The Role of Microbiome Diversity in Brain Health and Inflammation: A Clinical Conversation with David Perlmutter,MD,FACN,ABIHM,and Robert Rountree,MD

David Perlmutter, MD, FACN, ABIHM, received his undergraduate degree in biology from Lafayette College in 1976 and his MD from the University of Miami School of Medicine in 1981. During this time, he was awarded the Leonard G. Rowntree Research Award for best research by a medical student. Dr. Perlmutter completed residency training in general surgery at Mt. Sinai Hospital in Miami Beach, Florida in 1981–1982. This was followed by two residencies in neurosurgery and neurology, at the University of Miami, between 1982 and 1986. He now works in private practice in Naples, Florida, and serves as an associate professor at the University of Miami School of Medicine.

Robert Rountree: Would you give us some background on why you chose to be a neurologist?

David Perlmutter: I had an early exposure to neuroscience. My dad was a neurosurgeon, and he used to quiz me on bizarre disease processes at the dinner table. When I was an early teen, he would wake me up in the middle of the night to go to the emergency room with him. At 12-years-old, I would be in the operating room at 2 am with my dad while he was dealing with a patient. In college, I had a summer job in a research laboratory in Gainesville, Florida. During my junior year, I did some extensive research involving the microsurgical anatomy of one part of the brain. This work was published in the Journal of Neurosurgery, as well as in a chapter in a book entitled Microneurosurgery. ^{1 –3} I had the opportunity to present my research at the American Stroke Council of the American Heart Association. These opportunities gave me my first taste of involvement in the area of brain research and science. I liked the notion that people were interested in research that was important to me. That experience initiated the idea of becoming a doctor and a teacher.

I have continued to utilize these skills in my day-to-day life since that moment. It was during this time that I was thinking about medical school. However, I still spent a year exploring the microsurgery ideas further. It was during this period that the operating microscope was just being implemented in neurosurgery. Neurosurgeons around the world were beginning to use the microscope to perform delicate vascular anastomoses and work on aneurysms with much less brain retraction. However, no one had yet defined the anatomy that we could use in the operating room. So, I dedicated that first year out of college to helping to write a book on microsurgical anatomy, giving neurosurgeons around the world a roadmap.

During this time, we were recruiting neurosurgeons to our laboratory. They came from around the world to learn the anatomy and how to use the microscope. They learned how to anastomose very tiny arteries and how to approach the pituitary gland, for example, using the microscope. After that, I decided I needed to go to medical school. I always knew I wanted to be a clinician. However, my neuroanatomy background was so good during medical school that I actually taught part of the neuroanatomy class I was taking. In the end, I was able to perform neurosurgery and eventually do neurology research to promote improvements in surgery. While I was practicing neurology, I was in Seattle at an American Holistic Medical Association meeting. There, I met Jeffrey Bland [PhD]. This was about 25 years ago. His interest in functional medicine resulted in the beginning of a friendship. He would listen to my ideas regarding brain health from an integrative medicine perspective.

Dr. Rountree: Please help us understand the level of knowledge in the area of brain health when you first began in the field.

Dr. Perlmutter: The early years of my career began not long after the work of Wilder Penfield [MD]. Dr. Penfield would do brain surgery on people while they were awake and flag sections of the brain that corresponded with parts of the anatomy. Even now, this method is used if a surgeon is trying to link a part of the brain with a locus of a firing point for seizures, for example. These are the Brodmann areas of the cortex. We now focus on more of a functional anatomy perspective. My early research involved microscopic examination of brains to examine vascularity in the depths of the brain. With the help of magnetic resonance imaging, this information is used to insert probes into regions of the brain to determine their functions.

Another thing about early brain health knowledge was this idea that neurogenesis did not exist. We thought that we were stuck with our set of neurons. We knew then that neurogenesis was occurring in rodents, and even in primates. However, there was almost a religious backlash against the notion that humans could create new brain cells. It was finally proven by Peter Eriksson [PhD], a researcher who was treating patients with bromodeoxyuridine [BRDU] as a way of charting recurrence of squamous-cell carcinoma on the face. ⁴ The presence of BRDU in the hippocampus of the brains of patients who had succumbed to their cancers implied that neurogenesis, or division of cells in the brain, was occurring. This work was eventually published by Dr. Eriksson and colleagues in the journal Nature Medicine in 1998. The story suggests that his research was rejected by four other journals before Nature Medicine decided to publish it. ⁴ This has happened to other scientists as well and speaks to the need for persistence.

