Sarkis Mazmanian
We are trying to leverage the ability of the microbiome to communicate with the brain. Our idea is to drug the gut and not the brain.” ndash;Sarkis Mazmanian

Sarkis Mazmanian, PhD, is revolutionizing microbiome research. The Luis B. and Nelly Soux Professor of Microbiology at the California Institute of Technology (who also happens to be a 2012 MacArthur Genius Award recipient) started his career studying the basic mechanisms of bacterial pathogenesis. However, his current research focuses on how the bacteria in our gut can be used to treat human neurological disease.

Mazmanian’s work goes far beyond cataloging the panoply of bacteria that can be found in the gut. Rather, his lab and the two companies that he has started are developing novel ways to use those bacteria to be at the center of treating human disease. Senior Editor Julianna LeMieux, who first met Mazmanian 10 years ago at a bacterial genetics conference, recently found time to catch up with him to discuss his current work in the field.

What inspired you to go into microbiome research?

Sarkis Mazmanian: At the end of my graduate work studying infectious disease, I started thinking about what I wanted to do next. I love microbes, but I wanted to do something different from what everyone else was doing—to go off the beaten track. I was inspired by a one-page editorial written by Jeff Gordon, one of the few people working on the microbiome at that time, on the trillions of bacteria that are found in our gut. The microbiome, at that time, was at the fringe of mainstream science. With the tools just starting to come online to study the microbiome, off the heels of the Human Genome Project, I saw a huge opportunity in studying the microbiome. I just needed to find a place to do it. I presented my ideas to Dennis (Kasper) who was studying Bacteroides fragilis. His response to me was, “Sarkis, I have no idea what you are talking about, but you can come to my lab and work on that.” I decided to join Dennis’s lab and canceled all of my other interviews.

What is the most exciting work going on in your lab right now?

Mazmanian: We are incredibly excited by the potential to change drug development in neuroscience. At the moment, almost exclusively, drug development efforts in neuroscience try to get drugs across the blood brain barrier (BBB.) In most cases, even in the drugs that do successfully cross the BBB, only a percent or a fraction of a percent get into the brain in pharmacological doses. The rest float around the body, hitting off target sites and causing side effects. So, the current approach is very challenging and not without its problems. We are trying to leverage the ability of the microbiome to communicate with the brain. Our idea is to drug the gut and not the brain.

What is the rationale that drugging the gut will successfully treat neurological disorders?

Mazmanian:  There is a lot of evidence that the microbiome (in mouse models) affects the function of the brain, the development of the brain, the activity of circuits in the brain, and behaviors. This goes both ways. There are organisms and pathways that exacerbate these conditions and others that are protective. Our work centers around understanding all of them. We want to know what the molecules made by the bacteria in the gut are,and how they are mediating the gut-brain connection. Once we know that, we can think about ways of drugging them.

At the company that I started, Axial Biotherapeutics, we are executing this plan for both autism and Parkinson’s disease (PD.) We know that you can deliver molecules to the gut, drugging microbial pathways (that inherently do not exist in humans or mice), and by manipulating those, you can exacerbate or ameliorate neurodegeneration and behaviors linked to autism.

The drugs that are being developed are completely gut retentive—they do not enter the circulation. Yet, there are incredible changes in the brains of the animals that are being drugged. So, the main focus of our work is to bypass the hurdle of getting the drugs across the brain, and to let the microbiome do the work to connect the gut and the brain.

Can you tell us, more specifically, about how the microbiome could treat a neurological disease like Parkinson’s disease?

Mazmanian: It is widely believed that the driving pathology of PD is the aggregation of the neuronal protein α-synuclein found in presynaptic vesicles. In its normal function, it is a monomer that aids in dopamine transmission. When it aggregates, it leads to the death of the cell.

One interesting finding about PD patients that was first documented in 1817 in the first paper written on PD—at that time, referred to as “shaking palsy”—by James Parkinson, was that many patients had GI issues. We now know that up to 80% of PD patients suffer from constipation.

We wanted to follow up on why people with a neurological condition have GI issues. What we showed is that if you remove the microbiome from a PD mouse model, the mouse exhibits no motor symptoms (hallmark disturbances in gait and posture stability). Additionally, the germ-free version of this mouse has no motor symptoms, which gave us a tool to test the human microbiome.

We knew, through research that sequenced the DNA in fecal samples, that the microbiome is different between a PD patient and a healthy control. But we wanted to test the causal relationship between the human microbiome and PD. So, we took microbiota from human PD patients and healthy controls and transplanted them into the germ-free mice. The mice that received the microbiomes from PD patients developed severe PD symptoms (motor symptoms, α-synuclein, neuroinflammation). However, mice that received microbiota from a healthy human control had much less disease.

