Biology subjects

Friedman, E. S.

Publications and source records attributed to Friedman, E. S..

5 recordsLinked to original sources

bioRxiv2025

Carbohydrate consumption drives adaptive mutations in Escherichia coli associated with increased risk for systemic infection

Dissemination of organisms from the gut microbiota is a major contributor to sepsis and critical illness. Patients with cirrhosis are prone to systemic infections and are commonly prescribed the carbohydrate lactulose to manage hepatic encephalopathy (HE) 1. Commensal metabolism of lactulose is believed to reduce pathobiont colonization through short-chain fatty acid production, but its direct effects on gut pathobionts remain unexplored 2. Here, we show that lactulose consumption unexpectedly selects for mutations in Escherichia coli lactose (lac) operon regulation, enhancing its metabolic fitness and colonization capacity. This is mediated by selection for constitutive expression of the lac operon through mutations in its regulatory components. Using in vitro systems, murine models, and clinical samples, we demonstrate that these mutations enable E. coli to exploit lactulose as a carbon source, bypassing host carbohydrate metabolism and increasing its intestinal colonization. Despite its long-standing use in HE treatment, we find that lactulose has a paradoxical association with risk of infection hospitalization in patients with cirrhosis in a large epidemiologic study. The emergence of lactulose-adapted E. coli strains could be suppressed by a dietary oligosaccharide that competitively inhibits lactulose uptake. These findings reveal a mechanism by which dietary substrates exert selective pressure on the microbiome, with implications for diet-based strategies to modulate microbial evolution and infection risk.

microbiology↗

bioRxiv2024

Amino acid competition shapes Acinetobacter baumannii gut carriage

Antimicrobial resistance is an urgent threat to human health. Asymptomatic colonization is often critical for persistence of antimicrobial-resistant pathogens. Gut colonization by the antimicrobial-resistant priority pathogen Acinetobacter baumannii is associated with increased risk of clinical infection. Ecological factors shaping A. baumannii gut colonization remain unclear. Here we show that A. baumannii and other pathogenic Acinetobacter evolved to utilize the amino acid ornithine, a non- preferred carbon source. A. baumannii utilizes ornithine to compete with the resident microbiota and persist in the gut in mice. Supplemental dietary ornithine promotes long-term fecal shedding of A. baumannii. By contrast, supplementation of a preferred carbon source--monosodium glutamate (MSG)-- abolishes the requirement for A. baumannii ornithine catabolism. Additionally, we report evidence for diet promoting A. baumannii gut carriage in humans. Together, these results highlight that evolution of ornithine catabolism allows A. baumannii to compete with the microbiota in the gut, a reservoir for pathogen spread.

microbiology↗

bioRxiv2023

Colonization and Dissemination of Klebsiella pneumoniae is Dependent on Dietary Carbohydrates

Dysbiosis of the gut microbiota is increasingly appreciated as both a consequence and precipitant of human disease. The outgrowth of the bacterial family Enterobacteriaceae is a common feature of dysbiosis, including the human pathogen Klebsiella pneumoniae. Dietary interventions have proven efficacious in the resolution of dysbiosis, though the specific dietary components involved remain poorly defined. Based on a previous human diet study, we hypothesized that dietary nutrients serve as a key resource for the growth of bacteria found in dysbiosis. Through human sample testing, and ex-vivo, and in vivo modeling, we find that nitrogen is not a limiting resource for the growth of Enterobacteriaceae in the gut, contrary to previous studies. Instead, we identify dietary simple carbohydrates as critical in colonization of K. pneumoniae. We additionally find that dietary fiber is necessary for colonization resistance against K. pneumoniae, mediated by recovery of the commensal microbiota, and protecting the host against dissemination from the gut microbiota during colitis. Targeted dietary therapies based on these findings may offer a therapeutic strategy in susceptible patients with dysbiosis.

microbiology↗

bioRxiv2021

SARS-CoV-2-specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens

The baseline composition of T cells directly impacts later response to a pathogen, but the complexity of precursor states remains poorly defined. Here we examined the baseline state of SARS-CoV-2 specific T cells in unexposed individuals. SARS-CoV-2 specific CD4+ T cells were identified in pre-pandemic blood samples by class II peptide-MHC tetramer staining and enrichment. Our data revealed a substantial number of SARS-CoV-2 specific T cells that expressed memory phenotype markers, including memory cells with gut homing receptors. T cell clones generated from tetramer-labeled cells cross-reacted with bacterial peptides and responded to stool lysates in a MHC-dependent manner. Integrated phenotypic analyses revealed additional precursor diversity that included T cells with distinct polarized states and trafficking potential to other barrier tissues. Our findings illustrate a complex pre-existing memory pool poised for immunologic challenges and implicate non-infectious stimuli from commensal colonization as a factor that shapes pre-existing immunity. One Sentence SummaryPre-existing immunity to SARS-CoV-2 contains a complex pool of precursor lymphocytes that include differentiated cells with broad tissue tropism and the potential to cross-react with commensal antigens.

immunology↗

bioRxiv2021

Stable Isotope Tracing In Vivo Reveals A Metabolic Bridge Linking The Microbiota To Host Histone Acetylation

The gut microbiota influences host epigenetics by fermenting dietary fiber into butyrate. Although butyrate could promote histone acetylation by inhibiting histone deacetylases, it may also undergo oxidation to acetyl-CoA, a necessary cofactor for histone acetyltransferases. Here, we find that epithelial cells from germ-free mice harbor a loss of histone H4 acetylation across the genome except at promoter regions. Using stable isotope tracing in vivo with 13C-labeled fiber, we demonstrate that the microbiota supplies carbon for histone acetylation. Subsequent metabolomic profiling revealed hundreds of labeled molecules and supported a microbial contribution to host fatty acid metabolism, which declined in response to colitis and correlated with reduced expression of genes involved in fatty acid oxidation. These results illuminate the flow of carbon from the diet to the host via the microbiota, disruptions to which may affect energy homeostasis in the distal gut and contribute to the development of colitis.

biochemistry↗