Dr. Rountree: You also speak about how difficult it is to move forward. You even mention it in your latest book (with Kristen Loberg), Brain Maker . ⁵

Dr. Perlmutter: Yes, that is correct. In Brain Maker, ⁵ I included a quote that I had stumbled upon as I walked into the office of a friend of mine, Amar Bose [PhD], the inventor of sound-canceling headphones. On the door of his office it said: “At every crossway on the road that leads to the future, each progressive spirit is confronted by 1,000 men appointed to defend the past.” I have also always liked the quote of Ronald Reagan [R] about the term status quo. He said: “Status quo is the Latin term for basically the mess we are in.”

I think we do have to push. However, if everyone fully embraced and accepted every idea that we had, there would be no progress, because we would simply be parroting the standard byline. So, we also have to continue to challenge these notions. One example is where we are now in terms of understanding human hygiene. For years, we have believed that we have to always wash our hands and that our food needs to be sterilized. We now know that soil-based organisms are critically important for enhancing the diversity and health-giving properties of the human microbiome. Look at how dietary fat was demonized for the past 3 decades, and we now know how fundamentally critical dietary fat is to human health and disease resistance. Another example is the notion that having a baby by Cesarean section [C-section] is a safer option for the baby. We now know that there are lifelong consequences for immunity and the inflammation set-point that are imparted by undergoing a C-section. So, we need to keep open minds and be able to relinquish some of these long-held beliefs. We need to revisit these closely held notions and challenge them.

Dr. Rountree: When you first met with Dr. Bland, long before we knew about neuroplasticity, did you have a sense of what might be ahead of you? Did you think that you might be involved in some exciting research in this field?

Dr. Perlmutter: There have always been issues along the not-so-easy road to the future. While many of us who were watching the science were expecting it, people in the mainstream were not expecting it and were a bit blindsided by it. However, they ultimately adapted to it and adopted it as one of their own. The biggest issue that I have seen is the body of science that we were not expecting, in terms of its application to medicine—the role of the microbiome in the influence of every aspect of human health, physiology, and pathology. After decades in the field and only being able to treat symptoms, we finally have the ability to possibly get to the root cause of so many of our pernicious maladies. Examples are diseases such as Parkinson's, Alzheimer's, amyotrophic lateral sclerosis [ALS], autism, attention-deficit hyperactivity disorder, and depression.

We finally have access to a causality model. If one speaks to medical students or many practicing neurologists about the cause of Alzheimer's disease, they will discuss the role of beta-amyloid toxicity within the brain and the importance of identifying the causes of beta-amyloid buildup. We have hundreds of interventional or animal studies in which researchers have tried to target beta-amyloid. However, I lectured a decade ago about the role of beta-amyloid as an antimicrobial peptide and its role in the response to underlying infection. As a response to infection, beta-amyloid is a good thing. We know that with chronic herpes simplex virus infection or fungal infections, such as Candida albicans, beta-amyloid is created as an antimicrobial peptide in response to chronic infection. We are finally asking why beta-amyloid is secreted and we are targeting the cause. ⁶

Another example of challenging a long-held belief is related to ALS. With respect to ALS, clinical studies are demonstrating elevated lipopolysaccharide [LPS] with increased levels correlating with the disease. ⁷ LPS is a covering over gram-negative organisms in the gut and a potent inflammatory compound. LPS can be measured by itself, but many laboratories measure antibodies to LPS as surrogate markers to circulating levels of LPS. When LPS levels are elevated in the serum, this suggests that the gut is permeable to LPS, allowing it into the systemic circulation. Finding dramatic elevations of LPS in ALS is—for the very first time—taking our focus off the brain and redirecting it toward the gut, specifically toward the one-cell-thick gut lining, the epithelium. We need to look at all the factors that threaten the epithelial integrity. Interestingly, very recently there was a call for research subjects by a researcher at Massachusetts General Hospital in Boston, Massachusetts, asking for patients with ALS who were willing to have their microbiomes analyzed genetically. What are the possibilities that, in 5 years, we may be discussing the fact that people are doing fecal transplant procedures as an interventional treatment for ALS?

