Of Humans and Our Microbial Guests: A Dynamic and Living Balance

Stephen L. Talbott

RSS Feed for Biology Worthy of Life Life:    

Posted: December 9, 2014   (Article 25)

I always find it amazing to see how powerfully biologists yearn to identify controlling causes in the organism. The desire persists despite the fact that at least since Immanuel Kant’s 1790 Critique of Judgment* any biologists who have actually bothered to think about such things have recognized that the organism is typified by a mutuality, ambiguity, and circularity of cause and effect. A cause that appears to “control” something in one context might just as well appear to be “controlled by” that thing in a different context — or even in the same context.

This is part of the reason why Kant declared that “there will never be a Newton of the blade of grass”. Organic activity cannot be elucidated in terms of causal constants. He may have been wrong about the impossibility of a fully scientific understanding of organisms (see the note here), but there is no question that he was right about the inability of the usual scientific approach to give us any adequate understanding of organic performances.

To elaborate ever so slightly: the self-assertive unity of every living creature precedes and governs the causal relations among its parts. The organism begins its life as a functioning whole and, through coordinated internal differentiation, produces its own, ever-changing parts. Moreover, this organism continues to coordinate and pattern the play of relations among its parts — a fact obvious enough if we simply look at an octopus or domestic cat carrying on with its life. And it all happens in relation to aim and need. Physical laws (and the “causal factors” we associate with them) are enlisted in the service of current needs, not the other way around.

This strongly suggests that the natural order of organic explanation is not from below upward — from the parts to the whole — but rather from above downward. In other words, it turns conventional notions of scientific explanation upside down. And yet, however often acknowledged, this evident truth seems to have little effect upon the mindset of biologists, as revealed in their routine communications and technical papers.

Virtually every field of research illustrates the perplexities of causation when we attempt to offer biological explanation in the usual way. One topic recently drawing my attention has to do with the diverse roles of microorganisms in human life, health, and disease. The stunning discoveries in this field, now occurring at a rapid rate, can usefully illustrate the crucial role of context (a word closely related to “whole”) in transforming causal relationships.

My Organisms and I

A rapidly swelling literature is testifying to human dependence upon the diverse microorganisms — collectively, the microbiome (or microbiota) — we play host to. By common admission, we have hardly begun to figure out how these microorganisms affect us — or, I should perhaps say, how they are part of us. But we know enough to appreciate that we could not live normally and healthily (if we could live at all) without them.

The bacteria and other microorganisms in our gut are said to outnumber the cells in our body by a factor of ten to one, and their collective genome is orders of magnitude larger than our “own” genome. Remarkably, “one-third of the metabolites in the blood are coming from gut bacteria”, according to Phillip Hylemon, a microbiologist and immunologist at Virginia Commonwealth University in Richmond (quoted in Bourzac 2014*). Altogether, our microorganisms “function as another organ, complementing and interacting with human metabolism in ways not fully understood” (Gravitz 2012*).

We now know, for example, that the gene expression of our intestinal flora plays an important role in our lives. The fact that Japanese can digest seaweed carbohydrates more easily than North Americans appears due in part to horizontal gene transfer among microbes. This has given the Japanese intestinal microbes the ability to produce two enzymes important for digesting seaweed carbohydrates. Such interactions raise the question whether “human genetic effects on diet might be overwhelmed by the bacteria we carry...‘It’s something I use in my slide presentations now to worry geneticists’” (Eisenstein 2010*, quoting Jeremy Nicholson, a biological chemist at Imperial College London).

But beyond this sort of effect, microorganisms can directly play into the host organism’s genetic performances. When a mouse is suffering a listeria infection, gut microbes alter the expression of the mouse’s microRNAs in the intestinal ileum. That is, when an infected mouse possesses normal intestinal flora, its own microRNAs are expressed differently than they are in infected mice lacking normal microbiota (Archambaud et al. 2013*). This, of course, has implications for all the gene expression influenced in turn by the wide-ranging regulatory activity of those microRNAs.

In a field far away from listeria infections, a paper in the December 2013 issue of Cell had the rather surprising title, “Toward Effective Probiotics for Autism and Other Neurodevelopmental Disorders” (Gilbert et al. 2013*, reporting on work by Hsiao et al. 2013*). The authors of the original research worked with mice in which an autism-like condition had been induced. The mice had “reduced intestinal integrity through altered gut bacterial community”, and the bacterial metabolites varied considerably from normal mice. Moreover, when the mice “were fed the probiotic, Bacteroides fragilis, a gut microbe with positive effects on the immune system, the abundance of 34% of these metabolites changed back, gut barrier integrity was improved, the gut-microbiome was restored to a state similar to control mice, and a number of ASD [autism- spectrum disorder]-related behavioral abnormalities were ameliorated”.

Perhaps rather ambitiously, Gilbert and co-authors write:

Several reports indicate that probiotics can treat anxiety and posttraumatic stress disorder in mouse models ... Therapies that target our microbial side may hold the key to making progress against a wide range of notoriously difficult psychiatric illnesses.

We can hope so. But, as we will see in a moment, it’s always wise to beware the scientist whose imagination is free to run riot with a new kind of “cause” — especially if it is supposed to be a curative one.

From mucus-eating
gut bacteria to
fecal transplants

Overall, the editors of Science* were impressed enough by recent investigations of the microbiome to include the collective findings in their top “breakthroughs of the year” for 2013. They cite research linking gut microbes to obesity, to some cancers, and to severe malnutrition in children with the Kwashiorkor syndrome. Regarding obesity, the journal writes:

In a study of obese mice, the animals lost weight and had better insulin control — even on a high-fat diet — when researchers boosted the amount of the mucus-eating gut bacterium Akkermansia muciniphila in their guts. Obese mice, as well as obese people and people with type 2 diabetes, typically have reduced numbers of these bacteria.

You’ve doubtless heard of the sometimes dramatic therapeutic benefits produced in humans by fecal transplants. For example, a potentially dangerous form of infectious diarrhea associated with the bacterium, Clostridium difficile, often follows upon microbiome-disturbing antibiotic treatment, and frequently becomes recurrent. People in health treatment facilities are increasingly liable to the affliction. Fecal transplants for such patients — much more effective than targeting the problem with an antibiotic — are sometimes described as almost miraculous in their benefits.

It may not be the most pleasant thought, but such success usefully directs attention to our essential companionship with creatures about as far removed from our usual sense of self as they could possibly be. As the editors of Science put it: the recent studies “make it increasingly clear that personalized medicine will need to take our microbial guests into account to be most effective”.

We might indeed ask whether any absolute distinction can be made between host and guests. Do gut microbes belong less to our own life than, say, our fingernails and hair — or even the cells floating in our bloodstream? At a different level: when does my airy environment become part of me? When it’s the fairly intimate layer of humidified and otherwise chemically distinctive air that immediately surrounds my skin and that I tend to drag along with me? Or when it resides in the hollow spaces of my lungs? Or when various portions of it have become blood gases?

Like all other organisms, we humans are in continual flux with the world around us, making it our own in varying degrees while also placing our imprint upon it. Our skin is both a barrier protecting us from the world and a home for diverse “foreign” microbial populations required for our own health (Hannigan and Grice 2014*).

There is no mechanistic
control of living
organic intentions

Despite the interwoven contextuality of ourselves and our microorganisms, the overwhelming temptation is to “thingify” every particular microbiome — that is, to treat it as if it were a statically definable entity with fixed causal significance, allowing us to say, “This one is healthy, and that one is unhealthy”. Science writer Ed Yong recently had an excellent commentary on this in the New York Times. Under the title, “There Is No ‘Healthy’ Microbiome*”, he adroitly illustrates how “the microbiome is complex, varied, ever changing and context-dependent — qualities that are the enemies of easy categorization”:

“Healthy” microbes can easily turn rogue. Those in our guts are undoubtedly helpful, but if they cross the lining of the intestine and enter our bloodstream, they can trigger a debilitating immune response …

Conversely, “unhealthy” configurations of microbes can be normal, even necessary. Ruth E. Ley at Cornell University and colleagues demonstrated this in dramatic fashion when they found that microbiomes go through a huge upheaval by the third trimester of pregnancy. They end up looking like the microbiomes of people with metabolic syndrome — a disorder that involves obesity, high blood sugar and a higher risk of diabetes and heart disease. These communities might indicate someone on the verge of chronic disease — or merely motherhood. Packing fat and building up blood sugar makes sense when you are nourishing a growing fetus.

Here is another example. Common medical wisdom says that healthy vaginal microbiomes are dominated by the acid-making Lactobacillus group that creates an inhospitable environment for disease-causing microbes. But Larry J. Forney at the University of Idaho and colleagues found that a quarter of women didn’t fit this pattern, despite being perfectly healthy. They also showed that their vaginal communities can change dramatically and rapidly, even over a single day, flitting in and out of states that are supposedly conducive to disease, but with neither clear causes nor ill effects.

It takes little reflection to wonder, “How could we possibly classify a microbiome as if it were a given thing with fixed qualities?” After all, it consists of countless organisms, each pursuing its own kind of life while interacting moment-by-moment and in endlessly complex ways with many other organisms — all in a larger context that is infinitely variable. As Yong puts it, “Your microbiome has shifted since your last meal or sunrise”. It’s as complex and dynamic as any ecological landscape.

None of this would come as any great surprise to the community of biologists. And yet ...

A good “culprit” in biology
is hard to find

An article in the November 21, 2014 issue of Science analyzes the “Dialogue Between Skin Microbiota and Immunity” (Belkaid and Segre*). Focusing on the relation between microbes and inflammation, the authors are admirably cognizant both of causal ambiguity and context-dependence:

Whether alterations of the microbial composition described in various disease states are the results of inflammation rather than the cause remains difficult to evaluate. Furthermore, an important point to consider when exploring the potential role of the microbiota in inflammation is that pathogenicity is, in most cases, a contextual state. Indeed, the capacity of a given microbe to trigger or promote disease is highly dependent on the state of activation of the host, the host’s genetic predisposition, the localization of the particular microbe, or the coexistence of other microbial members.

“Ah”, one thinks. “These authors really do ‘get it’”. Then comes the next sentence: “Thus, the culprit microbe may remain elusive in most cases”. “Culprit”? Elusive indeed! Why not take that fact seriously? What just now happened to all those other contextual factors without which the inflammation-causing microbe is not an inflammation-causing microbe? We can have all the significant context we want, it seems, but there still has to be an ultimately responsible cause (a “bad guy” in the case of disease) which, of course, becomes the desired point of control.

It’s not an innocent way of speaking. It distracts from whatever contextual whole is under consideration, and it is this whole that needs to become healthy. Biologists are quick to condemn the health fads and nostrums that take such ready hold of large swaths of the public — take hold, that is, of people who have been told over and over again by those same biologists that their ills must have a pinpointable cause, otherwise known as the “culprit”. Given this simplistic notion of causal guilt, it’s hardly a surprise that many people go after imagined causes simplistically.

Such impoverished thinking is what seems to have impelled one individual to self-administer a fecal transplant with a Turkey baster. As Yong describes the matter, this gentleman figured that the Hadza tribesmen of Tanzania, from whom he managed to procure his “medication”, were much healthier than we degenerate Westerners — never mind the fact that the Hadza microbes presumably reflect the requirements of an environment radically different from that of Brooklyn or Peoria.

Perhaps we glimpse here the makings of a new fad. If so, then come next year you might want to keep an eye on the preparation of your Thanksgiving turkey. You’d hate for someone to grab the wrong baster¹.

To Conclude on a Note of (Dashed) Hope ...

Back in August William P. Hanage, an associate professor of epidemiology at the Harvard School of Public Health, wrote a piece in Nature entitled “Microbiome Science Needs a Healthy Dose of Scepticism*”. Hanage does not doubt the importance of discoveries about the microbiome, but he is worried that the public, and perhaps also some scientists, may be carried away. Companies, he says, are already offering “personalized analysis of the microbial content of faecal samples, promising consumers enlightening information” — this despite the fact that “Separate analyses from the same person can ... vary considerably, even from the same stool sample”. As for fecal transplants: “With how-to instructions proliferating online, desperate patients must be warned not to attempt these risky procedures on themselves”.

These concerns seem well-stated. Hanage remarks how previous enthusiasms for this or that “ome” — the genome, proteome, metabolome, and epigenome — “have faltered after murky work slowed progress”. He continues:

Technological advances that allowed researchers to catalogue proteins, metabolites, genetic variants and gene activity led to a spate of associations between molecular states and health conditions. But painstaking further work dampened early excitement. Most initial connections were found to be spurious or, at best, more complicated than originally believed.

The history of science is replete with examples of exciting new fields that promised a gold rush of medicines and health insights but required scepticism and years of slogging to deliver even partially.

Yes, and this gold rush mentality issues from the mistaken conviction that one or another body of research has put into our hands a set of levers and control knobs for managing the machine-organism. The “years of slogging” then naturally follow from the fact that the organism, refusing to behave like a machine, continually reorganizes itself and its causal processes around its own agenda. Biologists are forced to revise every proposed causal relation as new contexts are encountered in the laboratory or in the wild.

This is not quite Hanage’s line of thought, however. He offers a few “crucial questions” for microbiome researchers, and this is one of them:

What is the mechanism? All scientists are taught the catechism that correlation is not causation, but correlation almost always implies some sort of causal relationship. We just don’t know what it is. We must determine it with careful experiments … We can now design experiments to precisely define actions of components of the microbiome, for example by reconstituting communities but leaving out specific taxa … A return to a reductionist approach is essential if we are to pinpoint both whether the microbiome affects human health, and exactly how it does so.

