Functionally Understanding the Microbiome

This is the second article in a series about research related to the human microbiome at Partners’ academic institutions. We talk to Alessio Fasano, MD, Director, Mucosal Immunology and Biology Research Center, MGH.

In the past decade, technological advances have shown that what we thought we knew about the human microbiome was only the tip of a very large iceberg, says Alessio Fasano, MD.

“We now know more about the complexity of the microbiome, its plasticity and dynamic changes over time, and how its composition can be influenced by many factors, including lifestyle, infections and antibiotics,” Fasano says.

These insights have come from advances in high throughput sequencing, which has made it possible to study the genetic makeup of large numbers of patient samples, as well as new computing technologies that can process the large data sets that result.

“With these advances, we are not only capable of answering ‘who’s there’ but can also look at the whole genetic array of these microorganisms and see what genes are expressed at any given time,” Fasano says.

The next step will be to move from a descriptive approach of the microbiome (what it is) to a functional one (what it does).

A better understanding of this human-microbiome crosstalk could help in developing new precision medicine-based strategies to treat conditions such as celiac disease, type 1 diabetes, multiple sclerosis, autism and even cancer.

Fasano is taking a multifaceted approach to reaching this goal as Director of the Mucosal Immunology and Biology Research Center at MGH and the Center for Celiac Research and Treatment at Mass General Hospital for Children (MGHfC).

He is also Director of the recently launched Pediatric Translational Research Center at MGH, which encompasses many MGHfC investigators studying the development and changes of the microbiome that occur in children genetically predisposed to chronic inflammatory disorders, including autoimmunity, obesity and food allergies.

One goal of Fasano’s research is to develop new probiotic and prebiotic treatments that could treat disease by resolving imbalances in the microbiome. “A bolder and more ambitious goal would be to target the microbiome for primary prevention, meaning to completely avoid these diseases from developing in genetically predisposed individuals.”

While the recent technological advances have been encouraging, there is still a lot more that researchers need to understand, Fasano says.

“For example, we know how the microbiome in individuals who are affected by a variety of chronic inflammatory diseases is different from the microbiome of a healthy individual. But we still don’t know what a ’healthy’ microbiome entails and if these differences are why people develop these diseases.”

The Role of Zonulin

A key target of interest for Fasano is zonulin, a protein that modulates the tight junctions linking the epithelial cells in the intestines, kidneys and lungs as well as the endothelial cells that form the blood-brain barrier.

It was previously believed that these junctions between cells were fixed and impermeable. However, in 2000, a research team led by Dr. Fasano discovered zonulin and identified its role as a modulator of these junctions between cells.

After this discovery, Fasano and others began to revisit the hypothesis of the ‘so-called’ leaky gut syndrome, or intestinal permeability, as a condition with a role in many diseases.

He explains that there is general agreement that many pathological conditions—infectious diseases, autoimmune disorders, neurodegenerative diseases and cancer—have chronic inflammation as a common denominator.

It is also agreed that there are two key components necessary to develop those diseases—genetic predisposition and exposure to environmental triggers.

With the discovery of zonulin, Fasano and his research team now believe there are three additional elements at play in this process—an impaired epithelial/endothelial barrier, a defective immune response and an unbalanced microbiome.

The impaired epithelial/endothelial barrier, which results from an overexpression of zonulin, loosens the junctions between cells, allowing more molecules to pass through the intestinal lining into the body (and vice versa) and exposing the body to more environmental triggers.

If researchers can find ways to regulate levels of zonulin in the body, it could help in the treatment and prevention of these diseases.

Larazotide acetate, a zonulin inhibitor, is scheduled to soon enter Phase 3 clinical trials, and the Fasano lab has recently developed a transgenic mouse model that overexpresses zonulin, which will further aid in defining the role of zonulin in inflammatory diseases.

Studies and Initiatives

Fasano believes the recently launched Pediatric Translational Research Center will help to further define the relationship between the composition of the microbiome and the evolution of disease.

The center’s key effort is to establish a pediatric biobank, including recruiting large cohorts of at-risk infants and following them over time to learn what changes occur in the microbiome and how those changes relate to disease development. The team hopes to use these longitudinal studies to create mathematical models that predict who will develop disease and who will not.

Outreach to Industry

Fasano believes the path to progress requires a team-oriented approach that includes scientists from many disciplines as well as legislators, legal experts, investors, opinion leaders and members of the pharmaceutical industry.

To foster these relationships, the MGH Research Institute recently launched a Microbiome Think Tank that convenes stakeholders from each group to discuss scientific challenges and identify new opportunities.

The Think Tank is co-chaired by Fasano and Ashwin Ananthakrishnan, MD, from the Mass General Digestive Healthcare Center.

“Thanks to this initiative, we’ve been able to catalyze the involvement of investigators from the entire New England area along with investors and pharma that have their presence in Boston,” Fasano says. “Together, we are outlining a roadmap to bring the knowledge acquired on the human microbiome to clinical fruition.”

“The path is still long, but I feel that we are making tremendous progress in achieving our overall goal.”