Gerard E. Mullin, MD: The Influence of the Gut-Brain Axis on Health

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Gerard E. Mullin, MD, an internist, gastroenterologist, and nutritionist, is associate professor of medicine at Johns Hopkins University, where he also directs Integrative GI Nutrition Services. He is the author of the recently released book, The Gut Balance Revolution (Rodale).1 He lives in Baltimore, Maryland. (Altern Ther Health Med. 2015;21(suppl 2):73-76.)


Alternative Therapies in Health and Medicine (ATHM): You have written about the importance of the gut microbiome in the development and regulation of the hypothalamic?pituitary?adrenal axis, or HPA axis. Would you discuss this relationship and how our understanding of it is developing?

Dr Mullin: The gut microbiome does affect development of the HPA axis; it actually helps shape its formation early in life. The HPA access is really the body?s way of knowing how to react to external environments. For example, if you felt that you were under stress, internally, that would translate biochemically through the HPA axis. Eventually, your sympathetic nervous system would be triggered and that would get your body prepared for a response to counteract the perceived threat?the tiger chasing you, or one of those analogies. That is how one would react?through the HPA axis, which connects the brain to your sympathetic nervous system to your adrenals. You mount a hormonal response through that axis.

Research shows that the gut microbiome not only influences the development but, in its own way, can regulate its activities. The body is literally surrounded and bathed in gut microbes, which influence local and systemic physiology. What is also interesting is that every body has a unique composition and patter of the microbiome, which is akin to having a unique fingerprint. In discussing the body?s microbiome, we try to specify the gut, since it houses the vast majority of the body?s microbiome. The gut microbiome itself is very interesting?the way it controls our behavior, our moods, and our emotions. There is an identifiable bidirectional communication between the gut and the brain, which is also called the gut?brain axis. How these gut microbes control our appetite by influencing gut hormones that communicate with the brain is one example of these gut bugs influencing our behavior, which may impact our body weight. Examples of hormones include ghrelin and the glucagon-like peptides (GLPs), GLP-1, GLP-2, which have close linkages to gut microbial biodiversity. These gut-derived hormones, which are under gut microbial control, regulate insulin sensitivity, satiation, the rate of gastric emptying, ghrelin, GLP-1, GLP-2, and appetite?which plays a key role in influencing our energy consumption. Collectively, all these gut hormones ultimately affect our body weight and are controlled by the gut microbiome. To many, this all sounds like the movie the Matrix from 1999: invisible beings that control us in an altered reality.

A topic that I heavily emphasize in The Gut Balance Revolution1 is how we can control the biodiversity and heath of our gut ecosystem by the way we eat! Fibrous foods that are fermented by gut microbes and their byproducts influence gut hormone expression. So fiber-poor junk foods are metabolized into byproducts that foster the growth of fat-forming microbes and stifle production of these aforementioned gut hormones that favor a lean metabolism.
As you now see, many things are regulated through the gut microbiome. What is interesting is that the way that we react to different external environments?stimuli?also are regulated by gut microbes. Whether we view an event as being stressful and/or emotionally nonstressful, there is regulation of the HPA axis through the gut well after its developmental period early in life.

You have to realize that a lot of the research that reports these connections is from the usual laboratory animal experiments?they are not always easy to do in humans?in lab mice and rats under controlled environments, where you can present these different stimuli either sterile or having a gut microbiome and see how they react differently with different microbes.

A big area of investment, I know, for National Institutes of Health, or NIH, purposes?but I would also assume commercially?is to explore how the gut microbiome can change behavior, can change dynamics in the brain and cognition, and maybe even affect the development of different conditions or mitigate different conditions, like Alzheimer?s, dementia, Parkinson?s, and so on. You can change the lives of millions of people if you know how to re-engineer the gut microbiome in a more favorable manner. The research is really fascinating and it has all taken place within the last 5 years?this explosion in research examining how the gut microbiome accesses the brain.

ATHM: How does the brain influence the gut?

Dr Mullin: The brain has many ways to influence gut microbial balance by eliciting stressful biochemicals, which stifle friendly flora, induce inflammation, and loosen intestinal lining integrity?which is a disease-promoting combination. It is hard to get healthy and lose weight when the brain is bombarding the gut?s nervous system with stressful signals.

ATHM: At what stage is the research on the gut?brain axis and weight regulation?

Dr Mullin: Researchers are examining the gut-derived mediators that influence brain behavior. The gut itself makes a number of factors that cross into the brain: biochemicals, hormones, and neurotransmitters. It is thought that the microflora not only regulates gut-derived hormones but also regulates neurotransmitter function. Yes, gut microbiomes also regulate the gut?s production of serotonin?the neurotransmitter that influences mood. Over 95% of the body?s serotonin is made in the gut.

