Abstract
ABSTRACTThe Gram negative intestinal symbiont Bacteroides vulgatus mpk is able to prevent from induction of colonic inflammation in Rag1−/− mice and promotes immune balance in Il2−/− mice. These inflammation-silencing effects are associated with B. vulgatus mpk-mediated induction of semi-mature dendritic cells, especially in the colonic lamina propria (cLP). However the beneficial interaction of bacteria with host immune cells is limited due to the existence of a large mucus layer covering the intestinal epithelium. How can intestinal bacteria overcome this physical barrier and contact the host immune system?One mechanism is the production of outer membrane vesicles (OMVs) via ubiquitous blebbing of the outer membrane. These proteoliposomes have the ability to traverse the mucus layer. Hence, OMVs play an important role in immunomodulation and the maintenance of a balanced gut microbiota. Here we demonstrate that the stimulation of bone marrow derived dendritic cells (BMDCs) with isolated OMVs originated from B. vulgatus mpk leads to the induction of a tolerant semi-mature phenotype. Thereby, microbe- associated molecular patterns (MAMPs) delivered by OMVs are crucial for the interaction and the resulting maturation of immune cells. Additional to the binding to host TLR4, a yet unknown ligand to TLR2 is indispensable for the conversion of immature BMDCs into a semi-mature state. Thus, crossing the epithelial mucus layer and directly contact host cells, OMV mediate cross-tolerance via the transport of various Toll-like receptor antigens. These features make OMVs to a key attribute of B. vulgatus mpk for a vigorous acellular prevention and treatment of systemic diseases.
Highlights
The intestinal microbiota provides important features which are considered to be beneficial for the host organism, such as (1) the maintenance of the structural integrity of the intestinal mucosal barrier, (2) the development of epithelial cell function, (3) host nutrient metabolism, (4) modulation of the immune system and (5) prevention of bacterial overgrowth.[1,2] Hereby, a certain microbial diversity is considered to be required for the maintenance of the immune homeostasis and crucial for the optimal functionality and interaction with the host
The mechanism of outer membrane vesicles (OMVs) production is a key characteristic of Gram negative bacteria and commensal-derived OMVs seem to be important for the modulation of the host immune system.[29]
We demonstrated that the Gram negative symbiotic commensal B. vulgatus mpk produces outer membrane vesicles (OMV)
Summary
The intestinal microbiota provides important features which are considered to be beneficial for the host organism, such as (1) the maintenance of the structural integrity of the intestinal mucosal barrier, (2) the development of epithelial cell function, (3) host nutrient metabolism, (4) modulation of the immune system and (5) prevention of bacterial overgrowth.[1,2] Hereby, a certain microbial diversity is considered to be required for the maintenance of the immune homeostasis and crucial for the optimal functionality and interaction with the host. Concerning the interplay between microbiota and the host immune system, a disturbed or altered composition of the gut microbiota, called “dysbiosis,” is associated with the pathogenesis of both intestinal and systemic immunological disorders.[3] Such a dysbiosis of the intestinal microbiota, can influence the disease onset and progress in a variety of mouse models for autoimmune diseases (AID) such as rheumatoid arthritis (RA), type 1 diabetes (T1D) and inflammatory bowel disease (IBD).[4,5,6] This highlights the importance of a deeper knowledge of the interaction between the host immune system and the intestinal microbes Based on this cross talk, specific modulation of the intestinal microbiota composition is considered to be used as therapy for the treatment of microbiota-associated AID.[7,8] Hereby, intestinal commensals are decisive for the induction (pathobionts) or prevention (symbionts) of a pathological immune response in a certain predisposed host.[9] In this context, members of the genus Bacteroides were already demonstrated to exhibit symbiotic properties concerning the modulation of the intestinal immune system.[10]
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