This told us that the microbiome is, indeed, contributing to the symptoms and they are not a consequence of some other change. This experiment also developed a mouse model with human microbes as opposed to mouse microbes, (there is only a 5% overlap between the mouse and human microbiota) where the microbiome is driving the symptoms.

Gut
Source: chombosan / Getty Images

We then asked what is different about the human microbiota in PD? To find that, we mined our microbiome data and publically available databases and identified candidates of both species of bacteria and genetic microbial pathways that were dysregulated between healthy controls and PD patients.

Although we are working our way through all of the potential candidates, Axial is currently leveraging a single species of bacteria that induces all PD phenotypes in the mice upon transplantation. To take it one step further, we have identified the genes that are responsible for inducing the PD symptoms. When the gene is knocked out, the symptoms are no longer present. These genes are not found in metazoans—they are completely microbial pathways.

Axial has developed small molecule inhibitors against the gene produces in that pathway. Using them, they can, essentially, drug the ability of this bacteria to produce this product. When they do this, the bacteria are completely viable, but the mice are absolutely healthy. In addition, the molecules are made to be completely gut selective. Meaning that they do not enter the circulation—the molecule is not found in the urine, serum, nor the brain. This is proof of concept that we can deliver molecules that are highly gut specific and target microbial pathways to achieve benefits in a classic neurological condition.

Given these data, in theory, by drugging the microbiome, you should be able to restore health and that is what we are doing at Axial, by developing drugs and going into the clinic. Our first clinical trial will begin at the end of this year with a gut selective molecule that targets a microbial pathway, that is completely inert to a mammalian system, in about 100 PD patients.

Is the microbiome solely sufficient to induce PD?

Mazmanian: Well, I’m completely speculating, because no one has the answer to this. But, I think that it is possible. However, because the microbiome is so malleable and diverse, I don’t think that any particular state of the microbiome is going to be sufficient. Meaning that a particular composition of the microbiome would be sufficient if someone has an underlying genetic predisposition. And, we know that there are polymorphisms in genes that are more likely to be enriched in the PD population than healthy controls.

The microbiome has become a household word, in large part due to the increasing popularity of microbiome-based products and marketing. What do you think about all of the companies that are selling products based on the microbiome?

Mazmanian: I am inherently skeptical about many of the claims currently made about the benefits of the microbiome. The assertion that a company can tell you what diet to eat to ‘fix’ your microbiome is simply unsubstantiated. There is no way that anyone has enough information to be able to reshape your microbiome in a meaningful and healthy way, that is tailored to you. We have no idea what healthy even is, as far as the microbiome is concerned and, since my microbiome configuration is based on my genetics, diet, and life experiences, healthy for me is totally different from healthy for you.

It is really the function of the microbiome that is important to understand and that is where we have the least amount of evidence. Not which bacteria are there in terms of genus and species and not even what is there in terms of genes. Rather, what are the molecules that are being made? We have some glimpses of that answer from fecal and serum metabolomics. These bacterially derived molecules are almost completely unstudied and do not look like anything else that has never been studied before.

As we sit here today, we are much closer to knowing nothing than we are to knowing anything as far as function of the microbiome. Cataloging what bacteria are there has been done. But no one knows what that information is telling us about biology.

Do you change anything based on the skepticism that surrounds the microbiome field?

Mazmanian: I don’t change anything about the projects that we study in the lab based on microbiome skeptics. The skepticism is not an obstacle. In fact, it is balanced and maybe even outweighed by the optimism in the field. A lot of fields have not met the promises that they have made. The field of the microbiome is new—and therefore exciting—and has a ton of potential.

The hype and the claims that the companies make concerns me. Some people are making promises to society that will almost certainly not be kept. There are going to be consequences and backlash to that. If companies continue to make claims to customers who pay hundreds of dollars for a product and nothing is received in return, they will think that the microbiome is just another fad. The long-term issue of too much hype may come back to really hurt the field.

I know I can’t control that. But, I do know that if we do the most rigorous and informative experiments, if we ask the right questions, if we translate the findings from mice to humans and show clinical efficacy in people, it will validate the field. For me, that is the blueprint that will uncover the microbiome as an avenue to understand health and disease and to leverage it to help people. This is going to take time. It will take 5 to 10 years. But, once we have those clinical wins, and if we can achieve the goals, that will be validation needed to believe that the microbiome can be harnessed to help people.

 

This article was originally published in the November/December 2018 issue of Clinical OMICs. For more content like this and details on how to get a free subscription, go to www.clinicalomics.com.

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