Confronting the Mystery of the Microbiome

HMS researcher Marco Jost works to decode the cross talk between microbes and their human hosts

Portrait photo of Marco Jost
Marco Jost. Image: Rose Lincoln

Two years ago, with the unmistakable pop of a champagne cork, microbiologist Marco Jost launched his lab at Harvard Medical School. But that celebration was short-lived. Jost, sensing the vastness of the work ahead of him, set the bubbly aside and dove into his research on the human gut microbiome.

Jost, an assistant professor of microbiology in the Blavatnik Institute at HMS, is working to decipher how the bacteria, fungi, and viruses dwelling inside us regulate our metabolism, modulate the activity of our genes, alter our immunity and, ultimately, how they protect our health and shape our risk for disease.

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In recent years, science has made undeniable progress in understanding the human microbiome. Yet, the complex interplay between the trillions of microbes that inhabit our bodies and influence our health remains a biologic black box.

Jost’s lab seeks to decode the language of molecular communication between the human host and its microbes, using CRISPR-based gene editing tools, cell-based models to test the effects of different microbial molecules on various tissues and organs, and a variety of other approaches borrowed from disciplines including immunology, biochemistry, and chemical biology.

Jost describes the microbiome as “a global influencer of human health.” Understanding how the microbiome exerts this influence, Jost adds, will be possible only by translating the precise molecular signals and chemical messages exchanged between microbes and their human hosts.

Harvard Medicine News recently spoke with Jost to learn more about his work.

HMNews: You study the gut microbiome’s role in disease and health. What ignited your interest in this field?

Looping video of Marco Jost opening a bottle of champagne in his lab
Marco Jost celebrates the 2021 opening of his lab at HMS. Video: Manasvi Verma

Jost: I became interested in the microbiome in my graduate studies, when the first big surveys of the human microbiome were starting to appear. These surveys pointed to a remarkable ecological and chemical complexity of the microbiome as well as its all-important roles in human health. This all just seemed so fascinating! That's when I started following the field and thinking about one day working in it. I didn’t end up entering the field until later, during my postdoc work.

HMNews: You’ve described the relationship between gut microbes and the human body as a chemical dialog. But the bacteria that live in our guts number in the hundreds of trillions and our bodies are immensely complicated. How do you even begin to decipher this dialogue?

Jost: This is a fantastic question and one we think about almost daily. You're absolutely right that everything about this research is complicated: there are thousands of different bacteria, and even more unique small molecules that they produce. Each small molecule can, in principle, interact with lots of cell types in our bodies, and that triggers additional pathways that ultimately shape human biology.

Our main premise is that a lot of the effects of the microbiome on human health can be explained by small molecules from the microbiome acting at the level of human cell biology, for example, through activating or inhibiting signaling pathways or by blocking certain chemical interactions.

And so, building on this premise, we start a lot of our work by taking large collections of small molecules or mixtures of molecules from the microbiome, and adding them to cells from different organs or tissue types, and then reading out how the cells respond at the molecular level. We like these types of experiments because they allow us to be systematic.

For molecules that elicit interesting responses in human cells, we then use CRISPR-based screening to pinpoint the corresponding receptors and pathways in the human cells involved in these responses. What this basically means is that we can use CRISPR to add or remove genes in human cells to determine how the presence or absence of these genes affects the way human cells respond to the microbial molecules. And with these two approaches we can define concrete molecular links, which allows us to do much more defined experiments in more complex models such as animal models.

HMNews: What are some of your most interesting findings to date?

Jost: We’re excited about many different findings. For example, we discovered that small molecules produced by gut microbes impact hormone production, pathways that control homeostasis of the gut, and lipid metabolism — in essence, how the body strikes a balance between making and breaking down fats. All of these are examples of basic pathways in human cells that are important for human biology.

HMNews: What are some of the most tantalizing therapeutic applications of microbiome science you foresee in the next 10 to 20 years?

Jost: To me the most promising direction here is that the microbiome is essentially a window into new biology. It’s become clear that the microbiome is a global modulator of many aspects of human biology. And so, by following how the microbiome exerts these effects, we may come upon new pathways that regulate these aspects of human biology — and in turn this will create a foundation for the development of new therapeutics. For example, we may come upon new drug targets or new compounds to treat a wide range of neurological or autoimmune disorders.

HMNews: What do you like to do outside the lab?

Jost: I will admit that starting the lab and everything associated with it has kept me pretty busy, but I try to make time for other things, usually at least for relaxing with my girlfriend and our newly adopted little cat, cooking — I am responsible for all the cooking at home — a weekly soccer game, squash, and board games. We are deep into the board game Frosthaven with some friends right now.

Jost recently learned that he is one of eight Harvard Medical School researchers who have been awarded High-Risk, High-Reward Research program grants by the National Institutes of Health.

This interview has been edited for length and clarity.