In our 2012 paper on nutrient signaling, Franklin, Kuzawa and I wrote that humans and other mammals use nutrients as an early warning system, to alert the body to changes in the microbiota. For instance it is widely assumed that some diets cause the microbiome to be unhealthy, a condition known as dysbiosis. If so, nutrients that cause dysbiosis might have a useful “early warning” function for the organism, allowing the immune system to anticipate dangerous changes in the microbiome before they occur. From this hypothesis, we made a few broad predictions: First, we would expect that dysbiosis-causing nutrients would cause pro-inflammatory immune changes. Second, nutrients that protect against dysbiosis would elicit anti-inflammatory effects.

At least for dietary fats, we have shown that lipid effects on inflammation and the microbiome are largely in line with our predictions. That is, fats that cause dysbiosis (mostly long-chain saturated fats) also cause direct inflammatory changes. Fats that protect against dysbiosis (mostly omega-3 unsaturated fats) often have independent anti-inflammatory effects.

We proposed that the immune adjustments caused by nutrients are generally adaptive for mammals, resulting in antimicrobial peptides and other immune responses that keep the microbiota in check. Another assumption that we did not fully explore is the idea that immune changes caused by microbes themselves are also adaptive. To give one example, the detection of bacterial lipopolysaccharide by toll-like receptors causes pro-inflammatory changes that, on balance, promote survival. The immune system has a surveillance function that detects and responds to the microbial environment.  Toll-like receptors and other signaling systems cause immune responses to PAMPs (pathogen associated molecular patterns) and MAMPs (microbial associated molecular patterns). MAMPs identify not just pathogens, but good, bad, and indifferent microbes. Although some PAMPs and MAMPS cause inflammation, other MAMPs have anti-inflammatory effects, for instance those associated with Bifidobacteria.  One could argue that the rationale for the health-promoting effects of probiotics involves harnessing the beneficial immunomodulatory effects of MAMPS.

The effects triggered by PAMPs and MAMPs are probably adaptive (on average) for the host. On the other hand, we know that many microbes manipulate their hosts. Microbes are under strong selection to evade and co-opt host defenses. Therefore immune responses to microbes are may not be uniformly beneficial for the host. Is there a way to distinguish between those responses that are maladaptive, manipulative and those that are adaptive for the host?

One clue for adaptation is if diverse cell systems respond in the same way to a microbial signal. Manipulation would be less likely to be successful if it requires independent interference with multiple host signaling systems. Therefore, if neural, gastrointestinal, adipose, and vascular cells each converge on the same functional outcome, it might be evidence for adaptation.  One microbial signal that fits that description is LPS. LPS generates similar immunological and metabolic effects on many separate tissues and cell pathways.

Our body’s response to nutrients might show a similar similar functional convergence. Human milk oligosaccharides (HMOs) are indigestible carbohydrates that feed beneficial microbes, e.g. Bifidobacteria. It is notable that HMO have anti-inflammatory effects, as do Bifidobacteria. In other words, the prebiotic HMO and the probiotic Bifido have overlapping and concordant effects on immunity and metabolism.  This overlap provides evidence for an evolved adaptive response. HMOs are detected directly by mammalian cells and have immunological effects that are very similar to the response of mammalian cells to Bifidobacteria themselves. This is the pattern we would expect if nutrients have evolved a signaling function that alerts the body to changes in the microbiome.

What if there is a difference between the body’s response to nutrients and to the bacteria that they feed? Divergent effects might be evidence for a non-adaptive response: pathology, or manipulation. We will explore whether this makes sense in upcoming posts.

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine