Intervju med Joe Alcock

Kontrollerer tarmbakterier appetitten vår?

For en rekke år siden begynte jeg å mistenke at mikrobene som lever i tarmene våre har en kraftig påvirkning på vår appetitt, inkludert hva slags matvarer vi finner appellerende og smakfulle. Denne mistanken oppsto som følge av visse observasjoner og erfaringer jeg hadde gjort meg, og utviklet seg over tid til en total overbevisning, da blant annet fordi hardtslående forskning på området ble publisert.

Spesielt viktig i denne sammenheng var en banebrytende artikkel ved navn “Hypothesis: Bacteria Control Host Appetites“, som ble publisert i 2013, samt en etterfølger året etter med tittelen “Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms“, Spesielt denne siste artikkelen appellerte til meg, da i stor grad pga. dens solide evolusjonsbiologiske forankring. Med et ønske om å dra oppmerksomhet mot og ytterligere utforske sammenhengen mellom tarmbakterier og appetitt, kontaktet og gjennomførte jeg i 2017 et intervju med hovedforfatteren – en kunnskapsrik mann ved navn Joe Alcock, som har mange spennende idéer, studier og undervisningsopplegg relatert til tarmmikrobiota og evolusjonsmedisin.

1. Who are you? What’s your profession and educational background?
I am an emergency physician and professor of emergency medicine at the University of New Mexico Health Sciences Center, and I am an adjunct professor in the UNM Biology Department, where I teach a course on evolutionary medicine. I have a background in evolutionary ecology, with a master’s degree in neurobiology and behavior from Cornell University. I received my MD from UCLA in 1997 and did my residency in emergency medicine at UNM.

2. How did you get interested in Darwinian/evolutionary medicine and the human microbiome?
My original plan was to become an evolutionary biologist. I changed gears during graduate school after I heard a talk by Paul Ewald, the author of the book The Evolution of Infectious Disease. He explained why microbes like Vibrio cholerae (the one that causes cholera) have evolved to be deadly pathogens, untamed despite a long coevolutionary history with humans. I found his argument very convincing and I was excited to study evolutionary questions that apply to human health and disease. Soon after, I decided to go to medical school hoping to contribute to the emerging scientific field known as evolutionary medicine, or Darwinian medicine.

3. What’s the main focus of your research?
My research uses evolutionary principles to understand cooperation and conflict in the human gut microbiome, specifically in relation to diet, stress and sleep. One of the things I am interested in is the effect of workplace stress on gut bacteria, and how that affects on-the-job eating, especially during night shifts. It is known that overnight shift work causes weight gain, obesity, and mood disturbances. My current research is exploring whether there is a link between those outcomes and the microbiota.

4. 2014, you published an excellent review paper entitled “Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms” in the journal BioEssays. Can you briefly summarize what that article is about?
We proposed in that paper that unhealthy food preferences, cravings and aversions may serve the evolutionary interests of our gut microbes. One possibility is that microbes hijack our nervous systems with neurotransmitters and appetite peptides that mimic our own. If so, our food choices may be less an issue of willpower, and more the result of our gut bacteria.

Many examples exist of microbes manipulating the behavior of host organisms, and we hypothesized that microbes influence eating behavior, in part by rewarding us for eating the foods upon which they depend, and by making us feel bad if we do not provide a constant supply of growth-limiting nutrients. In other words, the problems of overeating, obesity and diabetes may lie less in our genes or our brains, and more in the composition of our guts.

5. It’s becoming increasingly clear that the gut microbiota plays a critical role in the pathogenesis of obesity and the metabolic syndrome. Overeating and obesity seem to develop because of a vicious cycle in which the microbiota is a key component. Can you briefly describe what you consider to be the main mechanisms linking gut bacteria with obesity and body fat regulation?
One important mechanism is called “metabolic endotoxemia.” This idea, proposed by Patrice Cani, is that endotoxin, a product of gut bacteria, cause a dangerous reaction from the immune system that results in obesity. It has long been understood that obesity, especially the kind of obesity around your waistline, is accompanied by low grade inflammation. This inflammation is partly caused by endotoxin – a building block of bacterial cell walls – traveling from the gut into the bloodstream. Activation of pro-inflammatory receptors by endotoxin changes how energy is used in the body: glucose is stored as fat in the abdomen, and voluntary muscle energy decreases. In other words, gut microbes make us couch potatoes who are soft around the belly. Cani showed that these effects can be blocked with antibiotics, highlighting that gut bacteria are responsible for causing obesity. Others have shown that body weight and metabolism can be transferred from one animal to another with fecal transplantation, i.e. feeding poop from one animal to another. Another mechanism involves metabolites from gut bacteria, especially short-chain fatty acids (SCFA) that are used as an energy source by the body. A decade ago, it was thought that SCFA might make us fat by harvesting extra energy from the diet. Now we understand that SCFA may prevent obesity, in part by changing hormones that regulate appetite and hunger. In addition to SCFA, many other links between the gut and the brain have been recently discovered. Activity of the vagus nerve, a “superhighway” of information between gut and brain, is a means by which bacterial products in the gut affect the brain and behavior. Not surprisingly, vagus nerve activity also affects hunger, satiety, and obesity.

