Biology subjects

Beresford-Jones, B. S.

Publications and source records attributed to Beresford-Jones, B. S..

4 recordsLinked to original sources

bioRxiv2024

Hexa-acylated lipopolysaccharides from the gut microbiota enhance cancer immunotherapy responses

Immune checkpoint inhibitors (ICI), such as anti-PD-1, have revolutionized cancer treatment, but they are only effective for a minority of patients. The gut microbiome plays a crucial role in modulating immunotherapy treatment responses, and previous studies correlated lipopolysaccharide (LPS)-producing gut microbes with poorer prognosis. However, LPS from diverse bacterial species have activities ranging from immunostimulatory to inhibitory. By functionally analyzing fecal metagenomes from 112 melanoma patients prior to anti-PD-1 therapy, we found that a subset of LPS-producing bacteria encoding immunostimulatory hexa-acylated LPS was enriched in the microbiomes of clinical responders. We confirmed robust activation of the NF-kB pathway by hexa-acylated LPS in vitro, and this activation was significantly inhibited by penta-acylated LPS in a dose-dependent manner. Importantly, oral administration of hexa-acylated LPS augmented anti-PD-1-mediated anti-tumor immunity in an in vivo mouse model of cancer immunotherapy. Microbiome hexa-acylated LPS may therefore represent an accessible predictor and potential enhancer of clinical anti- PD-1 immunotherapy responses. Statement of significanceFunctional rather than taxonomic profiling of patient gut microbiomes reveals hexa-acylated LPS as a novel biomarker of responsiveness and a targetable pathway for enhancing responses to anti-PD-1, informing future studies and current patient treatment.

microbiology↗

bioRxiv2023

Enterocloster clostridioformis induces host intestinal epithelial responses that protect against Salmonella infection

Promoting resistance to enteric pathogen infection is a core function of the gut microbiota. However, many of the host-commensal interactions that likely mediate this protection remain uncharacterised. By screening gnotobiotic mice monocolonised with a range of mouse-derived commensal bacteria we have identified Enterocloster clostridioformis as a protective species against Salmonella Typhimurium infection. Unlike the colonisation resistance induced by some commensal bacteria, E. clostridioformis selectively induces a previously uncharacterised microbe adaptation response at the level of the caecal intestinal epithelium and the underlying mucosal immune system to mediate host-dependent resistance to infection. Triggering this pathway may therefore constitute a novel strategy to enhance protective responses against enteric infections.

microbiology↗

bioRxiv2021

Functional and taxonomic comparison of mouse and human gut microbiotas using extensive culturing and metagenomics

Mouse models are essential for biomedical science and drug discovery, yet it is not known how the bacteria in the mouse microbiota - important determinants of phenotypes of health and disease -affect their relevance to human disease. To interrogate the taxonomic and functional differences between the human and mouse gut microbiotas, we developed the Mouse Microbial Genome Collection (MMGC), a compilation of 276 genomes from cultured isolates and 45,218 metagenome-assembled genomes (MAGs) from 1,960 publicly available mouse metagenomes. The MMGC reveals that while only 2.65% of bacterial species are shared between mouse and human, over 80% of annotatable functions are present in both microbiomes. Using drug metabolism and butyrate synthesis as examples, we illustrate that although the species harbouring these key functions can differ between hosts, the MMGC enables identification of functionally equivalent taxa in the mouse and human microbiotas. The MMGC thereby facilitates the informed use of mice in biomedical research by providing access to the conservation and taxonomic locations of bacterial functions of interest.

microbiology↗

bioRxiv2021

Novel gut pathobionts confound results in a widely used mouse model of human inflammatory disease

The mammalian gut microbiota consists of hundreds of anaerobic bacterial species that shape intestinal homeostasis and influence host immune responses. Although the causal roles of specific human gut bacterial species in health and disease are emerging, the role of indigenous gut bacteria in driving immunophenotypic variability in mouse models of human disease remains poorly understood. We performed a large-scale experiment using 579 laboratory mice designed to identify and validate the causes of disease variability in the widely used dextran sulphate sodium (DSS) mouse model of inflammatory bowel disease. Using microbiome analysis, coupled with machine learning and targeted anaerobic culturing, we identified and isolated the novel gut pathobiont species Duncaniella muricolitica and Alistipes okayasuensis and fulfilled Kochs postulates in mice to show that each pathobiont exerts dominant effects in the DSS model leading to variable treatment responses. We show these pathobiont species are common, but not ubiquitous, in mouse facilities around the world, raising experimental design opportunities for improved mouse models of human intestinal diseases.

microbiology↗