Microbiome Modulation: The Next Frontier in Clinical Therapeutics

In August 2017, the NIH hosted a workshop to mark the 10th and final year of the Human Microbiome Project (HMP), a two-phase program that greatly increased our understanding the role of human microbiota in human health and disease. Although this NIH initiative is over, it has spurred continued funding for human microbiome research from the NIH, other government agencies, and several dozen external institutions, including the UW-Madison Microbiome Initiative, the UC San Diego Center for Microbiome Innovation and various private foundations, most notably, the Bill and Melinda Gates Foundation.

In this post intended for a general audience, I share a few thoughts on how the targeted modulation of our microbiota and microbiome may provide a potential solution to our most vexing therapeutic challenges. First, a brief and thoroughly incomplete primer on the intimate relationship between humans and microbes. For a long time, microbial ecosystem in the human host (the human microbiota) was viewed largely for its ability to cause serious disease. In the past few decades, this “antagonistic vision” of the relationship between host and microbes has been has been turned on its head. According to a recent study from the Weizmann Institute of Science in Israel, the human body has an estimated 3 trillion or 30 trillion cells, depending on whether one includes non-nucleated red blood cells. Each one of us also carries an estimated 40 trillion microbes, primarily bacteria. These microbes reside on body surfaces including the gut, skin and oral mucosa, with the colonic bacterial population predominating.

The gut “microbiota” is a complex ecosystem that appears to have co-evolved with their host over many millions of years. Although they are sometimes the cause of illness, for the most part the microbiota colonize their human host in a non-harmful coexistence referred to as mutualistic, where both the microbiota and the host benefit from the activity of the other. Over the past decade, it has become increasingly apparent that the human microbiota perform vital functions essential for human survival. We now know that alteration of microbiota (i.e., dysbiosis) and dysfunctional microbiomes are associated with human diseases such as obesity, diabetes, asthma, inflammatory bowel disease, colon cancer, rheumatoid arthritis and atherosclerosis. Although new technologies have enabled exciting discoveries about the importance of microbiomes, we still lack sufficient knowledge and tools to manage microbiota and microbiomes in a manner that prevents dysfunction or restores optimal function.

A number of pharmaceutical companies are attempting to leverage the dysbiotic microbiome, including Enterome BioScience, Osel, Rebiotix, Ritter Pharmaceuticals Second Genome, Seres Therapeutics, Symbiotic Health, Symbiotix Biotherapies and Vedanta Biosciences. Ritter Pharmaceuticals claims pole position in the microbiome modulation space with its short-chain galactooligosaccharides (RP-G28) for the amelioration and potential elimination of lactose intolerance. RP-G28 has the potential to become the first FDA-approved prescription drug approved through microbiome modulation, in this case for the management of lactose intolerance. Lactase is necessary to cleave lactose into glucose and galactose which are then absorbed through the gut. In its absence, the undigested lactose moves into the colon, producing carbon dioxide, hydrogen, acetate and methane by gas-producing bacteria by fermentation. Lactose intolerance is characterized by abdominal pain, bloating, cramping, gas and diarrhea. Many consider lactose intolerance as a “minor gastrointestinal inconvenience”. In reality lactose intolerance is syndrome ranging in intensity from mild to severe, In its moderate to sever forms, lactose intolerance syndrome can produce debilitating symptoms, result in social stigma, and adversely affect the quality of life of affected individuals.

Americans of Northern European ancestry usually continue to produce considerable lactase into adulthood (lactase persistence), thus allowing them to tolerate dairy products. In contrast, many individuals of Asian, African, Hispanic and Native American ancestry produce little no lactase into adulthood (lactase non-persistence), resulting in lactose intolerance. Gobally, approximately 75% of the human population are lactose malabsorbers, while in the U.S., an estimated 40 million Americans have lactose intolerance, with about 9 million having moderate or severe lactose intolerance.

Presently, the most common recommendation to deal with lactose intolerance syndrome is avoidance of milk and other dairy products. However, this is difficult to do given the ubiquity of dairy sourced products in our diets. Dairy products are a great source of calcium, vitamin D, and other nutrients. In addition, low dairy intake is a risk factor for decreased bone accrual, osteoporosis and other adverse health outcomes At a 2010 NIH Consensus Conference on Lactose Intolerance and Health, there were calls for additional research efforts to encourage dairy food consumption while limiting symptoms of lactose intolerance. The avoidance of dairy also reduces lactose-digesting bacteria in the G.I. tract and makes sufferers even more sensitive when inadvertently exposed to lactose.

In a their Phase 2a and Phase 2b clinical trials, Ritter Pharmaceuticals RP-G28 showed robust, clinically meaningful benefit to subjects in the reduction in abdominal symptoms of lactose intolerance syndrome. Notably, the effect of RP-G28 was durable for at least 30 days (the final testing time point) suggesting that RP-G28 promotes long-term colonic adaptation of the human microbiota. This is supported by the observed long-term beneficial change in the fecal microbiome of lactose-intolerant individuals receiving RP-G28.

R&D efforts at Ritter, other pharmaceutical companies and academic institutions underscore the therapeutic potential of selective gut microbiome modulation as a strategic intervention for the primary or adjunctive treatment of a variety of diseases, including obesity, diabetes, asthma, inflammatory and functional bowel disease, colon cancer, rheumatoid arthritis and atherosclerosis.

Dr. Najib Babul, PharmD, MBA, is an accomplished drug developer and inventor with extensive experience in bringing several dozen new [505(b)(1)] and repurposed [5050(b)(2)] drugs to market. Presently Najib Babul provides consulting services to pharmaceutical companies, investment banks, and I.P. law firms, including licensing due diligence, orphan drug applications, Risk Evaluation and Mitigation Strategies (REMS), pediatric exclusivity, drug development planning, clinical trial design, and contract research organization (CRO) selection and management. Dr. Babul is also the Director of Medical and Pharmaceutical Consulting at the California Institute of Advanced Management. Najib Babul is an author of over 170 publications, including the LancetJournal of Clinical Pharmacology, Cancer, Journal of Clinical OncologyAnesthesiologyClinical Pharmacology & Therapeutics, JAMA and Anesthesia & Analgesia.