Biology subjects

Ellermann, M.

Publications and source records attributed to Ellermann, M..

4 recordsLinked to original sources

bioRxiv2026

Cannabinoid receptor 1 activity promotes microbial dysbiosis by stimulating the oxygen-dependent expansion of Enterobacteriaceae

The endocannabinoid system is comprised of bioactive lipids that signal via cannabinoid receptors, which can modulate barrier and immune functions along the gastrointestinal tract. Clinical studies indicate that endocannabinoid activity is dysregulated in inflammatory bowel diseases. Here, we show that endocannabinoid activity promotes metabolic dysfunction within the colonic mucosa, resulting in microbial dysbiosis and exacerbated colitis. Stimulation of the cannabinoid receptor CB1 resulted in the expansion of Enterobacteriaceae within the gut microbiome, a common feature of inflammation-associated dysbiosis. Preceding this microbial change, CB1 activity induced transcriptional signatures of mitochondrial stress and immune activation within the colonic mucosa. This was followed by a reduction in mucosal ATP production and the induction of aerobic respiration genes in luminal Escherichia coli. Genetic inactivation of aerobic respiration in E. coli limited its proliferation, indicating that CB1 activity stimulates oxygen-dependent Enterobacteriaceae growth. In IBD susceptible mice, endocannabinoid activity promoted mucosal infection by an E. coli pathobiont, which corresponded with elevated pro-inflammatory markers. In inflammation resistant mice, acute CB1 stimulation was sufficient to accelerate the infection dynamics of an Enterobacteriaceae pathogen, resulting in exacerbated colitis. Taken together, our data support a model in which endocannabinoid signaling at the CB1 receptor disrupts respiratory metabolism in the colon, compromising the anoxic environment of the lumen that is critical for maintaining aerobically respiring pathogens at low abundance. More broadly, our findings highlight a proinflammatory effect of endocannabinoid activity that can contribute to intestinal disease development.

microbiology↗

bioRxiv2024

Human gut commensal Alistipes timonensis modulates the host lipidome and delivers anti-inflammatory outer membrane vesicles to suppress colitis in an Il10-deficient mouse model

Correlative studies have linked human gut microbes to specific health conditions. Alistipes is one such microbial genus negatively linked to inflammatory bowel disease (IBD). However, the protective role of Alistipes in IBD is understudied, and the underlying molecular mechanisms remain unknown. In this study, colonization of Il10-deficient mice with Alistipes timonensis DSM 27924 delays colitis development. Colonization does not significantly alter the gut microbiome composition, but instead shifts the host plasma lipidome, increasing phosphatidic acids while decreasing triglycerides. Outer membrane vesicles (OMVs) derived from Alistipes are detected in the plasma of colonized mice, carrying potentially immunomodulatory metabolites into the host circulatory system. Fractions of A. timonensis OMVs suppress LPS-induced Il6, Il1b, and Tnfa expression in vitro in murine macrophages. We detect putative bioactive lipids in the OMVs, including immunomodulatory sulfonolipids (SoLs) in the active fraction, which are also increased in the blood of colonized mice. Treating Il10-deficient mice with purified SoL B, a representative SoL, suppresses colitis development, suggesting its contribution to the anti-inflammatory phenotype observed with A. timonensis colonization. Thus, A. timonensis OMVs represent a potential mechanism for Alistipes-mediated delay of colitis in Il10-deficient mice via delivery of immunomodulatory lipids and modulation of the host plasma lipidome.

biochemistry↗

bioRxiv2023

Human Gut Microbial Sulfonolipids are linked to Inflammatory Bowel Diseases through Toll-Like Receptor 4 Signaling

The trillions of microorganisms inhabiting the human gut are intricately linked to human health. At the species abundance level, correlational studies have connected specific bacterial taxa to various diseases. While the abundances of these bacteria in the gut serve as good indicators for disease progression, understanding the functional metabolites they produce is critical to decipher how these microbes influence human health. Here, we report a unique biosynthetic enzyme-guided disease correlation approach to uncover microbial functional metabolites as potential molecular mechanisms in human health. We directly connect the expression of gut microbial sulfonolipid (SoL) biosynthetic enzymes to inflammatory bowel disease (IBD) in patients, revealing a negative correlation. This correlation is then corroborated by targeted metabolomics, identifying that SoLs abundance is significantly decreased in IBD patient samples. We experimentally validate our analysis in a mouse model of IBD, showing that SoLs production is indeed decreased while inflammatory markers are increased in diseased mice. In support of this connection, we apply bioactive molecular networking to show that SoLs consistently contribute to the immunoregulatory activity of SoL-producing human microbes. We further reveal that sulfobacins A and B, two representative SoLs, primarily target Toll-like receptor 4 (TLR4) to mediate immunomodulatory activity through blocking TLR4s natural ligand lipopolysaccharide (LPS) binding to myeloid differentiation factor 2, leading to significant suppression of LPS-induced inflammation and macrophage M1 polarization. Together, these results suggest that SoLs mediate a protective effect against IBD through TLR4 signaling and showcase a widely applicable biosynthetic enzyme-guided disease correlation approach to directly link the biosynthesis of gut microbial functional metabolites to human health.

biochemistry↗

bioRxiv2019

Yersiniabactin producing AIEC promote inflammation-associated fibrosis in gnotobiotic Il10-/- mice

Fibrosis is a significant complication of intestinal disorders associated with microbial dysbiosis and pathobiont expansion, notably Crohns disease (CD). Mechanisms that favor fibrosis are not well understood and therapeutic strategies are limited. Here we demonstrate that colitis susceptible Il10-deficient mice develop inflammation-associated fibrosis when mono-associated with adherent/invasive Escherichia coli (AIEC) that harbor the yersiniabactin (Ybt) pathogenicity island. Inactivation of Ybt siderophore production in AIEC nearly abrogated fibrosis development in inflamed mice. In contrast, inactivation of Ybt import through its cognate receptor FyuA enhanced fibrosis severity. This corresponded with increased colonic expression of profibrogenic genes prior to the development of histological disease, therefore suggesting causality. FyuA-deficient AIEC also exhibited greater localization within sub-epithelial tissues and fibrotic lesions that was dependent on Ybt biosynthesis and corresponded with increased fibroblast activation in vitro. Together, these findings suggest that Ybt establishes a pro-fibrotic environment in the host in the absence of binding to its cognate receptor and indicates a direct link between intestinal AIEC and the induction of inflammation-associated fibrosis.

microbiology↗