ALS is not the only example of our shift from the brain to the gut. The upregulation of microglial activity is caused by inflammation within the brain, ultimately setting the stage for apoptosis or preprogrammed cell death. ⁶ It is possible that the reason we have not yet found an answer for Alzheimer's disease, for ALS, for the root cause of multiple sclerosis [MS], for Parkinson's, or for autism, is that we have been looking in the wrong place. There appears to be a role for LPS in other disorders associated with the brain, including autism, Alzheimer's disease and depression. ^{8 –10} We need to take our focus away from the brain and look at factors that are not directly brain related if we are going to be able to find new ways of understanding those very important disease processes.

Given that blood levels of LPS would be indicative of systemic inflammation, this process could also relate to non–brain-related issues, such as arthritis, diabetes, coronary artery disease, and even some types of cancer. ¹¹ Understanding the role of the integrity of the gut lining and global inflammation, and the ability to measure antibodies against lipopolysaccharide, redirects our interest from not only a diagnostic perspective, but from a therapeutic perspective. What can we do to improve gut-barrier integrity?

Dr. Rountree: In Brain Maker, ⁵ you discuss the idea that countries that have less hygiene, or exposure to more microbial diversity, have a lower incidence of Alzheimer's. Given that residents of these countries presumably have a higher load of infections, does it follow that the antimicrobial protein beta-amyloid is found in higher levels in these individuals?

Dr. Perlmutter: A 2013 University of Cambridge study examined individuals in well over 100 countries, and measured their degree of bacterial and microbial diversity—specifically, parasite load. ¹² The researchers then correlated that with the prevalence of Alzheimer's in those countries. You ask if their levels of beta-amyloid would be higher; that is unclear. However, in these areas with poorer hygiene, we can paradoxically expect a decreased risk of systemic infection because of exposure to increased bacterial diversity and enhanced integrity of the gut lining. Burkina Faso in sub-Saharan Western Africa is one area that has been studied heavily. ¹³ These individuals are at a lower risk for hyperimmune or autoimmune situations, and inflammatory markers are commonly reduced in these people. This results in a lower risk for blood–brain barrier permeability and the ability of things, such as herpes simplex virus or fungi, to get into the brain.

This does not mean that we should be going after these agents. In fact, I am saying the opposite. Individuals with compromised immune function are at risk for various opportunistic infections. This is common knowledge when we think about the various fungal infections in individuals with untreated human immunodeficiency virus, for example. I hypothesize that our diets today are affecting our microbiomes and therefore challenging our immune systems. Our diets are setting us all up for these opportunistic issues. They might not be full-blown infections, like you might see in people whose immune systems are truly compromised, but might exist at a lower level. We are opening the door to somewhat opportunistic microbes by virtue of our immune challenges as dictated by what we are doing to our microbiomes. Therefore, the very drugs that we take to combat these infections, the antimicrobials, are actually paving the way for further opportunistic infections. There has never been a free ride when it comes to taking antibiotics, and yet antibiotics are incredibly overused and are going into the foods that we eat. Martin Blaser [MD], of the New York University School of Medicine, pointed out in his book Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues that these antibiotics are being added to animals to help make them fatter. This is also happening in humans. ¹⁴

Dr. Rountree: How do you feel about the use of antibiotics to prevent sepsis in newborns—sepsis related to group B streptococcus [strep], in the United States?

Dr. Perlmutter: The reality is that not a large number of women who even test positive for the presence of group B strep would go on to have this issue in their children. In terms of the risk–benefit ratio, we have got to investigate the risk. The risk is creating antibiotic-resistant bacteria. It is just beginning to be understood that changes occur in the microbiome from a single course of antibiotics. ¹⁵ We know that the microbiome does rebound within weeks or months of antibiotic use, and can get back to a similar array, but this never happens fully. We do not understand fully if these subtle changes in the microbiome can affect the various metabolic processes. And we do not understand the epigenetic downstream effects of changing even subtle microbial communities over the long-term. We do know that subtle changes in microbial communities can turn on and turn off various genes. ¹⁶

