Gastroenterology

Microbiome Health

Recognizing a symbiotic organ

By Byron Vaughn, MD and Carolyn Graziger

What we didn’t fully appreciate until the early 2010s is that it is actually the microorganisms (bacteria, fungi and viruses), populating the gut, collectively called the gut microbiota, that mainly determined that health status. In fact, there are multitudes more bacteria in our guts than there are cells overall in our bodies–a vast, interactive population that we are just now beginning to meaningfully understand. We now recognize the intestinal microbiota as a symbiotic organ needed for our survival. There are more cells and genes in the intestinal microbiota than the human body. If you were to weigh the intestinal microbiota, they would be about three pounds, roughly the same as the human brain.



Starting at birth, the intestinal microbiota teach our immune system how to distinguish harmful bacteria and are essential in developing a healthy immune system. In fact, germ-free mice that are maintained in a sterile environment die early as they are severely malnourished and immunocompromised. The intestinal microbiota is essential for digestion of certain foods, in particular vitamin K and the B group vitamins. Moreover, the microbiota are involved in other complex metabolic activities, such as drug metabolism. Microbes produce and are influenced by certain types of neurotransmitters.

There are multitudes more bacteria in our guts than there are cells overall in our bodies.

The collective genomes of the microorganisms in the gut are called the intestinal microbiome. With the advent of low-cost mass sequencing, it became possible to measure the diversity and relative abundance of different species within the bacterial genome of our guts. The Human Microbiome Project, launched in 2007 by the National Institutes of Health, was an ambitious undertaking that laid the initial groundwork. Using these tools, researchers could begin to characterize what constitutes a healthy microbiome vs. the divergence or “dysbiosis” observed in various disease states. As the largest lymphoid organ in the body, the lining of the gut or colon serves a vital role as the barrier that keeps healthy bacteria where they’re supposed to be. And every sort of inflammatory gut disease can impinge on that role.

We know that almost every disease affecting humans, from rheumatoid arthritis, liver disease and multiple sclerosis, to pulmonary hypertension has an effect on the gut microbiota.

There are studies underway on a number of these conditions to see if we can determine which comes first – does the disease lead to dysbiosis in the microbiota or do microbiota issues cause the disease? Altered microbiota are associated with almost every disease affecting the human body. For example, inflammatory bowel disease, pulmonary hypertension and autism all have consistent alterations of the intestinal microbiota. By healing or restoring the intestinal microbiota, can we heal the systemic diseases? Given the nearly 400 IMT (Intestinal Microbiota Transplantation) studies currently listed on clinicaltrials.gov, it is clear there is keen interest in finding answers.

We do know that antibiotics, a critically important tool in treating infectious bacteria during this past century, have had a significant impact on the microbiota by decreasing the diversity of bacteria found in the gut. This phenomenon is markedly more prevalent in developed countries. C. diff, or Clostridioides difficile colitis, is a rather common result of antibiotic use that has historically, and ironically, been treated with antibiotics, which isn’t always successful.

C. diff can be a devastating condition of the colon that can lead to severe damage or even death if not treated effectively. Unfortunately, a number of people who develop C. diff infection develop recurrent infections after their course of antibiotics. This leads to a vicious cycle of antibiotics to treat C. diff, but the antibiotics also devastate the healthy bacteria. The devastated healthy bacteria are then unable to protect against recurrent C. diff infection. This is one condition where microbiota transplantation makes a significant difference.

Originally known as fecal microbiota transplantation or FMT, the procedure was recorded nearly 1700 years ago by a Chinese researcher who administered it orally with limited success. However, in 1958, surgeons in Colorado performed an experiment to treat a few patients critically ill with pseudomembranous colitis using fecal enemas from healthy donors. The success of that procedure led to a limited number of treatments over the following two decades with a 94% success rate.

Today we treat recurrent C. diff with IMT as the most effective way to replenish the healthy diversity of bacteria that will support recovery, with treatment methods now including an encapsulated, freeze-dried preparation of purified intestinal bacteria that is administered orally.

Increasingly, patients are choosing this option when a surveillance colonoscopy is not indicated. This procedure is so effective it is now recommended in multiple guidelines for the treatment of recurrent C. diff infection. While there remain regulatory issues with widespread availability of IMT, novel microbiota-based products are likely to be FDA approved for recurrent C. diff infection in the near future.

The next disease where IMT may play an important role is ulcerative colitis. The University of Minnesota is one of the first to study the use of capsule-based IMT material for treating ulcerative colitis and Crohn’s disease. Early results from small pilot randomized controlled trials suggest that IMT may work about as well as some biologic therapies, with approximately one in five patients achieving remission of the colitis. Treating the microbiota is a paradigm shift for patients with ulcerative colitis. Typically, treatment is aimed at suppressing the immune system. However, this approach is likely over-treating a person’s intestinal microbiota. It is unlikely that IMT alone will cure ulcerative colitis, as in the case of recurrent C. diff infection. However, treating the microbiota along with the immune system will hopefully lead to more patients living normal lives. Ultimately, with enough understanding of the interaction between the intestinal microbiota and the immune system, ulcerative colitis may be cured.

