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Breaking bad – the microbiome edition

Is your microbiome value-added? Does it provide benefits to your health and well-being? Does it produce vitamins and help with your digestion? Does it educate your immune system and prevent infection?

Unless you are hospitalized in the intensive care unit or suffering severe or critical illness, the answer is likely yes. We do benefit from our microbiomes. But the story does not end there. Microbiomes are also the source of much human suffering. Yes, microbes in our guts can break bad too, a concept termed the Trojan Horse hypothesis.

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Careful readers of this blog need no definition of the microbiome. But here is the definition anyway.  There are actually two terms – the microbiome and the microbiota. The microbiota is the collection of microbes that inhabit our bodies. The microbiome is the collection of all of the genes of the microbiota. The vast majority of the microbes and their genes exist in the colon. About 30 trillion cells makes up the microbiota, about the same number as human cells. The microbiome consists of 10-100 times the number of genes as exist in the human genome. I often use the two terms interchangeably – because we use the microbe genes (microbiome) to figure out which microbial cells live in our bodies (microbiota).

The microbiome as a phenomenon in medicine has been overlooked in traditional medical education. Recent research by Rob Knight and others has demonstrated that the microbiome has a measurable imprint, a signature,  apparent in many disease states. I don’t want to oversell this – the microbiome may not be the most important feature in all diseases, but its impact is increasingly undeniable. The microbiome is vastly important in shaping the trajectory of a patient through health and disease

Mutualism misunderstood

There is a pervasive idea that the microbiome is a beneficial entity, a microbial organ that is as useful to you as any of your organs, such as your liver, or your heart. This idea – of a microbial organ – is commonplace in both the scientific literature and in media aimed at the lay public.  Where does this idea come from? As we have discussed in previous entries, the microbiome has an impact on our physiology, in a way that resembles a hormonal effect produced by an endocrine organ. This is a fact. There is another, deeper, idea with a long history that relates to evolution. This is the notion that two organisms that share a long relationship over evolutionary time will generally evolve to be of mutual benefit to each other – a mutualism to use the correct scientific term.

We have had a long, long history, indeed an intimate history, with a variety of microbes. We evolved in close association with microbes ever since the first multicelled creatures emerged on the planet. Certainly, for as long as humans have been on the planet we have lived in a microbial world. That shared history is an interesting and exciting thing to examine. But just because we have coevolved with these microbes does not mean that the relationship is always a benign happy co-existence. (Sorry to disappoint!) The best way to look at the current and past state of affairs with the microbiome is that of a wary alliance. Allegiances shift, coalitions form, and mutually beneficial outcomes occasionally happen. But cooperation frequently breaks down. That breakdown is what I am most interested in. As an emergency physician I see the outcome of that breakdown in patients presenting to the ER.

I see the breakdown of cooperation all the time when microbiomes turn bad – most obviously when patients suffer life threatening gastrointestinal obstruction and inflammation, but also when they suffer from hepatitis from fatty liver, when they get a kidney infection with a strain of E. coli from the gut, and when they have peritonitis from a perforated appendix.

The idea of evolving towards mutualism derives from this observation:  Microbes need a place to live. Microbes need to be fed. Humans provide that – by creating a habitat that is suitable for high densities of microbes, and by feeding them with food from diet, and with mucus secreted by intestinal cells. Thus, microbial survival and reproduction might be tied with keeping their host alive. Therefore, we might expect our microbes to be protective and friendly. The implication of this view is that the fitness interests of host (us) and microbiome are intertwined and in alignment. According to this idea, modern diseases are simply the result of the loss of Old Friends. Justin Sonnenburg has called this an extinction crisis in our intestines, caused by antibiotics, excessive hygiene, and ultra-processed diets. In this view, people living traditional lifestyles have co-evolved mutualist microbes, a garden of Eden in the intestine. The only problem with this notion of an intestinal Eden is it is wrong, like the noble savage myth that precedes it.

