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Identifying the Significance of Microbiome Diversity

In This Article

  • Microbiome diversity confers protective effects on human health, and decreased diversity can increase susceptibility for a number of allergic and autoimmune diseases
  • Researchers at the Center for the Study of IBD study how microbiome composition contributes to health—identifying associations between bacterial species and disease states—in order to find novel treatments and methods of delay or prevention
  • Key findings stemming from research on the microbiome in early childhood and in IBD—e.g., identification of biological markers associated with response to IBD treatment—will guide treatment development
  • Future research is expanding into the potential role of the microbiome in HIV and diseases such as autism, food allergy and schizophrenia

Research suggests links between the gut microbiome and diabetes, autism, cancer, obesity and other conditions. Researchers at the Center for the Study of Inflammatory Bowel Disease (CSIBD) at Massachusetts General Hospital, are studying how the gut microbiome helps maintain health and contributes to disease.

The Director of the CSIBD, Ramnik Xavier, MD, is collaborating with physician-scientists on human studies to find more effective treatments and ways to delay and ultimately prevent disease. Two key areas of focus are the effects of early-life microbiome development on childhood health and the role of the microbiome in IBD.

Understanding the Microbiome in Early Childhood

Based on studies from CSIBD researchers and others, evidence is clear that development of the gut microbiome in the first year of life is critical in the education and maturation of the immune system. Depletion of certain protective bacterial populations in children with untreated ulcerative colitis resulted in increased disease severity, highlighting the importance of microbiome diversity. Furthermore, response to therapy was associated with changes in specific bacteria over time, characteristics that may aid in the prediction of an individual's response to treatment.

In an earlier landmark study published in 2015, Dr. Xavier and his team identified a connection between microbiome changes in infancy and early childhood onset of type 1 diabetes (T1D). The researchers followed children who were genetically predisposed to T1D from birth to age three. They collected stool samples to track the microbial composition in the children's microbiomes and found an increase of inflammation-associated bacteria prior to the onset of the disease.

In subsequent studies, Dr. Xavier and his team compared the microbiomes of the children at high risk for T1D with those of children at normal risk.

"We've identified some really intriguing findings that point to the 'hygiene hypothesis,'" Dr. Xavier says. The hypothesis posits that microbial exposure early in life benefits immune system development and that sanitary conditions in developed countries hinder that development, leading to a missing microbiome.

Dr. Xavier and his colleagues are currently conducting studies with pregnant women, infants and children up to age three to better understand the natural history of the gut microbiome and the impact of antibiotics and environmental factors.

Studying the Microbiome in Inflammatory Bowel Disease

Dr. Xavier and his colleagues are working to identify early microbiome changes in Crohn's disease and ulcerative colitis. Their research can help scientists develop improved IBD treatments by correcting those microbiome changes.

The RISK Stratification study examined the microbiome in about 400 U.S. and Canadian children newly diagnosed with Crohn's disease. The study compared samples of intestinal tissues from these treatment-naive patients with samples from about 200 healthy control participants.

Similarly, the PROTECT study involved about 400 U.S. and Canadian children newly diagnosed with ulcerative colitis (UC). Researchers evaluated biospecimens from patients at the time of diagnosis and at four, 12 and 52 weeks into treatment. Studying children allowed the researchers to learn more about how early gut microbiome composition influences the risk of developing IBD and how subsequent treatment affects that composition.

"What these two studies have told us," Dr. Xavier says, "is that the currently available probiotics are not going to correct the microbiome changes seen in patients with Crohn's disease and ulcerative colitis."

Dr. Xavier and his team have also published leading studies on how bacteria influence the immune system, including a paper that identified a bacterium called Ruminococcus gnavus associated with flares of IBD. When IBD worsened, R. gnavus increased, and when it improved, the bacterium decreased.

Creating a Road Map for Better IBD Therapies

The RISK and PROTECT studies revealed that:

  • Diversity in the microbial population was significantly reduced in patients with Crohn's disease. Their microbiomes showed increased levels of pathogenic bacteria, decreased levels of beneficial bacteria and an even greater imbalance in patients with more severe symptoms
  • Antibiotic-resistant genes increased in the bacteria colonizing the colons of treatment-refractory patients with UC
  • The current standard UC treatments, mesalamine and prednisone, were effective in only about 35% to 40% of study participants

The R. gnavus study showed how bacteria make certain products and how those products are being recognized by the host immune system. "When these products are harmful, they cause inflammation. When the products are healthy, they promote healing," Dr. Xavier says.

These bacterial products offer targets for intervention that could be a starting point for developing more effective therapies for IBD.

Through their findings, Dr. Xavier and his colleagues are essentially providing a road map for researchers working on better treatments for Crohn's disease and UC.

Building Computational Tools to Design New Medications

With an eye toward precision medicine, investigators at the CSIBD have already translated their findings about the microbiome into computational approaches for designing novel therapies.

One such example is fecal microbiota transplant for recurrent Clostridium difficile infection, which commonly co-occurs with IBD. Because each individual's gut microbiome is unique, a more effective treatment could be developed by combining microbes from multiple donors. Using computational tools, Dr. Xavier and his team have identified the principles of designing these microbial cocktails.

Combining these principles with the microbial road map from the RISK and PROTECT studies could allow for individualized microbial cocktail treatments for IBD and other conditions affected by the microbiome.

The Microbiome Beyond IBD

Dr. Xavier notes that CSIBD's work is expanding to autoimmune diseases, allergies and other diseases with an urgent need to find contributing factors. The center has initiated studies on HIV and diseases such as autism, food allergy and schizophrenia that likely have a microbial influence.

Members of Dr. Xavier's team are now traveling to remote parts of the world where T1D and other autoimmune diseases remain at low levels. They are isolating specific bacteria from samples of people in those areas to create a repository of microbes that are missing in the developed world. This microbial bank could be used to replenish the missing microbiome, thereby treating or delaying the onset of autoimmune diseases.

Dr. Xavier says: "Once we collect these missing microbes, we'll be in a better position to redesign probiotics and prebiotics."

He and his colleagues are working to find ways to harness the microbiome for disease treatment and health management.

"By working at a place like Mass General," he says, "I have a unique opportunity to direct the traffic in microbiome research and contribute to high-impact studies with my collaborators."

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