6. Can you briefly explain how gut microbes are able to exert control over their host’s eating behavior and appetite? (Current theories, plausible mechanisms, etc.)
Short chain fatty acids generated by fiber fermentation by gut bacteria trigger changes in nervous system functioning and behavior. One way they do this is by activating a hormone – GLP-1 – that affects whether we feel full or hungry. In another example, bacteria like E. coli also produce a protein (ClpB) that is nearly identical to a hormone made by humans that regulates appetite. ClpB appears to cause an increase in satiety, or fullness, but also results in more frequent eating behavior. That example also highlights the fact that bacteria manufacture neuropeptides and hormones that are nearly or exactly the same as our own hormones and reward neurotransmitters. It is a mystery why bacteria do this, but one possibility is that they take part in manipulation of our nervous systems. Along those lines, many studies have shown that gut bacteria induce anxiety and depression-like behavior in animals and humans. Possibly, your mood is controlled at some level by the microbes in your guts. How does that affect eating? Anxiety can result in stress eating and is a plausible way that microbes influence our behavior. Interestingly, several studies have shown that probiotics lessen anxiety and depression. Those results are a clue that we can control mood, and possibly eating behaviors, by targeting gut microbes.

7. Health is contagious. Microbes are shared between organisms (e.g., humans) via various forms of contact. This means that diseases and health conditions characterized by dysbiosis likely are “contagious”, in the sense that microbes can be transferred from sick individuals to healthy ones. By itself, this transmission may not be sufficient to make the latter people sick; however, it could contribute to driving the development and progression of illness. In your paper you make the case that obesity may be among the health conditions that can be spread via this route. Can you briefly explain your current thoughts on this issue?
We humans are social animals. In addition to sharing social interaction, we also share our microbes at a constant low level. Much of that exchange probably involves skin microbes, but close contact, kissing etc., also transfer mouth and gut bacteria. Since this is the case, gut microbes involved in chronic disease might be contagious, possibly. Animal studies have shown this sort of dynamic when obese mice are housed along with lean ones. Sometimes, the “obese” microbes win, making lean animals fat. Sometimes, it works the other way and the “lean” microbes dominate both animals. In at least one instance, a woman who received a medical fecal transplant from her obese daughter rapidly became obese after becoming inoculated with the gut microbiota from her daughter. This does not prove that microbes transfer causes obesity in humans, but it is consistent with the animal experiments that show similar effects.

8. Do you think it’s primarily the colonic microbiota that’s involved in regulating host eating behavior, or are microbial communities associated with other body sites (e.g., small intestine) involved as well?
Good question. We have also studied the effect of microbes in the mouth on food preferences. Oral microbes respond to food intake; they are positioned near taste receptors. We have not yet published these results, but we have not yet found oral microbes that affect eating, at least so far. It is possible that microbes in other locations – the small intestine or colon – are more important.

9. What are the evolutionary mechanisms underlying the connection between gut bacteria and host eating behavior?
We have focused on the idea that there are conflicts of interest between microbe and human in the gut. These conflicts arise from the fact that we do not share genes with our microbial houseguests. Even though nonrelated organisms can and do cooperate sometimes, conflict between unrelated organisms is unavoidable. In the case of gut microbes, what you eat has enormous effects on the which microbes can grow and proliferate. These differences in reproduction (or fitness) mean that any microbes with a capacity to affect a human’s eating behavior would have an enormous fitness advantage. We expect those sorts of things to evolve, and we would also expect that humans would evolve ways to resist manipulation. In other words, there might be a constant tug of war between ourselves and our microbes involving appetite hormones, activity in the gut, and in our brains.

