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How "mostly harmless" bacteria manipulate the immune system

"It may be better to keep alive the goose that lays the golden eggs than to kill it. But this argument depends on the assumption that, if you do not kill the golden goose, no one else will either: that is, it assumes that the host is infected by a single clone of symbionts." -- Maynard Smith 1989 Nature 341:284-285.

This week, I'll discuss a paper recently published in Science: Has the Microbiota Played a Critical Role in the Evolution of the Adaptive Immune System?, by Yun Kyung Lee and Sarkis K. Mazmanian. They argue that gut bacteria produce "signals that are recognized by host receptors to mediate beneficial outcomes for both microbes and humans."

Well, how nice! What sort of outcomes would be beneficial for a gut microbe? Reproducing a lot in the gut and spreading to lots of new hosts would be good. How to do this? Diarrhea seems promising. That might sicken or even kill the human, but does that matter to the microbes? Paul Ewald has pointed out that pathogens whose spread depends on host mobility may evolve lower virulence, so people with the flu feel well enough to go to work and spread it. Pathogens that spread via sewage to drinking water, though, may spread more readily if they cause more severe diarrhea. But we also need to consider conflicts of interest among gut bacteria, not just conflicts of interest with the host. For example, species X might trigger diarrhea before species Y has had time to reproduce much. If so, then species Y might benefit from suppressing, or at least delaying diarrhea.

More generally, the diversity of bacteria in the gut creates a "tragedy of the commons", where bacterial strains that pursue their own interests would rapidly out-compete hypothetical strains that sacrificed their own interests for the "greater good", either of the host or of the entire gut bacterial community.

Or so I would predict. But what about those mutually beneficial "signals?"

According to the paper, some bacteria produce a molecule called PSA, which suppresses inflammatory gut defenses. An overactive immune response in the gut leads to colitis, so suppressing inflammation can benefit humans. But is that why some bacteria have evolved to produce PSA? It's more likely that individual bacterial cells (or clusters of clonally identical bacterial cells) benefit by suppressing inflammatory responses in their own immediate neighborhood. Any overall benefit to the host (or to other gut bacteria) is merely a side-effect. If so, then I would call this "manipulation" of the host, rather than a "signal." In areas where dangerous gut infections are rare, this down-regulation of the immune response would usually be beneficial, but perhaps not always.

Segmented filamentous bacteria (SFBs), also discussed in the paper, have almost the opposite effect from PSA-producers. SFBs stimulate differentiation of certain T cells, specifically TH17 cells. These help protect against pathogens, usually without causing colitis. But

"microbes that stimulate T helper cell development may (inadvertently) also increase the inherent immune reactivity of the host, potentially leading to host-destructive pathologies"

I guess we can't blame the bacteria, if they didn't mean to cause disease. So, what's the "signal?" Possibly ATP, according to the paper. But is ATP a "signal", benefiting both sender and receiver? Or is it a "cue", released inadvertently, perhaps by dying bacteria, and providing information useful to the receiver, in this case, the host?

To qualify as a signal, ATP would have to be actively released by SFBs. Furthermore, SFBs that release ATP would have to have greater fitness in the gut than mutants that don't release ATP. If both of these are true -- neither has been shown, as far as I can tell -- then ATP could be either a signal (if the host consistently benefits) or a form of manipulation, if the SFBs benefit consistently but the host only benefits haphazardly, if at all. Calling any information-bearing molecule a "signal" obscures the key issue of how transmission of that information affects the fitness of senders and receivers.

Comments

What small bacteria can do to living organisms is astounding. Over prescribing of medications and the patient's negligence in taking all of the prescribed antibiotics is putting ALL of humanity at risk. Isn't that how it usually goes, so many suffer because of the actions of a few.

You gotta be kidding... Having more gut bacteria is a good thing??? Naw, I dont think so. Not only do parasites get 1st pick and steal nourishment that is ment for critical host body systems and organs, they toxify the system. Just cant see how having more parasites is a good thing.

Talk to your friendly neighborhood cow. They can't digest cellulose without the bacteria in their rumen. But the point of my post was that it's naive to assume that all of our gut bacteria are working to improve our health.

What small bacteria can do to living organisms is astounding. Over prescribing of medications and the patient's negligence in taking all of the prescribed antibiotics is putting ALL of humanity at risk. Isn't that how it usually goes, so many suffer because of the actions of a few.

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