You’ll Never Walk Alone

Ready for a fascinating, “earthy” truth about ourselves? Our every surface and crevice teems with microbes—inside and out. In fact, bacterial cells in and on our body outnumber human cells by about ten to one. Most people walk around completely unaware of their invisible passengers. However, these little hitchhikers are an intimate part of what makes us who we are and, more to the point of this WEEKLY, how we are. In this issue, we explore the art of translating our growing knowledge of microbiota into mainstream healthcare.

Scientists and biopharma industry experts call the world of our personal bacteria, fungi, protozoa and viruses microbiota. Until fairly recently, they’ve pretty much ignored human microbiota. Doctors have largely concerned themselves with the minute percentage of bacteria and other microbes that cause illnesses such as pneumonia, tuberculosis and meningitis. Not anymore though! Almost every week, we find out more about how our personal ecosystem helps regulate processes such as digestion and immunity, and keeps disease-causing bacteria in check. Research has linked imbalances in this system to problems ranging from obesity to type 2 diabetes to mood disorders and even Parkinson’s disease.

What does this new perspective mean for biopharma? Experimental treatments involving fecal transplants (or bacteriotherapy) to restore healthy gut microbiota show promise in relieving the symptoms of inflammatory bowel disease. These approaches are unlikely to become mainstream, however, due to the lack of standardization and discomfort.

Easily Confused: Microbiome vs. Microbiota

The human microbiota consists of all of the microorganisms (bacteria, fungi, protozoa and viruses) that reside within us: on the surface and in deep layers of skin, in saliva and inside our mouths, on the surface of our eyes, and in our gastrointestinal tracts. The microbiome refers to genes inside of those microbes. Researchers study this genetic material to characterize the microbiota and their influence on health and disease.

Microbiota-Based Therapy: More Than A Gut Feeling

The premise of microbiota-based therapeutics is straightforward: identify ways in which the microbiota of people with a particular disease differs from a healthy person’s, and then try to make the unhealthy microbiota more like the healthy one. There are a few different approaches being studied to accomplish this, ranging from the broadest approach of fecal matter transplants to identifying specific beneficial bacterial strains to the most targeted approach of identifying specific bioactive compounds secreted by the microbiota. This week and next, we will examine each of these approaches.

The largest portion of our microbiota live in our gastrointestinal tract and is referred to as the gut microbiome. Fecal matter transplant (FMT), or bacteriotherapy, completely resets a patient’s gut microbiome with a healthy microbiome by transferring microbiota-containing fecal matter from a healthy donor through a colonoscopy or enema.

Feces as “medicine” in any capacity sounds unhygienic at best and just plain whackadoodle at worst. Surprisingly, the idea has been around for over a thousand years. Chinese health practitioners were administering a form of FMT to patients with life-threatening diarrhea as long ago as the fourth century, according to ancient medical texts.

Finally, in the past decade, clinical trials have suggested that FMTs effectively treat recurrent, antibiotic-resistant C. difficile, a serious bacterial infection that causes severe diarrhea and in some cases inflammation of the colon.   Bacteriotherapy also shows promise for other indications such as inflammatory bowel disease. Experiments in mice suggest that transferring the gut microbiome from one mouse to another impacts metabolism, turning a skinny mouse obese and vice versa. 

How do scientists think FMTs impart a therapeutic benefit? With C. difficile infection, it’s thought that most of us harbor low levels of C. difficile. Antibiotic use, however, sometimes wipes out the beneficial bacteria that keep C. difficile in check. Repopulating a patient’s gut via FMT restores the proper balance, reigning in C. difficile. The improvement of symptoms seen in inflammatory bowel disease patients after FMT likely has to do with immune modulatation – about 75% of people’s immune tissues reside in the gut! So unsurprisingly, our immune cells interact closely with our gut microbiota. Changes to the gut microbiome can change how immune cells behave, potentially resulting in inflammation.

FMT Standardization

One obstacle to FMT becoming routine therapy is the lack of standardization. Biopharm is on it though. Creating a standardized preparation for the transfers, Rebiotix (Roseville, MN) recently introduced RBX2660, a microbiota suspension of stool samples from rigorously screened, healthy donors. RBX2660 is currently in Phase 3 studies for recurrent C. difficile infection. It’s also in Phase 1 studies for vancomycin-resistant enterococci, pediatric ulcerative colitis, multi-drug resistant urinary tract infections, and hepatic encephalopathy. The FDA granted RBX2660 fast track, breakthrough, and orphan designations. Rebiotix is also developing a more user-friendly formulation of the treatment – a capsule. This less invasive treatment is now in Phase I clinical studies for recurrent C. difficile prevention.

Next week, we’ll discuss other, more refined approaches to working with our microbiome, such as isolating separate strains of native bacteria for clinical use. We’ll also feature some of the companies on the forefront of these efforts. Finally, we’ll look at microbiome-based diagnostics and how the FDA may regulate these emerging therapeutics.

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