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.

Increased mucin‐degrading bacteria by high protein diet leads to thinner mucus layer and aggravates experimental colitis

“…[26][27][28] Recently, Durant et al identify that nanosized outer membrane vesicles of Bacteroides_thetaiotaomicron OMVs promotes the level of IL-10 in colon dendritic cells of healthy human, but not for UC patients, implying that Bacteroides_thetaiotaomicron may have protective and pathogenic effect in different conditions. 29 In addition, it is clear that microbes in the mucosa are totally different from that of feces. 21,30 Our study showed that high-casein diet increased the abundance of Bacteroides_thetaiotaomicron in colonic mucus layer, which might lead to thinner mucus layer and higher susceptibility to acute DSS-induced colitis.…”

Interaction between intestinal microbiota and tumour immunity in the tumour microenvironment

“…Bt OMV induces the regulatory phenotype (such as IL‐10 expression) of DCs isolated from healthy human colon and blood. However, the ability of the bacteria to induce the regulatory phenotype of the DCs of IBD patients is significantly reduced [96]. In addition, hepcidin secreted by cDC2s promotes healing of the intestinal mucosa after enteritis caused by microbiota [97].…”

Extracellular vesicles released by the human gut symbiont Bacteroides thetaiotaomicron in the mouse intestine are enriched in a selected range of proteins that influence host cell physiology and metabolism

“…Vesicle suspensions were concentrated as described above. Following crossflow ultrafiltration, further purification of BEVs and EVs was performed by fractionation of the suspension [20] by size-exclusion chromatography using a CL2-B Sepharose (Sigma-Aldrich) (120 cm x 1 cm column) in PBS buffer. The absorbance of the fractions was measured at 280 nm and the first fractions corresponding to the first absorbance peak were pooled and concentrated to 1 mL with a Vivaspin 20 centrifugal concentrator (100 kDa molecular weight cut-off, Sartorius) and filtered through a 0.22 µm PES membrane (Sartorius).…”

“…BEVs can digest polysaccharides [13], phytate and inositol polyphosphate derivatives [16], and modulate the immune system [5,6,[17][18][19][20]. They can access and transmigrate boundary epithelial cells using different routes enabling them to interact with mucosal immune cells and to disseminate more widely via the bloodstream [7,14,20]. Our further understanding of BEV biology in general and of their interaction with the host in particular, is dependent on defining the factors that regulate their generation and the cargo they carry [12,21].…”