The Myth of Eden

When we look at the microbiomes of hunter gatherers or hunter horticulturalists, we find that these people have the most diverse microbiome on the planet. They have a close association with the natural world, very different from our hygienic and cloistered lives. As an example, Jeff Leach, who we have previously featured on this blog, has spent time with the Hadza in Tanzania, a group of hunter gatherers living a lifestyle thought to be similar to the ancestral human lifestyle. Leach famously was a recipient of a fecal transplant from a Hadza hunter gatherer, and documented changes in his own microbiome afterwards. People living in traditional lifestyles are protected from allergy, asthma, and obesity, associated with differences in their microbiomes. Another group, the Tsimane, are hunter horticulturalists living in lowland Bolivia. The Tsimane have been the subject of long-term study by groups led by Hillard Kaplan of the University of New Mexico and Chapman University and Michael Gurven of UC Santa Barbara. This work has culminated recently in a large scale study of the cardiovascular health of Tsimane men and women. Heart disease was found to be vanishingly rare in Tsimane as compared to people living an industrialized market economy lifestyle (us). The Tsimane who underwent CT scans of the chest revealed a strikingly low level of atherosclerosis (hardening of the arteries). Tsimane CT scans were not all good news; they revealed another common finding – tuberculosis. Tuberculosis is one of the most common infectious causes of death for Tsimane, a group that suffers from a very high infectious burden. This illustrates the tradeoff for people living traditional lifestyles and those living in industrialized societies. Traditional people have a low incidence of obesity, diabetes, hypertension, likely cardiovascular disease, and cancer. On the other hand they die frequently of infection.  In many Tsimane, tuberculosis is found in the lungs, in the mouth and in the gut. In some communities, it might be considered part of the typical microbiome. Kaplan and Gurven believe that Tsimane are spared from cardiovascular disease because immune cells that can cause inflammation in arterial walls (causing heart disease) are too busy responding to pathogens and fighting infection. This illustrates the two-edged sword of the microbiome. Most of us would not trade places with a Tsimane and accept the high level of infection in order to escape heart disease. Tsimane also die of gastrointestinal infections and have traditionally had very high parasite loads. Death, growth stunting, and disease happen because the human microbiome contains bad actors as well as good. Indeed, microbiomes have been going bad for a very, very long time.

We can see the evolutionary legacy of microbiomes gone bad in our genomes, and also in microbial genomes. There is no Eden; there is no perfect ancestral state. We cannot restore our microbiome to that of a hunter gatherer and return ourselves to perfect health. No, not even Jeff Leach. There is a tension built into the relationship between ourselves and our microbiomes. This is true even for the healthiest microbiomes. The alliance between ourselves and our microbiomes has a fatal flaw. The idea that fitness interests are aligned between human and microbe is not correct. Conflict is baked in. That genetic conflict explains many of the disorders that have their origin in the microbiome.  Stay tuned.

Copyright © Joe Alcock MD

Categories: Uncategorized

Joe Alcock

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

4 replies

  1. Great piece, Joe. I’m not an expert on the topic, but I’ve intuitively resisted conferring sainthood to our microbiota, in part because I, like you, have seen our “friends” turn against us. One point you might enjoy is that I frequently use the notion of a “wary alliance” (your words), or an “uneasy peace” (my words), to allay parent’s fears about about combination vaccines. Specifically, when they tell me they are worried that multiple vaccines might overwhelm their child’s immune system, I remind them that it is constantly parrying with the trillions of organisms that live on us and in us (with which we have a wary alliance), and so having to deal with a handful of vaccine antigens isn’t really a big deal.

    Best,

    Paul

  2. Great read! I have been trying to put to practice your theory on “conflict and cooperation” between self and non-self in my swine diets and believe that it has merit. Cooperation and reduction of conflicts between the host and the residing microbes may be one of the “secrets” to improving the quality of life and reducing morbidity and mortality. We still need modern medicine to help when the “conflict” raises it’s ugly head.

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