A conversation with Mike Lustgarten: Bacteria, viruses and the microbiome in aging and chronic disease

July 11th, 2020 by Amy Proal

Michael Lustgarten PhD is research scientist at the Tufts University Human Nutrition and Research Center on Aging. He studies how bacteria, viruses, and other organisms that persist in the human body can contribute to aging processes and diseases of aging. Several of his research projects focus on the role of the gut microbiome and blood metabolome (microbial metabolites) on muscle mass and function in older adults. Dr. Lustgarten has been a guest lecturer at the Friedman School of Nutrition Science and Policy and other Organizations on topics such as the gut microbiome, serum metabolome, oxidative stress, exercise, and sarcopenia. Learn more about Mike’s research at his YouTube channel, or follow him on Twitter at @mike_lustgarten.

(scroll below the video for more information)

Here is more context on some of the terms Mike and I use in the video:

HSV1 = Human herpes virus 1

HHV6 = Human herpes virus 6

CMV = Cytomegalovirus

Pathobiont: an organism (bacteria, virus, fungi etc.) in the human body that can be present in a healthy person, but may also change the way it expresses it genes to act as a pathogen under conditions of immune suppression, imbalance, or inflammation. You can listen to me talk more about pathobionts and chronic disease development here. 

Polymicrobial: “Poly” means “many.” A polymicrobial disease is one in which different organisms (bacteria, viral, fungal etc.) interact together to collectively disable the human immune response or drive other pathological processes. The word “polymicrobial” is also sometimes used to describe the fact that entire communities of microbes and viruses can evolve together towards a state of pathology or imbalance. This microbiome and/or virome “dysbiosis” is increasingly being documented in patients with a range of chronic inflammatory conditions.

Virome: The word virome refers to the ecosystems of viruses that persist in human tissue and blood – along with bacteria, fungi and other organisms. The virome includes DNA viruses, RNA viruses, and a large number of bacteriophages (viruses that infect bacteria.)

Here are some highlights from our conversation and some additional clarifications:

Mike’s funded research focuses on how metabolites (discussed more below) created by microbes in the gut and blood may impact muscle mass in older adults. On the side, he’s also interested in optimizing fitness and health by blood testing and tracking diet. He also wrote a book several years ago called “Microbial Burden“, with the goal of educating the public about the how microbes and viruses in the human body can play a role in health and disease. In the book he talks about the gut microbiome, but also explains how pathogens and/or communities of organisms capable of persisting in human tissue and blood can contribute to chronic disease and aging. He also discuses strategies for optimizing our microbiomes to delay aging and aging-related disease… to hopefully help people live as long as possible! 

I (Amy) have always loved the title of Mike’s book Microbial Burden. That’s because while research teams focus on how “good” microbes in the human body (and especially the gut) might promote health, Mike and I share an interest in better understanding how many of these same microbes can change their activity under conditions of immune suppression or imbalance to drive chronic disease. If and when that happens, the microbes that live in and on us can become more burden than benefit, a dynamic that the title “Microbial Burden” captures well. Many of the microbes (and viruses) that can become a “burden” in chronic disease are now understood to be capable of persisting in blood or other areas of the body previously regarded as sterile – such as brain or placenta.

Mike and I are both very interested in studying how intracellular pathogens contribute to chronic disease. Intracellular pathogens have evolved the capacity to infect and enter a human cell. They often persist in the nucleus, or center, of the cell they infect. Once in the nucleus, they gain access to the DNA of the human cell, allowing them to dysregulate or modify the way the human cell decodes and expresses its DNA (transcription and translation). Intracellular pathogens may also  dysregulate the epigenetic environment, or interfere with DNA repair. They can even hijack the metabolism of the cells they infect (all virus modulate host cell metabolism in order to replicate). Overall, in simple terms, intracellular pathogens can “hack” how human cells express and control their own genes and metabolic programs. In this way, intracellular pathogens can drive many chronic disease processes and symptoms, and both Mike and I think this topic is very understudied. You can listen to me talk more about how intracellular pathogens “hack” human cell function here.

We also talk about how many persistent viruses and bacteria drive disease by creating proteins/metabolites that are very similar in size and shape to human proteins/metabolites. This overlap between pathogen and host proteins is sometimes called “mimicry.” I point out this study as an example: certain viruses can create proteins similar in size & shape to human insulin proteins. Those viral proteins can then bind into human insulin receptors, which can dysregulate downstream insulin signaling in a manner that might contribute to diabetes. Mike recently submitted a grant that, if funded, will test if metabolites created by gut bacteria can enter the blood and impact the muscle mass of older adults.

