Abstract
The gastrointestinal (GI) tract harbours a complex microbial community, which contributes to its homeostasis. A disrupted microbiome can cause GI‐related diseases, including inflammatory bowel disease (IBD), therefore identifying host‐microbe interactions is crucial for better understanding gut health. Bacterial extracellular vesicles (BEVs), released into the gut lumen, can cross the mucus layer and access underlying immune cells. To study BEV‐host interactions, we examined the influence of BEVs generated by the gut commensal bacterium, Bacteroides thetaiotaomicron, on host immune cells. Single‐cell RNA sequencing data and host‐microbe protein‐protein interaction networks were used to predict the effect of BEVs on dendritic cells, macrophages and monocytes focusing on the Toll‐like receptor (TLR) pathway. We identified biological processes affected in each immune cell type and cell‐type specific processes including myeloid cell differentiation. TLR pathway analysis highlighted that BEV targets differ among cells and between the same cells in healthy versus disease (ulcerative colitis) conditions. The in silico findings were validated in BEV‐monocyte co‐cultures demonstrating the requirement for TLR4 and Toll‐interleukin‐1 receptor domain‐containing adaptor protein (TIRAP) in BEV‐elicited NF‐kB activation. This study demonstrates that both cell‐type and health status influence BEV‐host communication. The results and the pipeline could facilitate BEV‐based therapies for the treatment of IBD.
Highlights
The human gastrointestinal (GI) tract microbiota consisting of bacteria, viruses, archaea, and eukaryotic microbes, contributes to intestinal homeostasis by communicating with various host cells in the intestinal mucosa
We identified potential candidates from the proteome of bacterial extracellular vesicles (BEVs) obtained from a culture of Bacteroides thetaiotaomicron (Bt) grown in the complex medium Brain Heart Infusion (BHI), which totalled 2068 proteins
The same proteins were identified in BEVs extracted from the caecum of germ-free mice monocolonized with Bt (Stentz et al, 2020)
Summary
The human gastrointestinal (GI) tract microbiota consisting of bacteria, viruses, archaea, and eukaryotic microbes, contributes to intestinal homeostasis by communicating with various host cells in the intestinal mucosa. The administration of Bt in murine models of IBD ameliorates inflammation (Chang et al, 2020; Fábrega et al, 2017) with the anti-inflammatory effects being at least in part mediated by its production of bacterial extracellular vesicles (BEVs). BEVs are released by both commensal Gram-negative and Gram-positive bacteria and have the potential to mediate cross-kingdom interactions with host cells via the delivery of their contents and cargo to affect host cell physiology and function (Chang et al, 2020). BEVs produced by Gram-negative bacteria, such as Bt, are small, spherical bilayered structures (20–400 nm) composed of phospholipids, lipopolysaccharides, peptidoglycan, outer membrane proteins, periplasmic contents including proteins, and some inner membrane and cytoplasmic fractions (Chronopoulos & Kalluri, 2020; Schwechheimer & Kuehn, 2015). BEVs can permeate through the sterile mucus layer of the colon to access and transmigrate boundary intestinal epithelial cells through different routes (Jones et al, 2020) enabling them to interact with underlying mucosal immune cells (Cecil et al, 2019; Durant et al, 2020; Hickey et al, 2015; Kaparakis-Liaskos & Ferrero, 2015; Shen et al, 2012) and the intestinal vasculature which facilitates their wider, systemic dissemination (Durant et al, 2020; Jones et al, 2020; Stentz et al, 2018)
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