How do gut bacteria boost our immune system?

Tedros, Yemane (2021) How do gut bacteria boost our immune system? Doctoral thesis, University of East Anglia.

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It is well known that the gut microbiota plays a role in numerous systems in our body through multiple mechanisms and that alterations in its functional composition, can lead to disease. Large-scale research programs have allowed the identification of new strains and/or new microbial functions and components supporting the development of potential therapeutic applications. One approach is the use of live biotherapeutics. Lactobacillus species are one of the most widely used live biotherapeutic products and can be found in a large variety of food products throughout the world. Limosilactobacillus reuteri (L. reuteri) is an excellent model organism to identify host-specific immunomodulatory properties of commensal bacteria because it is widespread gut symbiont found in many vertebrate hosts and one of the first to colonise the human gut. The underlying mechanisms by which L. reuteri exerts its well-documented host-specific therapeutic effects in the gut are not fully characterised. L. reuteri strains express cell-surface adhesins such as mucus binding protein (MUB) or serine rich repeats proteins (SRRP) which mediate bacterial adhesion to the host tissue. These adhesins has recently been shown to be glycosylated and can be recognised by lectins. This project will test the hypothesis that the ability of L. reuteri strains to colonise the gut and trigger immune response is mediated by protein-glycan interactions occurring between cell-surface structures and lectins found at the mucosal interface and immune cells.

We showed that the binding of the human (PTA ATCC 6475) and pig isolates (ATCC 53608) to mucin and epithelial cells was strain-dependent and that the binding was shown to be dependent on the surface expression of CmbA and MUB. Moreover, using ex-vivo binding assay, we demonstrated both the expression and glycosylation of SRRP is important for the adherence of the rat isolate (100-23 strain) to the mice forestomach. Here, we demonstrated that host strain-specific glycosylated adhesins SRRP100-23 and MUB53608 contribute to the immunomodulatory effects of L. reuteri 100-23 and ATCC 53608 in vitro by (i) mediating enhanced surface activation marker expression and (ii) inducing pro-inflammatory and anti-inflammatory cytokines by DCs. Using BMDCs lacking surface expression of Dectin-2, we also showed that Dectin-2 contributed to the L. reuteri 100-23–induced production of cytokines and internalisation by DCs. Moreover, we purified and characterised the L. reuteri-derived bacterial extracellular vesicles (BEVs) and showed that they could mediate bacteria-host interactions.

The data produced in this work provided novel insights into how L. reuteri cell surface glycosylation plays a crucial role in the interaction with the host’s immune system furthering our understanding of the underpinning mechanisms behind their beneficial interactions with the host.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 10 May 2022 07:45
Last Modified: 30 Nov 2022 01:38

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