Current Research | Microbiota Therapeutics

CURRENT RESEARCH AT THE UNIVERSITY OF MINNESOTA

Partnership with OpenBiome

The University of Minnesota Microbiota Therapeutics Program is partnering with OpenBiome, a non-profit organization operating in Boston, to provide safe microbiota transplant to patients suffering with recurrent and refractory Clostridioides difficile infections. Intestinal Microbiota Transplantation (also known as Fecal Microbiota Transplantation) is recognized as a highly effective treatment option for C. difficile infections. However, this treatment is still quite novel and there are many unknowns. There is mounting evidence that certain patient populations suffering with C. difficile infections are more difficult to cure, including patients with inflammatory bowel disease, patients with kidney failure, elderly patients. Many patients also suffer with post-infection irritable bowel syndrome. Large scale, pragmatic clinical trials that track outcomes of treatments are essential for development of optimal treatment regimens.

Our program manufactures microbiota transplant products in different formulations. The volunteer stool donor program is overseen by the Institutional Review Board and monitored by the Clinical and Translational Science Institute of the University of Minnesota. All manufacturing is done in accordance with the FDA-approved Investigational New Drug Application using Good Manufacturing Practices protocols. OpenBiome distributes these products to many clinical programs across the United States and ensures collection of treatment outcome data into de-identified registries. All clinical programs are encouraged to participate in the American Gastroenterological Association FMT registry

Ulcerative Colitis

Ulcerative colitis in an inflammatory disease of the colon and one of the two major types of inflammatory bowel disease (the other one is Crohn’s disease). It affects ~ 500,000 people in the US alone. Ulcerative colitis is associated with a different microbial composition in the colon, although it is not clear whether that is the result or the cause of inflammation. It may be both. All currently available therapies target the immune system to lower the inflammation, and these treatments unquestionably help many patients. However, the responses are often incomplete or fail altogether. Also, none of these treatments targeting the immune system are curative.

We are working to develop next generation microbiota-based therapeutics tailored to ulcerative colitis. Specifically, we are developing rational selection methods to identify donor microbial communities that can dampen the colon inflammation or even cure ulcerative colitis. Mechanistic understanding of the interactions between the host and its microbiota is essential for these efforts. The clinical interventional trials are led by Dr. Byron Vaughn

Link to Clinical Trial

Checkpoint Inhibitor Colitis

One possible complication of immunotherapy is checkpoint inhibitor colitis, which is a type of inflammatory bowel disease. Development of this condition can interfere with life-saving immunotherapy against cancer. There are provocative reports that this condition can be ameliorated by transferring microbiota from healthy donors into patients. Dr. Amit Kulkarni is also leading a clinical trial of microbiota transplant therapy in checkpoint inhibitor colitis.

Link to Clinical Trial

Post-IMT diet in recurrent Clostridioides difficile infections

Patients commonly ask what they should be eating after receiving IMT in treatment of recurrent C. difficile infections. This is almost an obvious question since IMT only provides the inoculum of microbes, but diet is what provides their nutrition. The right diet should support the stability and resilience of the recovered microbes in the gut. It is also important to recognize that for many patients, recovery from recurrent C. difficile infections is complicated by post-infection irritable bowel syndrome. We are currently conducting a clinical trial that tests two different post-IMT diets in patients treated for recurrent C. difficile infections. This trial is led by Drs. Levi Teigen and Alexander Khoruts.

Link to Clinical Trial

Crohn’s Disease

Crohn’s disease is an inflammatory disease that can affect different parts of the gastrointestinal tract. The inflammation can lead to many complications, including strictures and bowel obstructions. Therefore, many patients must undergo surgeries to remove parts of the intestine that are causing the problem. Unfortunately, the disease typically comes back, and the patient may require more surgeries. Medicines that target the immune system to dampen the inflammation have proven to be invaluable in management of Crohn’s disease. However, the responses are often incomplete.

We are developing microbiota-based therapeutics to target the gut microbiome in different challenging situations caused by Crohn’s disease. The clinical interventional trials are led by Dr. Byron Vaughn.

Link to Clinical Trial

Acute Myelogenous Leukemia (AML) and Hematopoietic Stem Cell Transplantation (HSCT)

Treatment of leukemia and stem cell transplantation involve harsh chemotherapy that destroys the immune system and damages the gut. Antibiotics are used routinely to prevent and treat infections that commonly complicate these treatment regimens. However, damage to the gut microbes also disrupts the normal, tonic interactions between the healthy gut microbes and the intestinal tract. This may delay gut healing, paradoxically lead to more infections, and result in abnormal repair of the immune system and worsen graft-versus-host disease. We hypothesize that normalization of the gut microbes via microbiota transplant therapy may mitigate these problems. Drs. Armin Rashidi and Shernan Holtan led the placebo-controlled clinical trials to test the safety of microbiota transplant therapy in AML and HSCT patients.

Link to Clinical Trial

CLINICAL TRIALS SUPPORTED BY MICROBIOTA THERAPEUTICS PROGRAM

Food Allergies

Dr. Rima Rachid at the Boston Children’s Hospital is leading the clinical trials investigating microbiota transplant therapy for food allergies.

Patients with food allergies have been shown to have an altered composition of gut microbiome. Gut microbes have the potential to calibrate the immune responses. Prior pilot clinical trials have shown that fecal microbiota transplants can strengthen the regulatory immune circuits that inhibit allergic responses to foods. Understanding of these mechanisms is critical to development of microbiota-based therapies for food allergies.

Link to Clinical Trial

Pitt Hopkins Syndrome

Pitt-Hopkins syndrome (PTHS) is a rare, genetic, neurological disorder resulting from a mutation in the TCF4 gene. TCF4 plays important roles in nervous system physiology and development. Children with PTHS have intellectual disability, speech delay, and decreased muscle tone. Most patients engage in intense repetitive movements or behaviors and satisfy criteria for an autism spectrum disorder, although symptoms are variable. Gastrointestinal dysfunction (mainly constipation) and abdominal pain are very common. Dr. James Adams is leading the clinical trials of MTT for PTHS.

Link to Clinical Trial

Alcohol-Associated Liver Disease

Dr. Jasmohan Bajaj at the Virginia Commonwealth University has previously observed that fecal microbiota transplantation correlated with a reduction in alcohol cravings in patients with alcohol-associated liver disease. This observation is now being followed up in an NIH-funded placebo-controlled trial using microbiota transplant therapy.

Link to Clinical Trial

Autism Spectrum Disorders

Dr. James Adams at the Arizona State University has pioneered microbiota transplant therapy for autism spectrum disorders. An early trial has shown remarkable promise of MTT for the potential to improve the gastrointestinal symptoms and behavioral problems of patients with autism. Follow-up placebo-controlled trials are nearing completion, and the results are being analyzed.

Link to Clinical Trial

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