Efficacious protective and controlled immunity against gastrointestinal (GI) infection requires critical regulatory signals induced by a balanced gut microbiota and associated metabolites resulting in functional homeostasis that prevents the manifestation of pathologic intestinal disorders. We demonstrated that human breast milk, when compared to formula given to preterm infants, critically reshapes the gut microbial composition and increases beneficial bacteria genera (e.g., Propionibacterium). First draft genome-sequence analysis of one of these newly identified probiotic strains, tentatively designated, P. UF1, is closely related to, and yet distinct, (85% sequence homology) from known Propionibacterium species, including P. freudenreichii. Obtained data demonstrate that P. UF1 significantly governs the regulation of induced inflammatory cytokines (e.g., IL-1?) in germ-free (GF) mice transfaunated with imbalanced microbiota derived from the feces of formula-fed preterm infants. P. UF1 not only regulated Th17 responses against pathogen infection, but also fortified the intestinal mucosal barrier function. Such immune regulation is tightly controlled by the surface layer (S-layer) of the bacterium binding to specific intercellular adhesion molecule-3-grabbing nonintegrin-related 1 (SIGNR1) expressed by colonic dendritic cells (DCs), resulting in S-layer-specific Th17 differentiation. This homeostasis significantly deteriorated in Signr1-/- mice, further emphasizing the crucial role of this molecular interaction in protective gut immunity. Th17 formation was significantly ablated in H2-Ab1-/- (MHC II-/) mice, suggesting S- layer-dependent Th17 differentiation. Mono-associated GF-mice given P. UF1 exhibited specifically Th17 differentiation and key metabolites (e.g., kynurenine) involved in tryptophan catabolism that regulates Th17 function. Additionally, the dihydrolipoamide acyltransferase (dlaT) gene was deleted in P. UF1 designated, ?dlaT P. UF1, to elucidate the role of this critically important S-layer component in S-layer-specific Th17 differentiation, intestinal microbial composition, and related induced metabolites. Preliminary data strongly indicate that ablation of the dlaT gene in P. UF1 fundamentally diminishes the regulatory function of this bacterium to control induced gut proinflammation (e.g., IL-1?). The objective of this research proposal is to clearly delineate the role of the S-layer of P. UF1 in the induction of regulated protective S-layer-specific Th17 responses against intestinal infection. Thus, we hypothesize that the newly identified P. UF1 species not only induces S-layer-specific Th17 differentiation upon interaction with SIGNR1 to confer protection against pathogens, but that the bacterial S-layer dlaT gene is significantly involved in these antigen-specific Th17 responses.
The Specific Aims are: 1) Elucidate S-layer-specific Th17 differentiation and its regulation by SIGNR1 signaling, and 2) Delineate the critical involvement of bacterial dihydrolipoamide acyltransferase (DlaT) in S-layer-specific Th17 differentiation. Such mechanistic insights will unravel integral mechanisms involved in the regulation of induced protective S-layer-specific immune responses against pathogen infection.
The beneficial role of our newly identified probiotic bacterium called, P. UF1, will be tested for its ability to regulate induced intestinal and systemic inflammation generated by microbial infection.
|Colliou, Natacha; Ge, Yong; Gong, Minghao et al. (2018) Regulation of Th17 cells by P. UF1 against systemic Listeria monocytogenes infection. Gut Microbes 9:279-287|
|Colliou, Natacha; Ge, Yong; Sahay, Bikash et al. (2017) Commensal Propionibacterium strain UF1 mitigates intestinal inflammation via Th17 cell regulation. J Clin Invest 127:3970-3986|