation and pro-inflammatory cytokine secretion in vitro and decreased colitis severity in vivo. In a chronic high-fat diet model, wGS-FDMs attenuated weight gain and improved glucose and insulin tolerance, consistent with stimulation of GLP-1 secretion in vitro. Collectively, these findings establish FDMs as biologically potent dietary components capable of simultaneously modulating immune, microbial, and metabolic homeostasis across multiple physiological systems, positioning metabolites from fermented foods as an important and underappreciated class of dietary effectors in the context of chronic disease.

microbiology↗

bioRxiv2024

Improved mouse models of the small intestine microbiota using region-specific sampling from humans

Our understanding of region-specific microbial function within the gut is limited due to reliance on stool. Using a recently developed capsule device, we exploit regional sampling from the human intestines to develop models for interrogating small intestine (SI) microbiota composition and function. In vitro culturing of human intestinal contents produced stable, representative communities that robustly colonize the SI of germ-free mice. During mouse colonization, the combination of SI and stool microbes altered gut microbiota composition, functional capacity, and response to diet, resulting in increased diversity and reproducibility of SI colonization relative to stool microbes alone. Using a diverse strain library representative of the human SI microbiota, we constructed defined communities with taxa that largely exhibited the expected regional preferences. Response to a fiber-deficient diet was region-specific and reflected strain-specific fiber-processing and host mucus-degrading capabilities, suggesting that dietary fiber is critical for maintaining SI microbiota homeostasis. These tools should advance mechanistic modeling of the human SI microbiota and its role in disease and dietary responses.

microbiology↗

bioRxiv2023

Metagenomic Immunoglobulin Sequencing (MIG-Seq) Exposes Patterns of IgA Antibody Binding in the Healthy Human Gut Microbiome

IgA, the most highly produced human antibody, is continually secreted into the gut to shape the intestinal microbiota. Methodological limitations have critically hindered defining which microbial strains are targeted by IgA and why. Here, we develop a new technique, Metagenomic Immunoglobulin Sequencing (MIG-Seq), and use it to determine IgA coating levels for thousands of gut microbiome strains in healthy humans. We find that microbes associated with both health and disease have higher levels of coating, and that microbial genes are highly predictive of IgA binding levels, with mucus degradation genes especially correlated with high binding. We find a significant reduction in replication rates among microbes bound by IgA, and demonstrate that IgA binding is more correlated with host immune status than traditional microbial abundance measures. This study introduces a powerful technique for assessing strain-level IgA binding in human stool, paving the way for deeper understanding of IgA-based host microbe interactions.

microbiology↗

bioRxiv2022

Fermented foods restructure gut microbiota and promote immune regulation via microbial metabolites

Fermented foods are ancient and ubiquitous, thought to be consumed in nearly every culture over the last 10,000 years and as part of the hominin diet for millions of years. A growing body of evidence supports their potential health benefits, but the mechanistic basis of their effects on the gut microbiome and host immunity remain to be elucidated. Fermented foods are diverse, each representing a complex mixture of food, microbes, and metabolites creating a significant challenge to disentangle the effects of individual components. Herein, we further define the chemical signature of individual fermented foods to categorize them based on the primary metabolic end-products of fermentation. Using mouse models, we find that fermented foods have both microbiome directed as well as differential host directed effects that correspond to their metabolite composition. Fermented food brine drink shows site-specific restructuring of the gut microbiome and promotion of tolerogenic barrier immunity; fractionation of the brine to examine the effects of the microbe-free, metabolite rich supernatant shows similar activity. Lactate, the main metabolite of lactic acid fermentation and the major metabolite within the brine drink, when administered in water, fuels a trans-kingdom metabolic network to selectively promote the growth of Akkermansia muciniphila. in the small intestine, while promoting immune tolerance via an increase in microbiota-dependent Regulatory T-cells. These findings suggest that the beneficial effects of fermented food consumption can be mediated by microbial metabolites within fermented foods, independent of microbial content, and highlight the importance of further defining the diverse chemical landscape of fermented foods to inform their potential health benefits and therapeutic use.

microbiology↗

bioRxiv2022

Ultra-deep Sequencing of Hadza Hunter-Gatherers Recovers Vanishing Microbes

The gut microbiome is a key modulator of immune and metabolic health. Human microbiome data is biased towards industrialized populations, providing limited understanding of the distinct and diverse non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing and strain cultivation on 351 fecal samples from the Hadza, hunter-gatherers in Tanzania, and comparative populations in Nepal and California. We recover 94,971 total genomes of bacteria, archaea, bacteriophages, and eukaryotes, 43% of which are absent from existing unified datasets. Analysis of in situ growth rates, genetic pN/pS signatures, high-resolution strain tracking, and 124 gut-resident species vanishing in industrialized populations reveals differentiating dynamics of the Hadza gut microbiome. Industrialized gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource that expands our understanding of microbes capable of colonizing the human gut and clarifies the extensive perturbation brought on by the industrialized lifestyle.

microbiology↗

bioRxiv2020

Enteropathy-induced regulatory T cells inhibit intestinal CD4+ T cell responses against oral vaccines

Environmental Enteric Dysfunction (EED) is an intestinal disease caused by malnutrition and infection that leads to malabsorption and stunting. EED is also associated with a reduced efficacy of oral vaccines. We show in a microbiota and diet-dependent model of EED that oral vaccine-specific CD4+ T cell responses fail in the small intestine but responses in the draining lymph node were unaffected. Accordingly, the number of immunosuppressive ROR{gamma}T+FOXP3+ Tregs in the small intestine inversely correlated with the response to oral vaccination. Depletion of ROR{gamma}T+FOXP3+ Tregs indicated that they were necessary for EED-associated inhibition of the vaccine response. Additionally, ROR{gamma}T+FOXP3+ Tregs are important to regulate EED-associated inflammation as their depletion significantly worsened stunting. We have shown that EED-associated intestinal inflammation leads to a localized intestinal blockade of CD4 T cell immunity. These results support a modular model for immunity where tissue responses can be regulated independently of systemic immunity to prevent autoinflammation.

immunology↗