The developing serotonergic system appears to be influenced prior to the emergence of a stable adult-like gut microbiota. Likewise, decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The gut microbiota are known to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress responsive, and they are utilized in the brain?gut axis. Certainly, inflammation, which is modulated by gut microbes, also plays a role in cognition, mood, and behavior. Obviously, the gut microbiome plays a central role in whether we ultimately have systemic inflammation, and its severity can be either mitigated or promoted by the gut microbiome.

Gut microbes have been shown to have a controlling influence over emotions, behaviors, mood, and mating preferences, and imbalances of gut bacteria have been linked to autism spectrum disorders, schizophrenia, depression, anxiety, ADHD, other behavior and mood disorders, migraines, and headaches. Now, I would say much of the research is derived from laboratory animals and in humans is ?associative.? In the next 5 years, research will be aimed at causality and therapeutics. If you manipulate the microbiome, can you manipulate behavior? That research is being done, as well, although it is more recent. This line of research could end up being a shot in the dark, because it is hard to predict which probiotics will affect an individual?s behavior. Experts call this area ?psychobiotics.? It may be largely individualized, at least in animals and in certain humans. For example, in autism, there are studies on the effects of probiotics?some favorable, of course, some not. It is the same with anxiety and depression. People are looking to mitigate those mood disorders through probiotics and even fecal transplantation.

While I applaud this area of research, the suggestion that a concoction of microbes or engineered bacterial byproducts administered either orally or rectally may improve autism, or neurodegenerative diseases, is likely an avenue for investigation. The danger is to adopt the mantra that magic bullets can solve life?s problems, which is propagated by the pharmaceutical industry and even the supplement industry, or green pharmacy. Scientists and clinicians who help patients approach balancing the gut flora understand that probiotics alone do not achieve lasting benefits and have variable content and product quality control.

Finally, fecal transplant has been reported to cause autoimmune disease and more, which has caused the FDA to highly regulate this controversial approach to therapy. Achieving gut balance requires dietary restriction of proinflammatory and sugary rich foods that disrupt the gut ecology followed by the introduction of prebiotic-fertilizing food and seeding the gut microbiome with probiotic foods such as kefir, sauerkraut, yogurt, and others. As Hippocrates, the Great Greek Physician and father of Western medicine once said, ?Let food be thy medicine and medicine be thy food.?

However, the fact that observing some efficacy means that manipulating the microbiome may have a beneficial outcome. That is where the research is, currently. It is more in the associative, forward stages, in terms of linkage and in terms of the mediators and ways to manipulate the biome to improve outcome. We are at the beginnings of that.

ATHM: When considering the range of gut microflora that can be successfully cultured and supplemented, is that a small fraction of the total population?

Dr Mullin: Interestingly, that is where the ?revolution? came along?all based on the technology derived during the human genome project. Scientists used pyrosequencing and other methods to sequence out the microbiome like they sequenced out the genome. They found at least double the number of organisms present in the gut microbiome, if not more, using those methods because culture is so unreliable. This technology also expanded our knowledge about ecosystems, biodiversity, and patterns of microbial ecology and, coupled with metabolomics, have revolutionized our understanding of the gut microbiome. We are learning more and more about the biome. Research in the biome has exploded, in part because now we know more or less what is in there.

ATHM: You mentioned that many upstream effects on the brain that begin in the gut microbiome are related to its metabolites. Even if you were to take a probiotic supplement, wouldn?t the metabolites be affected by a particular person?s environment and also by what they are choosing to feed their gut microbiome?

Dr Mullin: I would say yes to both. In fact, I think that is a great point. What you feed the gut microbiome, whether you are taking probiotics or not, will certainly shift the biome in a more biodiversified and sustainable fashion if you are eating good, fiber-filled whole foods that are prebiotic?which fertilize these health promoting gut microbes. But if you are eating junk, then you are going to have a less biodiversified microbiome that is going to result in a less robust ecosystem with less of the friendly flora that are making the metabolites that are more desirable for health and weight control.

This raises a larger question about the use of dietary supplements for weight control. Is there a magic pill to lose weight? No, but results of a national survey published in 2008 found that 33.9% of adults who had made a serious weight-loss attempt had reported using a dietary supplement. Weight-loss supplements remain a booming industry in the United States, with overall retail sales in 2009 of 26.9 billion. Unfortunately weight loss supplements do not demonstrate good evidence to support their use and have potential toxicity. This is why I reject the notion of aimlessly taking probiotics to promote weight loss. In fact, I am disturbed by a manufacturer who was recently sued for selling products with false labeling promoting probiotics for weight loss.

