Biology subjects

Pugin, B.

Publications and source records attributed to Pugin, B..

3 recordsLinked to original sources

bioRxiv2023

Transgenerational effects of early life stress on the fecal microbiota in mice

Stress in early life can affect the progeny and increase the risk to develop psychiatric and cardiometabolic diseases across generations. The cross-generational effects of early life stress have been modeled in mice and demonstrated to be associated with epigenetic factors in the germline. While stress is known to affect gut microbial features, whether its effects can persist across life and be passed to the progeny is not well defined. Here we show that early postnatal stress in mice shifts the fecal microbial composition (binary Jaccard index) throughout life. Further effects on fecal microbial composition and structure (weighted Jaccard index) are detected in the progeny across two generations. These effects are not accompanied by changes in bacterial metabolites and related predicted metabolic pathways in any generation. These results suggest that changes in the fecal microbial community induced by early life traumatic stress can be perpetuated from exposed parent to the offspring.

microbiology↗

bioRxiv2023

Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging

Endothelial cell (EC) senescence plays a crucial role in the development of cardiovascular diseases in aging population. Gut microbiota alterations are emerging as significant factors present in cellular senescence associated with aging. However, little is known about how aging-related changes in gut microbiota are causally implicated in EC senescence. Here we show that gut microbiota-dependent phenylacetic acid (PAA) and its derivative, phenylacetylglutamine (PAGln), are elevated in a human aging cohort (TwinsUK, n=7,303) and in aged mice. Metagenomic analyses revealed a marked increase in the abundance of PAA-producing microbial pathways (PPFOR and VOR), which were positively associated with the abundance of Clostridium sp. ASF356, higher circulating PAA concentrations, and endothelial dysfunction in old mice. We found that PAA potently induces EC senescence and attenuates angiogenesis. Mechanistically, PAA increases mitochondrial H2O2 generation, which aggravates IL6-mediated HDAC4 translocation and thereby upregulates VCAM1. In contrast, exogenous acetate, which was reduced in old mice, rescues the PAA-induced EC senescence and restores angiogenic capacity through markedly alleviating the SASP and epigenetic alteration. Our studies provide direct evidence of PAA-mediated crosstalk between aging gut microbiota and EC senescence and suggest a microbiota-based therapy for promoting healthy aging. HighlightsO_LIAging-related gut microbiota alterations contribute to a marked elevation of plasma PAA and PAGln in humans and mice C_LIO_LIClostridium sp. ASF356 contributes to PPFOR-mediated PAA formation in aged mice C_LIO_LIGut-derived PAA promotes endothelial senescence and impairs angiogenesis C_LIO_LIPAA induces mitochondrial H2O2 generation, by which drives epigenetic alterations and SASP in ECs C_LIO_LIAcetate rescues PAA-induced EC senescence and mitochondrial dysfunction C_LIO_LIAcetate improves angiogenesis by reducing HDAC4 phosphorylation and SASP C_LI

cell biology↗

bioRxiv2023

A flexible high-throughput cultivation protocol to assess the response of individuals' gut microbiota to diet-, drug-, and host-related factors

Anaerobic cultivation of fecal microbiota is a promising approach to investigate how gut microbial communities respond to specific intestinal conditions and perturbations. Here, we describe a practical protocol using 96-deepwell plates to cultivate stool-derived gut microbiota. Our protocol addresses key challenges in high-throughput culturing, including a thorough assessment of the impact of gas phase on medium chemistry, a modular medium preparation process to enable testing of several conditions in parallel, a medium formulation designed to maximize the compositional similarity of fecal cultures with the donor microbiota, and the creation of a step-by-step protocol detailing all practical procedures from material preparation to sample handling for analyses. Finally, we validated the protocol by demonstrating that cultivated fecal microbiota responded similarly to dietary fibers (resistant dextrin, soluble starch) and drugs (ciprofloxacin, 5-fluorouracil) as reported in vivo. This high-throughput cultivation protocol can facilitate culture-dependent studies, accelerate the discovery of gut microbiota-diet-drug-host interactions, and pave the way to personalized and microbiota-centered interventions. MOTIVATIONThe human gut microbiota is a complex ecosystem unique to each individual. The extent of this diversity has limited our capacity to fully comprehend microbial dynamics that apply to the entire human population. To probe the response of donor-specific microbial communities to intestinal conditions or perturbations, in vitro cultivation of stool-derived gut microbiota can be employed. However, cultivating gut microbiota under strictly anaerobic conditions is commonly performed using individual gas-tight tubes, which is a highly time-consuming strategy that limits the number of conditions and donor microbiota that can be tested in parallel. A flexible high-throughput protocol to cultivate and test donor-specific gut microbiota is therefore required. Hence, we developed a robust procedure for cultivating stool-derived microbiota (and pure gut microbial cultures) in 96-deepwell plates within an anaerobic chamber.

microbiology↗