Altered microbiota are associated with almost every disease affecting the human body.

Safety of IMT remains one of the key concerns related to the widespread implementation for indications such as C. diff. The University of Minnesota developed a national registry to track efficacy and safety outcomes of IMT in the real-world setting. This registry represents the largest cohort of IMT patients treated with encapsulated IMT material. The first results of this registry are due out later this year. In addition to safety, the University of Minnesota’s Microbiota Therapeutics Program is examining changes in body composition over time following IMT, developing a novel pediatric formulation for IMT administration among other ongoing projects.

The University has one of the most robust clinical programs for both trials and treatments in the world. Our program is the only one in the U.S. at an academic medical center that can produce its own material in a GMP certified facility. That on-campus facility allows the University to support a number of trials in other parts of the country by producing their materials.

The University’s clinical and research team is supporting studies on Crohn’s disease, hepatitis, cirrhosis of the liver, and on autism’s connection to a healthy microbiome. Overall, hundreds of patients have been enrolled in these trials. An interventional trial conducted in collaboration with the Masonic Cancer Center is nearing completion. This trial is seeking answers about whether the use of IMT has the potential to reduce infection rates and/or complications of graft vs. host disease in patients with a type of acute leukemia. Recruitment is nearly complete as of Spring 2022 and results are expected soon. In addition, there are local studies on the microbiome’s impact on obesity and pre-diabetic conditions.

All of these studies make the microbiota and its health of great interest to patients and their families, leading to complex regulatory issues. To understand how to regulate treatments, first there needs to be ways to define what the microbiota actually is. Is it an organ? Is it a supplement? Is it a drug? If a person takes ten different probiotics, is that a microbiotic supplement?

The FDA has classified microbiota treatments as a biologic therapy that is regulated much like a drug. That opens the door for the commercialization of new microbiota derived therapies that may be coming to the market within this year. One type in development is not IMT, but rather a mixture of purified spores produced by healthy bacteria separated from fecal matter. This collection of spores (SER-109) appears to be significantly better than placebo at preventing C. diff from recurring. If the FDA approves this therapy, it would be a pivotal tool in the treatment of recurrent C. diff infection. 

Until a microbiota-based therapy is approved, the FDA has allowed IMT to be conducted for treatment of C. diff refractory in standard therapy, but for all other conditions, access to IMT is still rather tricky. Patients must be part of a clinical trial to access IMT for most conditions, which requires physicians to file an application for an Investigational New Drug or IND, a lengthy and complex procedure.

What’s In the Future

Our deepening understanding of the microbiome will lead to a much healthier population in the future. In fact, discoveries related to the microbiome will definitely lead to great advances in medicine.

Certainly, antibiotics have been a significant advance in medicine, allowing deadly diseases of the past hundred years to be treated effectively. In many ways antibiotics herald the age of modern medicine. Infections like streptococcus pyogenes or aureus, bacterial meningitis, tuberculosis and pneumococcal pneumonia are now treatable rather than commonly fatal, saving hundreds of thousands of lives each year.

At the same time, we now recognize and can manage the unintended consequences of the use of antibiotics and their effect on our organs. Beyond just C. diff, we are also faced with multi-drug resistant organisms as a result of widespread use of antibiotics both in people and in the food we eat. Along with antibiotics, we must also learn to protect our intestinal microbiota. By treating the microbiota and its important function, we can prepare patients for the impact of necessary antibiotics.

Unlocking the secrets of the microbiome will be as influential on human health as our understanding of the human genome is proving to be. In combination with the increasing proficiency of big data science to ferret health knowledge from vast quantities of information, we will be able to pinpoint treatments in the future for a variety of microbiota-related conditions.

For example, C. diff will move from being a common hospital acquired infection to a very rare occurrence in the future. IMT may also aid in preventing the development of multi-drug resistant organisms. We will be able to target these organisms in our gut for elimination, while building a more rigorous library of knowledge for promoting health. With the understanding that a healthy gut bacteria environment will help us live longer and better, the microbiome will influence all parts of human health. For now, the easiest way to improve the health of our gut microbiota is by giving them the food they need to thrive: mostly soluble fiber. In other words, eat your oatmeal.

Byron Vaughn, MD is an associate professor of medicine and gastroenterologist at the University of Minnesota Medical School. Carolyn Graziger is a research associate in the Microbiota Therapeutics Program at the University of Minnesota Medical School.



Carolyn Graziger is a research associate in the Microbiota Therapeutics Program at the University of Minnesota Medical School.