Mike and I both agree that studies of microbiome/virome imbalance or pathogen activity in chronic disease must go beyond documenting just “what’s there.” In other words, identifying the presence of organisms in a microbiome community is only a first step. The real key to understanding how such microbes might contribute to chronic disease is to use other tools and technologies to study “what they do” (their activity). Studies of microbe activity include what genes they are expressing, but also studies of the proteins and metabolites they create under different conditions (these include virulence factors, biofilm quorum sensing molecules etc).

One reason this trend matters is that the same organisms & pathogens can be harbored by both healthy and sick people, but in a person who develops chronic disease these organisms may start acting in a new way. For example, almost half of all people harbor Herpes Simplex Virus 1 (HSV1). But, in patients who develop certain chronic symptoms, a virus like HSV1 might change its gene expression, causing it to make different proteins than it would in a healthy person. HSV1 might also infect a different tissue, nerve, body site, or cell type in a sick individual. The virus may also begin to persist inside the cells of the immune system, or it may begin to interact with other organisms in the body in a detrimental, polymicrobial fashion.

Mike and I are both interested in immunotherapy – treatments that stimulate or support part of the human immune response, so that a patients’ own immune system may better manage a persistent infection and/or microbiome/virome dysbiosis. For example, cancer immunotherapies that activate T cells to target tumors are showing great promise as therapeutics. Because a growing number of viruses and bacteria are being identified in human tumors, cancer immunotherapies may allow the immune system to better target tumor-associated pathogens. If that’s the case, similar immunotherapies could be extended to the growing number of chronic conditions tied to viral & bacterial activity.

Mike and I also agree on the following: while nearly every chronic disease is now tied to “inflammation” or “inflammatory processes,” the key to better understanding this trend is to always ask, “what is driving the inflammation!?” That’s because there is almost always a root cause or a reason for inflammation (for example, inflammation is generated when the immune system targets pathogens). Although this sounds obvious, Medicine is currently more focused on palliating inflammation to temporary lower symptoms, rather than performing extended testing or research to figure out the root cause of the problem.

When Mike mentions Cosmo he’s talking about our friend and very smart scientist Cosmo Mielke. You can read more about Cosmos’ work on how viral infection contributes to the development of aging, obesity, and other metabolic issues here.

When Mike brings up “toxo” he means Toxoplasma gondii – a parasite that can persist in the central nervous system, where it is capable of driving psychosis. He mentions Lena Pernas’ work on Toxoplasma and mitochondria, with a focus on this paper her lab published in the journal Cell. Dr. Pernas shows how Toxoplasma gondii can compete with the mitochondria of the cells it infects for access to nutritional fatty acids. 

Overall, both Mike and I think bacteria, viruses and other organisms are dramatically understudied as drivers of chronic disease. We dream of a global effort in which a tremendous amount of funding, resources, and brain power are dedicated to the study of the human pathogens and pathobionts already implicated in chronic disease. We should be studying pathogens like Epstein Barr Virus, HHV6, and Pgingivalis etc., with the same urgency and funding as COVID-19. However, such a global effort (similar to the Moon Shot or Manhattan Project) would require a paradigm shift in how the scientific & medical communities think. At the moment, too many PhDs and MDs were educated by textbooks that (incorrectly) claim the blood and brain are sterile. Science education must be updated to include more recent data on organisms’ activity in body sites outside the gut. Mike and I hope that younger researchers are willing to become “warriors” in pushing this paradigm shift forward.

When it comes to implicating persistent pathogens in chronic disease, a barrier that both Mike and I note is that many such pathogens are not easily identified in the blood. Consequently, we need to keep perfecting tools and methods that allow identification of these pathogens in other body sites, including tissues and nerves. Also, persistent pathogens are often present in low quantities (low biomass) but may still drive chronic disease processes. In other words, “quality” (what a pathogen does) often matters more than “quantity” (how much pathogen is present). A good example of this is how oral pathogen P.gingivalis can drive periodontitis progression even when it’s present in very low amounts in an oral biofilm.

Mike and I talk about COVID-19, and both of us are somewhat frustrated that most drug development and attention is focused on late-stage COVID-19 (when patients are already in the ICU). We hope that efforts grow to better combat the virus in early-stage disease, when viral load is lower. We are even interested in strategies – both pharmacological and nutritional – that might prevent people from getting a bad case of COVID-19 in the first place (preventative medicine).

In fact, we both think that disease prevention (predictive and preventative medicine) is the future. Mike hopes that one day, most of the pathogens and organisms capable of contributing to chronic disease processes can be “mapped” along with other associated immune parameters, diet metrics, and aging biomarkers. We would have personalized testing that can indicate what pathogens/microbes might become problematic for a given person over time. Then we could intervene early with immunotherapies, antivirals, antimicrobials, vaccines, or other therapeutics to stop many chronic diseases processes from occurring in the first place – possibly allowing people to live longer and healthier lives.

 

 

 

 

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