10. What would you recommend to someone who struggles with cravings for unhealthy foods, binge eating, and/or other problems associated with impaired appetite regulation?
I cannot offer any iron-clad advice, especially since we are at the beginning stages of this research. My research partners are studying gut microbes in people with eating disorders with the goal of findings ways to treat them. For now, I would recommend keeping a close eye on research involving probiotics. Also, studies have shown that certain short chain fatty acids, and eating fiber-rich diets that produce them, can reduce food cravings. These diet strategies need to be tested in people who have eating disorders, such as those with binge eating.

11. Dysbiosis and loss of microbiota diversity seem to play a critical role in the pathogenesis of many modern diseases and health problems. What can we do to repair our damaged microbiomes? In general, which strategies/interventions do you think would be the most effective? Also, are there any drugs/products/treatments that haven’t become widely available yet that you’re looking forward to seeing on the market?
Having a diverse gut microbiome that includes a wide variety of microbe species appears to be very important to human health. We speculate that having a diverse microbiome prevents overgrowth of “weed” species that are harmful to human health. Preserving a diverse gut microbiome should be a goal of medicine. Unfortunately, few studies have been done that measure microbiome diversity over time, so there is an urgent need to do more studies on this topic. We do know that diets low in processed foods and simple carbohydrates are associated with more microbiota diversity. Living in rural areas, being exposed to farm animals, and pet keeping also seem to increase microbe diversity. Finally, it is important to avoid unnecessary antibiotics – that requires buy-in from the medical community. We are working on that!

12. I’ve gathered that you are currently teaching evolutionary medicine to medical trainees, undergraduates and graduate students in Biology and Anthropology. What is your experience with teaching evolutionary medicine to these groups? Do you feel students are excited about this field and eager to learn about it?
Many of my students tell me they are excited about evolutionary medicine, and they tell me that this topic stimulates their thinking about ourselves and our health. It is easy to get students excited, since evolutionary concepts in medicine offer concrete, real-world, and innovative insights into health care. It might be slightly more difficult to teach medical students who are already deep into their medical education. Medical students are distracted by the many competing demands on their time, but the ones who take my course are self-selected and very interested in the practical possibilities of evolutionary medicine.

13. What do you consider to be the most important things Darwinian/evolutionary medicine has to contribute to our current medical system?
We need to start thinking of ways to harness evolution for our benefit. Many important examples of evolutionary medicine involve evolutionary harms. For instance, microbes evolve resistance to antibiotics, cancer cell lineages evolve ways to resist the effects of chemotherapy. We can use evolution as a force for good in medicine too. Public health strategies can slow or reverse antibiotic resistance. Creative solutions can leverage evolutionary concepts to make patients healthier. Some current strategies are in line with the “Less is More” movement in medicine, like watchful waiting for self-limited infections and approaching certain slow-growing cancers with a containment approach. By being more selective in using powerful tools like antibiotics and chemotherapies, we avoid unintended consequences and contain evolutionary processes that happen in deadly diseases.

14. What would you do if you were put in charge of improving public health? What would you focus on?
This is a great question. I would focus on unnecessary antibiotic prescribing – in part because we know that microbiome diversity is so important. We need to do more research in finding solutions that balance the public interest (preventing antibiotic resistance) and individual concerns (avoiding infectious disease and preventing harmful changes to the microbiome). I would also redouble our efforts to prevent opioid overuse and abuse. This too has an evolutionary dimension. Our brains are adapted to sense pain, and we compensate with increased nerve activity when pain is dulled by disease or medicines. With chronic opioid medication use, our bodies amplify the pain response. This “hyperalgesia” makes pain sufferers need more and more drug, and too many people end up dead because of it.

15. How do you envision the future of Darwinian/evolutionary medicine? Do you think evolutionary theory will soon be widely incorporated into medical training and/or practice, or do you think the evolutionary approach will continue to take a backseat to the conventional medical approach, which largely focuses on the molecular and physiological mechanisms underlying disease?
Medical progress is uneven, and progress is expensive. In my view, a marriage of evolutionary theory and conventional molecular/physiologic approaches will make biomedical research and health care more efficient, cost-effective, and productive. It might take a high-profile breakthrough to more fully integrate evolutionary biology with conventional approaches, but that combination is the future of medicine.

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