In 2010, there was a study in pregnant women in which the organisms in the women's stools were measured. It was determined that women with higher levels of the phylum Firmicutes, in comparison to the Bacteroidetes, were activating genes that were maladaptive, that increased issues related to negative fat metabolism and risk for cardiovascular disease. ¹⁷ These activations occurred in correlation with changes in the array of organisms in the gut. We do need to realize that certain diseases or illnesses need to be treated with antibiotics. However, what can we do to offset the effects of chronic or repeated antibiotic therapy? It might be that we need to suggest that the patients take a good probiotic, or even push that a little bit and suggest the need for probiotic enemas or a fecal microbial transplant. These are good discussions to have. It is important to recognize that this is a way to potentially offset some of the severe issues that are going to be occurring because of this antibiotic exposure.

These are difficult and challenging problems. We need to understand that, the more antibiotics are being used, the more likely it is that the disease is not fully eradicated in the long run, because of increased gut permeability and inflammatory responses, ultimately translating to mitochondrial dysfunction. Lyme disease, an opportunistic infection, is an example; the organism does its damage as an acquired mitochondropathy. We need to look at things with our eyes wide open. Clinicians should begin thinking about how to offset the damage if long-term antibiotics are required.

Dr. Rountree: Can prebiotics play a role in this scenario?

Dr. Perlmutter: Prebiotics are part of a comprehensive protocol. In general, our modern cosmopolitan diet is low in prebiotic fiber. This may be setting the stage for the other issues that then happen even if we take antibiotics out of the equation. It has been suggested that our hunter–gatherer forebears consumed a diet resulting in microbial diversity. ¹⁸ They may have consumed as much as 125 g each day of prebiotic fiber. Typically, Americans now may get an average of 5 g of prebiotic fiber per day. If we do not have adequate prebiotic fiber, a lot of interesting things happen. One example is that the good probiotic organisms are not producing enough of the short-chain fatty acids that play an important part in the signaling messages for satiety. ¹⁹ These short-chain fatty acids produced by our probiotic bacteria signal intestinal cells, the L cells. This results in a signal mediated through glucagon-like peptide 1 that controls bowel motility.

In prehistoric humans, prebiotic fiber intake was associated with available food. During this time short-chain fatty acids were produced and gut motility was enhanced. This resulted in food getting passed through the body quickly. However, if food sources were poor and the body was starving, the creation of short-chain fatty acids was reduced, resulting in a signal inhibiting gastric and intestinal motility. This allowed food to remain in the intestine longer, resulting in increased time available for extraction of calories. This is a highly conserved signaling mechanism that alerts the organism to food scarcity, mediated through the production of short-chain fatty acids.

With our modern diet, we have an incredible abundance of calories. However, because of a lack of prebiotic fiber, we still do not have much in the way of short-chain fatty acids. Therefore, we have a signaling mechanism that is saying that we are starving, even though food is aplenty, resulting in increased extraction of calories from the foods that we are eating. The signaling system that we have relied upon since Paleolithic times has not been activated.

Dr. Rountree: Would you discuss the role of the short-chain fatty acid, propionic acid? Given some of the negative things we hear about in the scientific literature regarding propionic acid, is this a paradox?

Dr. Perlmutter: The three most important short-chain fatty acids are acetic acid, propionic acid, and butyric acid. We have to look at these in terms of balance. Derrick MacFabe [MD], from Western University in London, Ontario, has discussed a role of propionic acid in autism. ²⁰ In that situation there is too much propionic acid. What we understand is that there are certain microbial species, such as clostridial species, that tend to produce more propionic acid. There is a relationship between the finding of these species in the gut microbiomes of patients with autism and higher levels of propionic acid. In experimental models of higher levels of propionic acid, this acid leads to autistic-like behavior. So, that suggests that we should be asking if there is something that could be done to reestablish balance of the organisms in the gut, in order to reestablish more normal relationships among butyric, propionic, and acetic acid. Once balanced, maybe there will be some clinical manifestation in terms of a reduction in autistic symptomatology.