The reader will be forgiven for responding, “How long, O Lord?” Hanage seems willing to encourage the same simplistic reduction he was initially bemoaning. No one will quarrel with the need to learn, and learn precisely, all we can about every element bearing on the life of the organism. But the complex contextuality of life — the distinctive way in which an organism pursues its own ends — will not yield its secrets to an ever more determined search for isolated and well-defined causal relations. The microbiome in its relation to the whole organism will never be understood merely by identifying the “effects” of individual microorganisms in particular contexts and then summing those effects. This is to ignore the central role of context itself — in particular, the coordinating and directing activity of the organism as a “willful” whole.

To proclaim, as every biologist seems to do these days, that “context matters”, is to acknowledge (whether one knows it or not) that there is a kind of causation directed from the larger whole to its parts. These parts cannot even be fully defined except in relation to the whole, and therefore cannot be seen as the source of determinate effects in their own right. After all, by saying that “context matters”, the biologist is surely claiming that it somehow matters “causally”.

But to talk about causation that runs from a whole (context) toward its parts requires us to say something about the identity and character of this causally effective whole — a difficult undertaking to which biologists seem pathologically allergic. This is tragic for biological understanding, since it is certain that the kind of causal explanation grounded in the activity of a whole differs radically from the usual part-to-whole reasoning. (See under “Further information” below, and also the “Tag” links at the beginning and end of this article.)

All this desperately needs explicit reckoning with. But, as near as I can judge from the literature today, most biologists seem incapable of rousing themselves toward any such reckoning.

Notes

1. As I was completing a draft of this article, a piece came out in Nature (Bourzac 2014*) dovetailing with nearly everything I’ve been saying. A series of brief extracts will give you the idea:

• “Imbalances in gut bacteria have been implicated in the progression from liver disease to cancer”. (Study in mice.)
• “Studies have found that people with non-alcoholic fatty liver disease have a different composition of bacteria in their gut from healthy individuals”.
• “It could be possible to stop liver disease from turning malignant by targeting microbes in the gut”.
• However (citing remarks by immune system researcher Gyongyi Szabo at the University of Massachusetts Medical School in Worcester), “changes in the microbiome are not sufficient to cause disease, she says. Instead, she sees an emerging picture of liver disease and cancer as a process in which various factors — including a high-fat diet, alcoholism, genetic susceptibility and the microbiome — can each contribute to the progression from minor to severe liver damage, and from severe liver damage to cancer”.
• “As blood leaves the intestines it passes through the liver, carrying nutrients extracted from our food. It also carries our own digestive chemicals as well as fragments of the bacteria that live in the digestive system (such as bits of DNA and cell walls) and their metabolic by-products. Some of these by-products help us to access energy and nutrients in food, but some are toxic. And a few might provoke an inflammatory immune response in the liver — if the inflammation becomes chronic, cancer can be the consequence”.
• On an experiment to induce cancer in mice: “For the disease to occur, the mice needed all three factors: an active immune pathway, the harmful bacteria and the carcinogen”.
• The bacterial products thought to be the “culprits” in this experiment (as the article puts it) are also produced by bacteria considered helpful, making a therapeutic attack against the supposed culprits problematic.
• One researcher, looking for the “mechanism” explaining the experimental results, points to “an out-of-balance microbiome [that] promotes a constant state of inflammation, which can contribute to cancer progression”. Of course (not mentioned in the article), a system that is out of balance doesn’t give us well-defined causal mechanisms. Nevertheless, researchers are determined to find “the exact mechanism of cancer progression and the exact cell type in the liver” targeted by the bacterial products.
• Other bacteria produce a different product thought to be contributory to liver cancer. This product is normally present in all people at low levels, but it can become a problem when (again) an out-of-balance condition occurs. “The ability to stave off the disease seems to depend on maintaining the appropriate microbial balance”.
• And finally, this worthy caveat: “Not everyone is convinced that individual bacterial species are to blame. Some researchers point out that dysbiosis [microbial imbalance], and therefore cancer risk, involves multiple strains of bacteria. And the bacterial mix can vary from person to person, meaning it is unlikely that scientists can pin all responsibility on a single species”.

Much of that, be aware, relates to mice and, at this early stage of investigation, is undoubtedly extremely simplistic compared to the reality.

This document: https://bwo.life/org/comm/ar/2014/microbiome_25.htm

Steve Talbott :: Of Humans and Our Microbial Guests: A Dynamic and Living Balance