Molecular Studies to Identify Mechanisms That Underlie Symptom Improvement in Microbiota Transfer Therapy Patients
Abstract
Chronic gastrointestinal (GI) symptoms are a common finding in individuals with autism spectrum disorder (ASD), and the GI symptom severity is correlated with negative behavioral manifestations in this population, creating an even broader negative quality-of-life impact. Although these clinical observations are generally accepted, the successful treatment of GI symptoms in children with ASD remains a significant challenge. One novel treatment strategy that has recently shown significant promise for the treatment of children with ASD and chronic GI symptoms is microbiota transfer therapy (MTT; aka fecal microbiota transplant [FMT]). The way this works is that fecal microbiome (mostly composed of bacteria) is isolated from the stool of exceptionally healthy donors and made into a pill that can be swallowed. These pills can then be used to treat patients with an unhealthy gut. In a small pilot study, 18 participants (children with an ASD diagnosis) who had GI symptoms had their guts “cleaned out” (i.e., a bowel cleanse, as you might do before a colonoscopy), including an antibiotic treatment to kill most of the bacteria in their gut, and were then given the microbiota from healthy donors to see whether their gut could be repopulated by the healthy bacteria. The study was testing to see whether (1) the treatment was safe, (2) the gut symptoms improved, (3) some of the “autism behaviors” improved and, (4) any improvements were long-lasting. The study found that the MTT was well tolerated with an 80% improvement in GI symptoms and a 25% improvement in autism symptoms. A follow-up at 2years after treatment found that most GI benefits were still apparent, and autism symptoms were now 45% reduced compared to baseline. This work was published in 2017 (Kang et al., 2017) and the follow-up study was published in 2019 (Kang et al., 2019). Based on the success of this Phase 1 trial, Dr. James Adams (Key Collaborator) and his team applied for and received funds from the Congressionally Directed Medical Research Programs’ Autism Research Program 2016 Clinical Trial Award mechanism to conduct a Food and Drug Administration-approved Phase II clinical trial in adults with ASD and GI symptoms. This study is currently enrolling 84 adults with ASD and GI symptoms and 84 typically developing adults without ASD, half of whom have GI symptoms. The goals of the funded Phase II trial are to (1) evaluate the safety and efficacy of MTT, (2) determine whether a longer treatment course is beneficial, and (3) determine the long-term safety and efficacy. Dr. Adams and his team will be collecting, in addition to GI and autism behavioral symptom data, multiple clinical specimens (whole blood, serum, and stool) at several time points throughout this clinical trial. The purpose of the study you are evaluating today (Dr. Stephen Walker, Principal Investigator) is to use these clinical specimens taken from patients before, during, and after the treatment to see whether, on a molecular level, we can determine what things change when patients get better. We will be measuring gene expression in their blood and metabolites in both their blood and stool to see what molecular changes have occurred in patients getting MTT that may help explain the improvements seen in most patients. We know that microbiota transfer therapy is very safe and works in children with GI symptoms and ASD to make their symptoms get better or go away all together. We don’t know exactly why. That is the point of the proposal in front of you, to try to understand at the molecular level why this therapy works. In order to do a study like we are proposing, it is obviously necessary to have the right specimens. These can only be obtained from a study such as the clinical trial that Dr. Adams has already been funded to perform. So by using samples that are already being collected as a part of a very important and very expensive clinical trial, we are adding value to the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010275
Entities
People
- Stephen Walker
Organizations
- United States Army
- Wake Forest University