Biology subjects

Ring, D.

Publications and source records attributed to Ring, D..

5 recordsLinked to original sources

bioRxiv2026

Gut microbiota within-host evolution enforces colonization resistance against enteric infection

Limited resource availability in the gut promotes competitive interactions between bacteria, which drive adaptive within-host evolution (1-3). While adaptive evolution of bacterial communities has been increasingly studied in the recent years (4-7), its functional implications for host physiology remain unknown. Here, we show that within-host evolution of the human commensal Enterococcus faecalis boosts colonization resistance to enteric Salmonella enterica serovar Typhimurium (S. Typhimurium) infection. During gut colonization, E. faecalis evolves the ability to metabolize fructoselysine, an abundant Amadori rearrangement product generated by thermal food processing. The depletion of this diet-derived nutrient prevents S. Typhimurium colonization by restricting an essential resource. This protective mechanism was conserved across independent mouse colonies and arises via diverse evolutionary trajectories, including nucleotide polymorphisms, gene amplifications, and a horizontal gene transfer event. Additionally, analysis of E. faecalis isolates from human infants revealed that adaptation to fructoselysine availability occurs in a diet-dependent manner. Isolates from infants fed with fructoselysine-rich formula were able to utilize fructoselysine, whereas those from infants fed with fructoselysine-poor breast milk were not. Conclusively, our results identify an inherent microbiome-driven self-healing mechanism, wherein bacterial evolution restores colonization resistance against enteric pathogens through evolved nutrient depletion. Understanding these evolutionary dynamics will inform microbiome-targeted approaches to prevent and treat infectious diseases by harnessing adaptive bacterial metabolism.

microbiology↗

bioRxiv2023

Contribution of bacterial and host factors to pathogen "blooming" in a gnotobiotic mouse model for Salmonella enterica serovar Typhimurium-induced enterocolitis

Inflammation has a pronounced impact on the intestinal ecosystem by driving an expansion of facultative anaerobic bacteria at the cost of obligate anaerobic microbiota. This pathogen "blooming" is also a hallmark of enteric Salmonella enterica serovar Typhimurium (S. Tm) infection. Here, we analyzed the contribution of bacterial and host factors to S. Tm "blooming" in a gnotobiotic mouse model for S. Tm-induced enterocolitis. Mice colonized with the Oligo-Mouse-Microbiota (OMM12), a minimal bacterial community, develop fulminant colitis by day 4 after oral infection with wild type S. Tm but not with an avirulent mutant. Inflammation leads to pronounced reduction in overall intestinal bacterial loads, distinct microbial community shifts and pathogen blooming (relative abundance >50%). S. Tm mutants attenuated in inducing gut inflammation generally elicit less pronounced microbiota shifts and reduction in total bacterial loads. In contrast, S. Tm mutants in nitrate respiration, salmochelin production and ethanolamine utilization induced strong inflammation and S. Tm "blooming". Therefore, individual Salmonella-specific inflammation-fitness factors seem to be of minor importance for competition against this minimal microbiota in the inflamed gut. Finally, we show that antibody-mediated neutrophil depletion normalized gut microbiota loads but not intestinal inflammation or microbiota shifts. This suggests that neutrophils equally reduce pathogen and commensal bacterial loads in the inflamed gut.

microbiology↗

bioRxiv2022

Nutritional and host environments determine community ecology and keystone species in a synthetic gut bacterial community

Microbe-microbe interactions are critical for gut microbiome function. A challenging task to understand health and disease-related microbiome signatures is to move beyond descriptive community-level profiling towards disentangling microbial interaction networks. Here, we aimed to determine members taking on a keystone role in shaping community ecology of a widely used synthetic bacterial community (OMM12). Using single-species dropout communities and metabolomic profiling, we identified Bacteroides caecimuris I48, Blautia coccoides YL58 and Enterococcus faecalis KB1 as major drivers of in vitro community assembly and elucidated underlying mechanisms of these keystone functions. Importantly, keystone species and bacterial strain relationships were found to strongly vary across different nutritional conditions, depending on the strains potential to modify the corresponding environment. Further, gnotobiotic mice transplanted with communities lacking B. caecimuris I48 and B. coccoides YL58 exhibited morphological anomalies and altered intestinal metabolomic profiles, exposing physiologically relevant functions of these keystone community members. In summary, the presented study experimentally confirms the strong interdependency between bacterial community ecology and the biotic and abiotic environment, underlining the context-dependency and conditionality of bacterial interaction networks.

ecology↗

bioRxiv2022

Bacteriophages targeting protective commensals impair resistance against Salmonella Typhimurium infection in gnotobiotic mice

Gut microbial communities protect the host against a variety of major human gastrointestinal pathogens. Bacteriophages (phages) are ubiquitous in nature and frequently ingested via food and drinking water. Moreover, they are an attractive tool for microbiome engineering due to the lack of known serious adverse effects on the host. However, the functional role of phages within the gastrointestinal microbiome remain poorly understood. Here, we investigated the effects of microbiota-directed phages on infection with the human enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm), using a gnotobiotic mouse model (OMM12) for colonization resistance (CR). We show that phage cocktails targeting Escherichia coli and Enterococcus faecalis acted in a strain-specific manner. They transiently reduced the population density of their respective target before establishing coexistence for up to 9 days. Infection susceptibility to S. Tm was markedly increased at an early time point after phage challenge. Surprisingly, OMM12 mice were more susceptible 7 days after a single phage inoculation, when the targeted bacterial populations were back to pre-phage administration density. The presence of phages that dynamically modulates the density of protective members of the gut microbiota provides opportunities for invasion of bacterial pathogens.

microbiology↗

bioRxiv2020

Helicobacter hepaticus as disease driver in a novel CD40-mediated model of colitis

Gut microbiota and the immune system are in constant exchange, which shapes both, host immunity and microbial communities. Here, improper immune regulation can cause inflammatory bowel disease (IBD) and colitis. Antibody therapies blocking signaling through the CD40 - CD40L axis showed promising results as these molecules have been described to be deregulated in certain IBD patients. To better understand the mechanism, we used transgenic DC-LMP1/CD40 animals, which lack intestinal CD103+ dendritic cells (DCs) and therefore cannot induce regulatory T (iTreg) cells due to a constitutive CD40-signal in CD11c+ cells. These mice rapidly develop spontaneous fatal colitis with an increase of inflammatory IL-17+IFN-{gamma}+ Th17/Th1 and IFN-{gamma}+ Th1 cells. In the present study we analyzed the impact of the microbiota on disease development and detected elevated IgA- and IgG-levels in sera from DC-LMP1/CD40 animals. Their serum antibodies specifically bound intestinal bacteria and we identified a 60 kDa chaperonin GroEL (Hsp60) from Helicobacter hepaticus (Hh) as the main specific antigen targeted in absence of iTregs. When rederived to a different Hh-free SPF-microbiota, mice showed few signs of disease without fatalities, but upon recolonization of mice with Hh we found rapid disease onset and the generation of inflammatory Th17/Th1 and Th1 cells in the colon. Thus, the present work identifies a major bacterial antigen and highlights the impact of specific microorganisms on modulating the host immune response and its role on disease onset, progression and outcome in this colitis model.

immunology↗