I had this discussion recently with the mother of one of my patients with autism. She asked what I suggested, and I recommended reestablishing good gut health by using a fecal transplant. This was a child who could not go to school, could not speak, and could not socialize. She got a donor, and now he is in a mainstream school, doing extremely well. He is conversant and socially appropriate. The University of Arizona is now just finishing recruitment for a fairly large study of fecal microbial transplants in a group of children with autistic spectrum disorder. This science is just starting to emerge.

In MS, there is a significant amount of work being done to look at what characterizes the microbiome. One organism, Faecalibacterium prausnitzii, is found to be depressed in patients with MS, compared to controls without MS. ²¹ It turns out that this is the same organism that is also underrepresented in the fecal microbiome in some individuals with inflammatory bowel disease [IBD]. So, what are the similarities here? When we recognize similarities—as opposed to being so involved in dissecting diseases and compartmentalizing them—we recognize the broad strokes of disease processes, such as inflammation or mitochondrial dysfunction. Only then can we start to unify our approaches across multiple platforms and start to leverage ideas, perhaps by taking information about one disease, such as IBD, and wondering if another autoimmune condition, such as MS, may be treated in a similar way.

Dr. Rountree: Would you compare your approach with that of Dale Bredesen [MD] of the University of California–Los Angeles? He sees diseases, such as Alzheimer's, as resulting from many individual issues and likens the intervention to patching “36 different holes in the ceiling.” This would seem like a slightly different approach than what you are saying, which is that we have to get back to looking at really basic processes, such as chronic inflammation, oxidative stress, dysbiosis, and glycation.

Dr. Perlmutter: Dr. Bredesen published some research in the journal Aging in September 2014. ²² This article reported on his approach of looking at the 36 different parameters he was measuring and attempting to modulate clinically. However, he recognizes that not one of his patients is fully engaged in maximizing therapies for each of those 36 parameters. He recognizes that people can do most of this program and do very well. His hypothesis takes us away from the “one disease, one drug” model that has failed with Alzheimer's disease. In addition, those basic phenomena, such as inflammation, glycation, and free radicals, resulting in mitochondrial dysfunction leading to apoptosis, are the targets of each and every one of the 36 points that he raises.

Dr. Bredesen recommends a very low-carbohydrate diet that is higher in both fat and fiber. This is a specific diet designed to nurture the microbiome, as well as to lower hemoglobin A1C [HbA1c] and the process of glycation. We know that HbA1c is one of the most valuable markers in terms of Alzheimer's risk and progression, because it is that process of glycating proteins that augments inflammation and free-radical production. Dr. Bredesen is also focused on optimizing vitamin D and omega-3 levels, ridding the body of heavy metals, and making sure that affected individuals get aerobic exercise. In other words, this is a diet and supplement regimen that would result in the outcome in terms of decreasing the major processes of inflammation, free-radical–mediated stress, while enhancing neurogenesis, enhancing neuroplasticity, etc. So, at the end of the day, his 36-point program accords perfectly with those major concepts that we know are fundamental to any degenerative process. He understands that, when there is inflammation and there are changes in the brain milieu away from normal, the balance is tipped. He says it tips the balance between synaptoclastic activity and synaptoblastic activity. In other words, the balance is forming new synapses versus destroying synapses.

We can compare this balance to osteoporosis, an imbalance between osteoclastic activity and osteoblastic activity. In the case of the brain, we want to try to favor synaptoblastis, to improve blastic activity and regeneration of neurons, neurogenesis, and neuroplastic activity. This would result in enhancement of synapses or connections, which are obviously fundamental in terms of creating new memories and memory function in general. This would also enhance brain-derived neurotropic factors [BDNFs] so that we can preserve those synapses that we have and increase neurogenesis in the subventricular zone, certainly in the hippocampus.

Very recently, in the Journal of Alzheimer's Disease, there was a report that demonstrated a relationship between aerobic exercise and neurogenesis over 30 years. ²³ The level of aerobic exercise correlated with both the thickness of gray matter, as well as risk for Alzheimer's disease. The report suggested that individuals who engaged in aerobic exercise regularly had a 50% reduced risk of developing that very disease for which we have no treatment. Even though the report was just published, nobody talked about it. It did not make many news services in the United States. It was not on any of the popular websites. Here is some evidence that exercise can reduce the risk of Alzheimer's by 50%. No prescription is needed, and all that is necessary is a pair of sneakers. Yet, this does not make the news. What gets in the news are breakthroughs in the treatment of the disease after it has already manifested.