The good news is that we can shift the gut microbiome to influence health and weight control. The gut microbiome gets laid down in the first 6 months to 2 years of life, but it can shift with diet, both good and bad. If you are looking to prevent and/or modify an illness through the biome, you can shift it in a favorable direction. Not to be fatalistic, but if we could not shift the biome?that our destiny is in the way we were born and the genes we have determine it?then what is the point of modifying diet if we can?t change that destiny? But we can, for good or for bad. In The Gut Balance Revolution,1 I outline a 3-step process to first reboot the gut microbiome to cut off the supply of the fat-forming microbes, then rebalance the gut flora by a combination of prebiotic fertilizing food to foster the growth of good gut microbes in tandem with fermented food, which actually contain the good gut microbes as a 1:2 combination. Finally the last step is a maintenance phase by eating a good whole-foods, anti-inflammatory diet while allowing flexibility for socializing.

ATHM: The digestive tract is home to a significant number of neurons and neural cells. How does the interaction between the microbiome and the neural system within the digestive tract affect the gut?brain relationship?

Dr Mullin: It is a bidirectional relationship. In other words, the brain itself can affect the gut microbiome in a number of ways as I briefly touched on earlier but will do so in more depth. It can affect the motility of the gut. Gut motility can affect the populations, biodiversity, and health of the gut microbiome. If the motility slows down, that results in more pathogenic bacteria that build up and can adversely shift the biome.

Also, if one is under a condition of stress, the microbiome is adversely affected because the microbiome becomes less and less biodiverse. Also, the gut lining becomes more permeable, and, therefore, the toxins of the microbiome?the bacterial toxins?can then circulate and cause systemic inflammation, which can affect mood and behavior and unfortunately is responsible for chronic inflammatory diseases afflicting over 50% of the US population. It becomes a vicious cycle. Someone becomes stressed or someone is anxious, and that will affect the microbiome in a negative way. In turn, that will cause more cytokines, and other inflammatory factors feedback on the brain and the person becomes stuck, from a behavioral-mood point of view, and sicker systemically.

The brain can affect microbiome and the microbiome can affect the brain. Thus, the gut?brain axis involves neural circuits, neurohormonal circuits, and neurotransmitter circuits. It can go through inflammatory circuits. That is what the science is looking at: which circuits are being utilized and how to intervene. At the end of the day, you will look at 2 schools of thought.

One is to manipulate the biome directly, through bacteria, and that is in the form of probiotic as discussed earlier. Under that, there is a subdivision of giving it in the oral form. Now, people are doing these fecal transplants and, of course, once you do it successfully for one thing, you are going to do it for everything, at least experimentally, and see if it makes a difference.
Other people will look at diet: how a proper diet can biodiversify the microbiome and what the impact of that is, in terms of mitigating some of these brain disorders. It is all very fascinating.

ATHM: Using anxiety as an example, from a clinician?s standpoint, what should a clinician look at in trying to affect a person?s anxiety through the microbiome?

Dr Mullin: A lot of people would have a different approach to anxiety and depression, but from an anxiety point of view, certain nutritionists, microbiome aside, would at least make sure that an individual is not on a lot of stimulants?meaning caffeine and even NutraSweet, as artificial sweeteners can be very stimulating?and, obviously, sugar and those products. All those do have effects on the microbiome, as well, besides being stimulants. These stimulants are called excitotoxins, which overstimulate the brain. That is one way to look at the foods. What are you giving so you do not shock the brain and make the person more anxious? Even in the end, if you give them too much sugar, they become hypoglycemic. They nose dive after having a high sugar rush and then under the condition of hypoglycemia, they can get anxious. It is not a very healthy thing to do.

The other thing is that those stimulants also affect the microbiome negatively, even NutraSweet. They did a study earlier this year showing that aspartame can cause the gut microbiome to become dysbiotic and imbalanced. That may be one way that people are getting diabetes. Research is linking aspartame use?NutraSweet?to diabetes, through reducing the biodiversity of the microbiome. That was big news back in February. The bottom line is that with diet, if you can manipulate the microbiome?which you can?you cut out, for someone who is anxious, some of these excitotoxins. The artificial sweeteners lower the seizure threshold as well.

Avoid those classes of stimulants, for one thing, and all the refined sweets. Then try to feed the microbiome fiber and prebiotic foods that selectively stimulate the growth of the good gut flora. By definition, that is what prebiotics are, the fibrous food substances that we cannot break down, which are broken down by gut bacteria and stimulate the growth of beneficial flora. If you can biodiversify the flora that way, through food, that is how many people approach anxiety, medication aside? just through diet, trying to avoid brain stimulation, to calm down the biome, and to biodiversify and enrich it. That is the gut balance revolution approach to improve anxiety and mood disorders by balancing the gut microbiome.

REFERENCE
1. Mullin GE. The Gut Balance Revolution: Boost Your Metabolism, Restore Your Inner Ecology, and Lose the Weight for Good! Emmaus, PA: Rodale Books; 2015.

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