Saturday, November 18, 2017

Salt-sensitive lactobacilli drive down TH17 cells and contribute to normal blood pressure

Most clinically diagnosed hypertensions, high blood pressure, are idiopathic in origin, meaning one can't determine what causes it. First thing patients are asked to do is to modify their diet habits and reduce salt intake. Diet high in salt thought to contribute to hypertension by water retention.

However, it could be that there is another, immunological pathway that contributes to high blood pressure. New study in Nature showed that in mice and maybe in humans as well, high salt diet depletes Lactobacilli, a gut microbiota species shown to lower TH17 differentiation and contributing in maintaining normal blood pressure.

Initially, the authors showed that in mice high salt diet (HSD) depleted several microbiota species, most notable, Lactobacillus murinus (initially identified through sensitive machine learning approach using the AdaBoost classifier from scikit-learn module run on Python).



In autoimmune model, adding Lactobacillus murinus could abolish high salt diet-induced increase in disease severity. Lactobacillus murinus appears to drive down TH17 differentiation (of note, high salt diet did not change TH17 population in germ-free mice).



Mechanistically, the authors showed that Lactobacillus murinus could inhibit TH17 differentiation by producing indole-3-lactic acid (ILA), a product of tryptophan metabolism.



Finally, volunteers on high salt diet display high TH17 differentiation and decrease in gut content for Lactobacilli.



In summary, the authors want to make the case that high salt diet could induce high blood pressure by depleting Lactobacilli and increasing TH17 cells which appear to initiate hypertension-related changes. 

It is clear that depletion of Lactobacilli per se is not sufficient for initiation of hypertension but we don't know what are other remaining microbiota species that actually induce TH17 in humans. Also, it is not clear whether microbiota-derived conserved molecules or metabolites (ILA) are sufficient for initiating hypertension or there are more complex events, such as chronic antigen-specific interactions that are ultimately responsible for sustaining chronicity of TH17 response and hypertension.    

posted by David Usharauli 



Sunday, November 5, 2017

Hidden arm against tumors: microbiota-enabled checkpoint immunotherapy

This week Science published two studies showing how diverse microbiota directly contributes to efficacy of PD-1 checkpoint immunotherapy in several tumors.

First, we need to mention that senior authors from both papers disclosed associations with for-profit pharma/biotech companies (as cofounders, stockholders, paid consultants or advisory board members). Such associations could, in general, be seen as problematic if one promotes therapy lacking particularities.     

Second, data presented do not advance our understanding how microbiota contributes to the effectiveness of checkpoint immunotherapy. The sole conclusion from both papers is that the more diverse cancer patient's microbiota the more benefit it provides during PD-1 immunotherapy. However, when it comes to narrow down beneficial correlation to particular species we find that one paper reported enrichment of Akkermansia muciniphila while other paper reported enrichment of Faecalibacterium and Clostridiales in Responders (as opposed to Non-Responders).

We still don't know much about the role of microbiota in cancer immunotherapy. I think real advance will come when we define how antigens derived from specific microbiota contribute to anti-cancer immunotherapy either by amplifying existing cross-reactive effector T cells or Foxp3+ Tregs. 

posted by David Usharauli





Wednesday, October 25, 2017

Molecular mimicry to gut microbiota antigen protects against colitis but induces diabetes

Current issue of journal Cell has one very interesting but at the same time confusing research paper. In it, the authors proposed that
(a) diabetes susceptible mice strain, NOD, harbor CD8 T cells specific for microbiota antigen that cross-react with β cell antigen, IGRP, and
(b) such molecular mimicry prevents colitis but at the same time could induce diabetes.

First, the authors showed that MHC I alelle expressed in NOD mice (H2Kd) could bind IGRP206-214 homologue derived from integrase family expressed by some gut Bacteroides species (BacIYL36–44). 



At high dosage, such binding was functional in stimulating high affinity IGRP206-214-specific T cells (17.4+ CD8 T cells).



Human T cells from PBMCs could apparently respond to it as well (though it is strange that it generated better stimulation index than Tetanus toxoid).



Then, the authors did the following experiment. They exposed IGRP-/- 17.4+ TCR transgenic mice to chemical irritant (DSS) and observed that high affinity IGRP206-214-specific T cells, 17.4+ CD8 T cells, but not low affinity ones (17.6+), could protect against colitis (I assume that they used IGRP-/-mice to avoid diabetes development).



It appears that colitis protection depended on perforin expression by 17.4+ T cells. The authors speculated that 17.4+ CD8 T cells prevented colitis by eliminating dendritic cells laden with microbiota-derived antigen (BacIYL36–44).



As a confirmation, the authors showed that germ-free TCR Tg NOD mice colonized with Bacteroides species expressing BacIYL36–44 were protected against colitis.



Colitis protection was observed even in classical, adoptive naive CD4+ T cell transfer colitis model.



Interestingly, however, transfer of T cells from pre-diabetic NOD mice into germ-free NOD.scid mice colonized with Bacteroides species expressing BacIYL36–44 did not accelerate diabetes development (here I assume DSS is required to accelerate T cells priming against IGRP by creating dysbiosis).



In summary, this study suggests the following scenario: diabetes-inducing CD8+ T cells cross-react with gut microbiota-derived antigen. When such microbiota-derived antigens become visible to T cells (during dysbiosis?) CD8+ T cells migrate to gut and eliminate dendritic cells laden with cross-reactive antigens. By eliminating DCs, other T cells are not able to induce inflammation in the gut, thus no colitis. However, the same beneficial CD8+ T cells later migrate to β cells, recognize similar looking antigen, IGRP, and mediate its destruction and diabetes.

Does such circuit makes any evolutionary sense? 

Update: Interestingly, other research group previously detected different set of gut microbiota antigens cross-reactive to IGRP206-214. They used TCR NY8.3 transgenic NOD mice (that recognize the same IGRP epitope) and found that these CD8 T cells cross-reacted with IGRP206–214 homologous peptide, W15944, derived from L. goodfellowii, a member of the phylum Fusobacteria (gram-negative anaerobe), a human and NOD mouse oral commensal. 


posted by David Usharauli