Dr. Rountree: This lends itself to the question about genetic testing. We now have people who have had genetic testing and discovered that they are homozygous for APOE-4/4, and at increased risk of early onset dementia. Even though they feel like there is nothing they can do, you and Dr. Bredesen are suggesting that there are quite a few things that can be done. Please discuss this.

Dr. Perlmutter: Exactly. Those of us, myself included, who have 1 parent with Alzheimer's have a significantly increased risk, which is likely conveyed by the APOE-4 allele. However, we are not the products of our genes. Genes influence our predispositions for certain things, but based upon override of gene expression and epigenetic issues, for example, we know that this is all it is. It is a predisposition—not a predetermination. It is not our destiny.

In 2012, a report appeared in the Journal of Alzheimer's Disease looking at how the omega-3 fatty acid docosahexaenoic acid [DHA] can counteract the risk that is imparted by carrying the APOE-4 allele. ²⁴ I have been undecided over the years about whether I should tell my patients that there is a test or not. Ultimately, I decided against that. People who see me want to be on a brain-healthy program to maintain and preserve cognitive function. How much of the program that they choose to participate in might be influenced by their knowledge about whether or not they were APOE-4 heterozygous or homozygous. However, people who are involved in health to the point that they are looking at the information themselves are typically the avid people. These are the ones who are going to want to use that information in terms of leveraging this whole mentality toward a better lifestyle.

In the end, everyone I work with gets the full program. I detail the program in my books for people who are not even going to be my patients. The program involves exercise and more exercise. Aerobic exercise is probably the biggest thing lacking in Western cultures. It is an extremely powerful epigenetic player to increase BDNF, which is nature's brain-protective chemical or the brain's growth hormone. ²⁵ I (with Ms. Kristin Loberg) wrote about this concept in Grain Brain: The Surprising Truth about Wheat, Carbs, and Sugar—Your Brain's Silent Killers ²⁶ and now it is validated in the Journal of Alzheimer's Disease with a 50% reduced risk for Alzheimer's in people who exercise aerobically. ²⁵ Beyond exercise, there is the value of the omega-3 fatty acid, DHA. This is why people need to eat fish or consume fish oils, or why people should get another source of DHA, such as algae-derived DHA. Beyond that, the other important parts of the program include making sure that blood sugar is under strict control by monitoring not just fasting blood sugar and A1C, but also fasting insulin as a predictor of insulin resistance.

When I see research showing that when markers of gut permeability and inflammation, such as LPS, are elevated in the blood in correlation with Alzheimer's disease, it suggests to me that, 5 years from now, we will see studies that correlate changes in the microbiome to Alzheimer's. I believe that people will start to question if we should even be more judicious in terms of the drugs we take, be they antibiotics or proton pump inhibitors, or the foods we eat, in order to consume foods higher in prebiotics and fermented foods that contain probiotics.

Dr. Rountree: Thank you for this take-home message. I see it as a message of hope. As a preface to Brain Maker , ⁵ this message is sophisticated in terms of the amount of research that has gone into it and contains a high level of detail. I appreciate that it would appeal to both the lay reader and the practitioner. Was this a challenge?

Dr. Perlmutter: That is always a big challenge. The more understandable a book is, the bigger the audience is going to be. However, one reaches a point of diminishing returns. If one makes it too simple, readers who are sophisticated and want more are not going to pay attention. The biggest challenge is to write a book that has the information but presents that information in such a way that it is going to appeal and be understood by the largest group, whether they have an eighth-grade education level, or they are have PhDs in microbiology. Fortunately, I have a terrific writer to help. I dictate the book, and then Ms. Loberg is a master at taking my information and presenting it in a way that readers can understand. To have formed a partnership with such an individual is really a huge honor.▪

To Contact Dr. David Perlmutter

David Perlmutter, MD, FACN, ABIHM

Private Practice, Naples, FL

Phone: (239) 404-2084

E-mail: DP@DrPerlmutter.com

Website: www.drperlmutter.com