Project description:East Africa’s Roots of Power: The microbiome, metabolomics, and the antimicrobial potential of Mondia whitei, an herbal medicinal plant
Project description:Exercise reduces inflammation, fatigue, and aids overall health. Additionally, physical fitness has been associated with desirable changes in the community composition of the athlete gut microbiome, with health-associated taxa being shown to be increased in active individuals. Here, using a combination of in silico and in vitro methods, we investigate the antimicrobial activity of the athlete gut microbiome. In vitro approaches resulted in the generation of 284 gut isolates with inhibitory activity against Clostridioides difficile and/or Fusobacterium nucleatum, and the most potent isolates were further characterized, and potential bacteriocins were predicted using both MALDI-TOF MS and whole-genome sequencing. Additionally, metagenomic reads from the faecal samples were used to recover 770 Metagenome Assembled Genomes (MAGs), of which 148 were assigned to be high-quality MAGs and screened for the presence of putative bacteriocin gene clusters using BAGEL4 software, with 339 gene clusters of interest being identified. Class I was the most abundant bacteriocin class predicted, accounting for 91.3% of predictions, Class III had a predicted abundance of 7.5%, and Class II was represented by just 1% of all predictions.
Project description:The alarming rise of antimicrobial resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has made tuberculosis (TB) control a global health priority. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the growth of multi-drug resistant isolates of M. tuberculosis. Repurposing NSAIDs, with known clinical properties and safety records, offers a direct route to clinical trials. Therefore we investigated the novel mechanisms of anti-mycobacterial action of the NSAID, carprofen. Integrative molecular and microbiological approaches revealed that carprofen, a bactericidal drug, inhibited bacterial drug efflux mechanisms. In addition, carprofen restricted mycobacterial biofilm-like growth, highlighting the requirement of efflux-mediated communicative systems for the formation of biofilms. Transcriptome profiling revealed that carprofen likely acts by inhibiting respiration through the disruption of membrane potential, which may explain why spontaneous drug-resistant mutants could not be raised due to the pleiotropic nature of carprofen’s anti-tubercular action. This immunomodulatory drug has the potential to reverse TB antimicrobial resistance by inhibiting drug efflux pumps and biofilm formation, and paves a new chemotherapeutic path for tackling tuberculosis.
Project description:Aim: Exercise has been increasingly recognized as a potential influencer of the gut microbiome. Nevertheless, findings remain incongruous, particularly in relation to sport-specific patterns. Methods: In this study, we harness all publicly available data from athlete gut microbiome shotgun studies to explore how exercise may influence the gut microbiota through metagenomic assembly supplemented with short read-based taxonomic profiling. Through this analysis, we provide insights into exercise-associated taxa and genes, including the identification and annotation of putative novel species from the analysis of approximately 2,000 metagenome-assembled genomes (MAGs), classified as high-quality (HQ) MAGs and assembled as part of this investigation. Results: Our metagenomic analysis unveiled potential athlete-associated microbiome patterns at both the phylum and species levels, along with their associated microbial genes, across a diverse array of sports and individuals. Specifically, we identified 76 species linked to exercise, with a notable prevalence of the Firmicutes phylum. Furthermore, our analysis detected MAGs representing potential novel species across various phyla, including Bacteroidota, Candidatus Melainabacteria, Elusimicrobia, Firmicutes, Lentisphaerae, Proteobacteria, Tenericutes, and Verrucomicrobiota. Conclusion: In summary, this catalog of MAGs and their corresponding genes stands as the most extensive collection yet compiled from athletes. Our analysis has discerned patterns in genes associated with exercise. This underscores the value of employing shotgun metagenomics, specifically a MAG recovery strategy, for pinpointing sport-associated microbiome signatures. Furthermore, the identification of novel MAGs holds promise for developing probiotics and deepening our comprehension of the intricate interplay between fitness and the microbiome.
Project description:Fibroblasts that reside in the gut mucosa are among the key regulators of innate immune cells, but their role in the regulation of the defense functions of macrophages remains unknown. MyD88 is suggested to shape fibroblast responses in the intestinal microenvironment. We found that mice lacking MyD88 in fibroblasts showed a decrease in the colonic antimicrobial defense, developing dysbiosis and aggravated DSS-induced colitis. These pathological changes were associated with accumulation of Arginase 1+ macrophages with low antimicrobial defense capability. Mechanistically, production of IL-6 and CCL2 downstream of MyD88 was critically involved in fibroblast-mediated support of macrophage antimicrobial function, and IL-6/CCL2 neutralization resulted in the generation of macrophages with decreased production of antimicrobial peptide cathelicidin and impaired bacterial clearance. Collectively, these findings revealed a critical role of fibroblast-intrinsic MyD88 signaling in regulating macrophage antimicrobial defense under colonic homeostasis, and its disruption results in dysbiosis, predisposing host to the development of intestinal inflammation.
Project description:Fibroblasts that reside in the gut mucosa are among the key regulators of innate immune cells, but their role in the regulation of the defense functions of macrophages remains unknown. MyD88 is suggested to shape fibroblast responses in the intestinal microenvironment. We found that mice lacking MyD88 in fibroblasts showed a decrease in the colonic antimicrobial defense, developing dysbiosis and aggravated DSS-induced colitis. These pathological changes were associated with accumulation of Arginase 1+ macrophages with low antimicrobial defense capability. Mechanistically, production of IL-6 and CCL2 downstream of MyD88 was critically involved in fibroblast-mediated support of macrophage antimicrobial function, and IL-6/CCL2 neutralization resulted in the generation of macrophages with decreased production of antimicrobial peptide cathelicidin and impaired bacterial clearance. Collectively, these findings revealed a critical role of fibroblast-intrinsic MyD88 signaling in regulating macrophage antimicrobial defense under colonic homeostasis, and its disruption results in dysbiosis, predisposing host to the development of intestinal inflammation.