Biology subjects

McParland, V.

Publications and source records attributed to McParland, V..

3 recordsLinked to original sources

bioRxiv2026

Kidney disease reprograms microbiome-host signaling to promote heart failure

BackgroundHeart failure is prevalent in chronic kidney disease (CKD) and linked to chronic inflammation. CKD-typical gut microbiome dysbiosis may stimulate inflammation, as bacterial aromatic metabolites are highly abundant and engage transcriptional programs through the aryl hydrocarbon receptor (AhR). Whether this axis drives cardiac remodeling and is therapeutically targetable remains unknown. MethodsWe used the subtotal nephrectomy model (STNx) and microbiome depletion by oral antibiotics. We investigated cardiac and renal function, AhR activity, metabolite profiles, and immunophenotypes by flow cytometry and transcriptomics. Candidate metabolite indoxyl sulfate (IxS) was tested in experimental HFpEF. In vivo and in vitro AhR inhibition (AhRi) was performed using a clinically tested compound. Mechanistic studies were performed in primary human and murine cardiac fibroblasts and T cells, as well as translational validation using UK Biobank data. ResultsMicrobiome depletion lowered bacterial metabolites and attenuated cardiac fibrosis and diastolic dysfunction in STNx, identifying AhR-driven expansion of interleukin-17A (IL-17A)-producing T helper cells (TH17) as key effector. Plasma IL-17A was stage-dependently elevated in CKD patients, particularly in HFpEF, and associated with all-cause mortality. Bacterial metabolite IxS promoted TH17 polarization and exacerbated cardiac dysfunction in HFpEF. AhRi using a small molecule inhibitor reduced TH17 abundance and attenuated cardiac fibrosis in STNx. Mechanistically, AhR and IL-17A signaling synergistically induced a conserved pro-fibrotic phenotype in human and murine cardiac fibroblasts, and AhR inhibition blocked ECM production in response to CKD patient serum. ConclusionA microbiome-AhR-IL-17A axis drives CKD-associated cardiac fibrosis. AhRi prevents remodeling, highlighting a potential therapeutic avenue to prevent cardiorenal multimorbidity.

immunology↗

bioRxiv2024

Intestinal interstitial fluid isolation provides novel insight into the human host-microbiome interface

AimsThe gastrointestinal (GI) tract is composed of distinct subregions which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools. Method and ResultsHere, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF and were differentially expressed when compared to matched serum, all suggesting local synthesis. ConclusionCollection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of fecal samples or serum, providing direct insight into this understudied compartment.

microbiology↗

bioRxiv2023

Mucosal washes are useful for sampling intestinal mucus-associated microbiota despite low biomass

Exploring the dynamic relationship between mucus-associated microbiota and host health is pivotal, yet prevalent studies using stool samples may not accurately represent these bacteria. Here, we explored mucus-associated microbiota in the gastrointestinal tract of mice and the terminal ileum in humans, using three different sample types: mucosal washes, scraping, and intestinal content in mice and biopsies and mucosal washes in humans. We employed DNA quantification and 16S rRNA sequencing to assess how comparable the information yielded from different sample types, evaluating findings relative to expectations from state-of-the-art and under controlled benchmarks. Mucosal washes in mice exhibited higher bacterial DNA and lower host DNA contamination than scraping samples. Similarly, in humans, washes surpassed biopsies in bacterial yield. Despite variations in read counts, microbiota diversity and composition remained remarkably similar between methods in both species, faithfully reflecting expected genotypic and phenotypic differences. We conclude that washes reduce host contamination without inducing substantial compositional bias when sampling mucosal microbiota. Our findings emphasize mucosal washes as alternatives to biopsies in humans and scrapings in mice, providing insights for improving result transferability across hosts. Our research underscores the importance of considering the mucus-associated microbiota to track host-microbiome interactions closer to their actual interface surface.

systems biology↗