Defining Innate Immune Responses to the Human Gut Microbiota from Phylum to Strain

Abstract

SUMMARYThe functional potential of the gut microbiota remains largely uncharacterized. Efforts to understand how the immune system responds to commensal organisms have been hindered by the large number of strains that comprise the human gut microbiota. We develop a screening platform to measure innate immune responses towards 277 bacterial strains isolated from the human gut microbiota. We find that innate immune responses to gut derived bacteria are as strong as responses towards pathogenic bacteria, and vary from phylum to strain. Myeloid cells differentially rely upon TLR2 or TLR4 to sense particular taxa, an observation that predicts in vivo function. These innate immune responses can be modeled using combinations of up to 8 TLR agonists. Furthermore, the immunogenicity of strains is stable over time and following transplantation into new humans. Collectively, we demonstrate a powerful high-throughput approach to determine how commensal microorganisms shape innate immune phenotypes.

The NQR complex regulates the immunomodulatory function ofBacteroides thetaiotaomicron

“…Stimulation of BMDMs generated from the bone-marrow of wild-type or TLR2 -/mice, also showed a role for TLR2 in producing IL-10 in response to B. theta (Supplemental Figure 1C), confirming that the requirement for TLR2 was not limited to the splenocyte assay. Conditioned media from an additional isolate of B. theta (strain 0940-1) also induced IL-10 in a TLR2 dependent manner (Supplemental Figure 1D), suggesting that TLR2 is a sensor for B. theta as a species, in keeping with a recent report showing that a large panel of distinct Bacteroides are sensed by this PRR 59 . TLR2 can coordinate activation of the immune system in concert with the PRR Dectin-1, and the dual engagement of TLR2 and Dectin-1 by B. fragilis derived PSA drives IL-10 production 30,60 .…”

“…This is exemplified by B. fragilis which produces the capsular polysaccharide, polysaccharide A (PSA), which is packaged into OMVs and drives IL-10 production via TLR2 8,[30][31][32][33]42 . Mirroring these findings, Bifidobacterium bifidum 10 and Helicobacter hepaticus 15 produce cellular polysaccharides that stimulate IL-10 production via TLR2, and members of the Bacteroidetes as a whole have recently been shown to promote IL-10 induction through a TLR2-MyD88 axis 59 . While our data reveal that B. theta secreted factors also stimulated IL-10 production through a TLR2-dependent mechanism, we found no requirement for any of the known capsular polysaccharides produced by B. theta in this process.…”

“…A failure in immune tolerance of the microbiome can lead to development of chronic diseases like inflammatory bowel disease (IBD) that severely impact host health 18,[21][22][23][67][68][69] . The intestinal immune system is therefore faced with the challenge of differentiating between potential pathogens and resident microbiome members, despite both types of microorganisms producing agonists of host-PRRs such as Toll-like receptor 4 (TLR4), TLR2, Dectin-1, etc 59,60,63 .…”

“…While the "Danger Theory" provides a conceptual framework to understand how this is achieved, the molecular processes that underlie this decision remain enigmatic 70 . Several studies have established that the gut microbiome can coordinate the induction of anti-inflammatory immune responses that limit inflammation and favor mutualism via the production of a variety of metabolites and cellular products [8][9][10][11][13][14][15][16]28,30,31,33,[36][37][38][39][40][41]43,51,[57][58][59]62,71,72 . Despite this, there remains a dearth of knowledge regarding the nature of these microbiome-derived molecules and the microbial pathways that govern their production and secretion.…”

The probiotic and immunomodulation effects of Limosilactobacillus reuteri RGW1 isolated from calf feces

“…This phenomenon might be explained by that some compounds in the surface of live L. reuteri RGW1 could stimulate host, thus slightly altering the immune status. As evidenced by Spindler et al (2022), who revealed that the gut commensals could also stimulate phylogenetically defined innate immune responses, including TNF-a expression.…”