Sunday, November 26, 2017

Allergen-sensitized mothers transfer protection against allergy to offspring through milk

In this study the authors showed that mouse pups born to mothers sensitized to allergen were significantly protected from developing allergic response to the same antigen.    

Protection in offspring was associated with the generation of antigen-specific Foxp3+ Tregs as observed in proliferation suppression assay or following short-term Treg depletion by DT (however, the authors did not analyze antigen-specificity of Tregs by tetramer staining). 

Further experiments showed that mother's milk contained allergen-specific antibodies and immune complexes (IC) and breastfeeding by allergen-sensitized mother (irrespective of birth mother status) was sufficient to transfer allergen protection to offspring.

In summary, this study suggests that breastfeeding by allergen-sensitized mothers can benefit offspring by preventing development of allergic response to the same allergen. However, it is not clear how exactly the authors see this mechanism working in humans. In mice, mothers were intentionally sensitized with allergen using epicutaneous (skin) application that supposed to mimic how humans with skin barrier dysfunction get sensitized to allergens. But the authors have not tested if milk from atopic human mothers can have the same effect on their offspring. For some reason the authors tested milk from nonatopic human mothers and showed that it 'worked' when fed to mice but did not provide any explanation why healthy, nonatopic human mother milk should contain any "protection" against allergen when mothers themselves are not sensitized as experiments in mice showed they must be for a milk derived immune complexes to work. So lots of unknowns and contradictions.

posted by David Usharauli

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