Microbiome Connections to Disease Get Stronger


A fair amount of what you read about the human microbiome is hype. There’s no way around it. It’s quite difficult to study this area in a meaningful, reproducible way, and even the best work in the area can only go so far, as things stand now. When differences in (say) gut flora are actually found and worked out, we generally don’t know what the chicken-and-egg relationship between that and human disease might be, or which particular bacteria (or ratio, or blend) is responsible, in either direction.

But just because an area is difficult, or because it has a lot of media noise in it, doesn’t mean that progress isn’t being made. There’s some new work, for example, that suggests that the gut microbiome might have a real connection to multiple sclerosis. That sounds like an exercise in headline-grabbing, but it looks more solid than that. This team found several bacterial types associated with MS, following up on numerous earlier studies, specifically noting that relapsing/remitting MS patients tend to have higher proportions of Acinetobacter (generally rare in gut flora) and Akkermansia, and lower proportions of Parabacteroides. The enhanced species, when put into other animals via fecal transplant, have very noticeable effects on T-cell differentiation and also exacerbate the pathology seen in the widely used EAE rodent model of the disease. The authors also note that one of the Acinetobacter species has already been shown in the literature to produce peptides that mimic sequences in myelin basic protein, which makes you wonder if MS is (at least partly) a misfiring immune response to gut bacteria in general.

That hypothesis has been kicking around for a while, but this sort of work really strengthens it. So does the second paper mentioned above, which looks at 34 pairs of twins, one of whom has MS while the other does not (an extraordinarily powerful and useful data set). This team also found increased Akkermansia in the gut flora of the affected twins. They transplanted gut material from the affected subjects versus unaffected controls into a mouse model (RR mice) that have a mutation causing them to spontaneously develop inflammatory demyelinating disease. Only some of the human-derived bacteria were able to colonize the mouse gut (as you’d expect), but even so, the mice with the transplants from the MS-diagnosed twins showed a significantly higher rate of disease onset.

When they looked more closely at the altered gut microbiota in these mice, they found lower levels of the Sutterella genus, compared to the transplants from human patients. (Interestingly, they don’t seem to have noticed as much difference with Acenitobacter). To be sure, other studies of gut flora in MS patients versus controls have also disagreed on the raised and lowered profiles across taxa, which is one of the things that makes this such a hard area to work in. (One explanation is that the concentration and localization of various species probably vary a great deal across the whole intestinal tract, in ways that are difficult to sample and account for, and stool samples are not necessarily a good proxy).

But overall, there really does seem to be something here, although it’s way too early to start talking about the therapeutic implications (for starters, we’d better be able to agree on just which bacteria are responsible and how they might be having their effects). These studies on bacterial transfer are really doing a lot, though, to address that chicken-and-egg problem mentioned above. If adding in the relevant bacterial population can bring on trouble in this way, that significantly raises the odds for the bacterial trouble being ahead of the CNS phenotype.

These papers dovetail nicely with yet another new paper, from a team at Rockefeller/Mt. Sinai/Sloan-Kettering. They’ve found that (1) commensal gut bacteria are enriched in genes for the synthesis of N-acyl amides, (2) that the compounds thus produced are, in many cases, micromolar ligands for various GPCRs that look quite similar to endogenous human ligands for these receptors and (3) that the GPCRs identified are, in turn, disproportionately localized in the gut as well. Taken together, it would appear that this is a signaling network that has evolved among the bacteria over time which modulates their own environment, and provides a direct mechanism by which changes in gut flora could affect the host organisms (that is, us). These lipid-like-signaling receptors (such as the endocannabinoid one, GPR119) are part of the same family, and can have a number of metabolic and inflammation-pathway effects.

Overall, it looks like the microbiota/disease connections are getting stronger, and getting some more detailed foundation under them. No doubt there are going to be a lot more twists and turns as these stories go on, and I would be very skeptical of anyone claiming (at this early stage) to have a great new therapeutic microbiome breakthrough for something as complex as MS. But the field in general is real stuff, generating some very interesting real results, and is worth keeping an eye on.

 

 

Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer



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