Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease

Abstract

Background: Bacteroides thetaiotaomicron (Bt) is a prominent member of the human intestinal microbiota that, like all gram-negative bacteria, naturally generates nanosized outer membrane vesicles (OMVs) which bud off from the cell surface. Importantly, OMVs can cross the intestinal epithelial barrier to mediate microbe-host cell crosstalk involving both epithelial and immune cells to help maintain intestinal homeostasis. Here, we have examined the interaction between Bt OMVs and blood or colonic mucosa-derived dendritic cells (DC) from healthy individuals and patients with Crohn's disease (CD) or ulcerative colitis (UC). Results: In healthy individuals, Bt OMVs stimulated significant (p < 0.05) IL-10 expression by colonic DC, whereas in peripheral blood-derived DC they also stimulated significant (p < 0.001 and p < 0.01, respectively) expression of IL-6 and the activation marker CD80. Conversely, in UC Bt OMVs were unable to elicit IL-10 expression by colonic DC. There were also reduced numbers of CD103 + DC in the colon of both UC and CD patients compared to controls, supporting a loss of regulatory DC in both diseases. Furthermore, in CD and UC, Bt OMVs elicited a significantly lower proportion of DC which expressed IL-10 (p < 0.01 and p < 0.001, respectively) in blood compared to controls. These alterations in DC responses to Bt OMVs were seen in patients with inactive disease, and thus are indicative of intrinsic defects in immune responses to this commensal in inflammatory bowel disease (IBD). Conclusions: Overall, our findings suggest a key role for OMVs generated by the commensal gut bacterium Bt in directing a balanced immune response to constituents of the microbiota locally and systemically during health which is altered in IBD patients.

Regulatory Dendritic Cells, T Cell Tolerance, and Dendritic Cell Therapy for Immunologic Disease

“…Thus, Bacteroides fragilis OMV signal to gut DC through TLR2, which induces the development of DCreg and Treg ( 188 ), but there can be heterogeneity in the way that gut DC respond to such signaling. Thus, while Bacteroides thetaiotaomicron OMVs induce IL-10 expression and a regulatory phenotype in colonic DC of healthy subjects, such immune regulation does not occur with DC from individuals with ulcerative colitis ( 189 ). Organisms with beneficial properties can also be found in the external environment.…”

From Welfare to Warfare: The Arbitration of Host-Microbiota Interplay by the Type VI Secretion System

“…Equally, it is reasonable to envision T6SS machineries and their effectors as direct inducers of immune tolerance at mucosal sites. In agreement with such possibility, host cells of the innate immune system may forge tolerance by acquiring antigens through OMVs (Shen et al, 2012;Kaparakis-Liaskos and Ferrero, 2015;Chu et al, 2016;Durant et al, 2020). The association of TseF, an iron-acquiring T6SS effector of Pseudomonas aeruginosa, with OMVs may represent an underappreciated role for T6SS effectors in host-microbe interplay (Lin et al, 2017).…”

The Role of Short-Chain Fatty Acids in the Interplay between a Very Low-Calorie Ketogenic Diet and the Infant Gut Microbiota and Its Therapeutic Implications for Reducing Asthma

“…B. thetaiotaomicron in vitro has the ability to produce regulatory IL-10 and protective IL-6 mediated by nanosized outer membrane vesicles (OMVs) [ 136 ]. B. thetaiotaomicron elicits anti-inflammatory activity in vitro through inducing nuclear export of the NF-κBrelaxedaspartate-auxotrophic (RelA)-PPARγ complex incolon carcinoma cell line (Caco-2) cells, causing downregulation of NF-κB-driven pro-inflammatory genes such as TNFα [ 137 ].…”