Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota

The human gut and brain interact in complex ways, and abnormal conditions in the gut may predispose individuals to neurodevelopmental disorders Individuals with Autism Spectrum Disorders (ASD) Parkinson’s disease, and Alzheimer’s disease⁵, for example, have been known to experience chronic gastrointestinal (GI) symptoms as a common co-occurring medical condition, suggesting the presence of a gut-brain axis. Hallmayer et al. investigated 192 twin pairs and found that both genetic and environmental factors contribute to the etiology of ASD. The gut microbiome represents an important environmental factor that may exert an influence on symptoms, and a growing number of research groups have observed that children with ASD have distinctive gut microbiomes compared to neurotypical children. Moreover, multiple mouse studies have reported that gut microbes and their metabolites can impact behavior through the gut-brain axis, including for ASD

Effective treatments for ASD include behavioral therapy, speech and social therapy, and dietary/nutritional/medical treatments, but no medical treatment has been approved to treat core symptoms of ASD, such as social communication difficulties and repetitive behaviors. Considering the link between the gut and brain, modulating the gut microbiome by antibiotics, probiotics, prebiotics, and/or fecal microbiota transplant (FMT) could be a viable therapeutic option. In FMT, a large diversity and number of commensal microbes from a healthy donor are used to transform a dysbiotic gut microbiome into a healthy microbiome. In fact, FMT is the most effective therapy to treat recurrent Clostridium difficile infection and has shown varying levels of success for treating other GI disorders which has drawn attention to the method for use beyond GI-associated disorders. Previously, we performed a pioneering open-label modified-FMT trial with an intensive combination called Microbial Transfer Therapy (MTT) consisting of two-week vancomycin treatment followed by a bowel cleanse and then high dose FMT for 1–2 days and 7–8 weeks of daily maintenance doses along with a stomach-acid suppressant, administered to children with ASD and chronic gastrointestinal problems. After this 10-week MTT treatment and an eight-week follow-up observation period (18 weeks in total), we observed an 80% reduction in GI symptoms and a slow but steady improvement in core ASD symptoms. At the same time, we learned that gut microbial diversity, including potentially beneficial microbes, significantly increased after MTT. Two years after this original clinical trial was completed, we re-evaluated the participants to determine whether observed improvements in behavior and GI symptoms persisted, and to ascertain the long-term impact of MTT on the gut microbiome of the study participants.

Improvements in GI and ASD symptoms remained two years after the MTT stopped

Two years after the MTT was completed, we invited the 18 original subjects in our treatment group to participate in a follow-up study, and all provided informed consent. We performed the same GI and behavior tests that we employed previously¹⁹. 12 of 18 participants made some changes to their medication, diet, or nutritional supplements, but these changes were well documented and were mostly minor (Supplementary Table S1). We note that due to the open-label nature of this initial trial, all of the assessments are subject to placebo effect, however the long-term improvements we observed here are promising. Two years after treatment, most participants reported GI symptoms remaining improved compared to baseline (Fig. 1a and Supplementary Fig. S1). The improvement was on average 58% reduction in Gastrointestinal Symptom Rating Scale (GSRS) and 26% reduction in % days of abnormal stools (Daily Stool Record or DSR) relative to baseline, and this result is similar to what we observed at the end of treatment. The improvement in GI symptoms was observed for all sub-categories of GSRS (abdominal pain, indigestion, diarrhea, and constipation, Supplementary Fig. ) as well as for all sub-categories of DSR (no stool, hard stool, and soft/liquid stool, Supplementary Fig.), although the degree of improvement on indigestion symptom (a sub-category of GSRS) was reduced after 2 years compared with weeks 10 and 18. This achievement is notable, because all 18 participants reported that they had had chronic GI problems (chronic constipation and/or diarrhea) since infancy, without any period of normal GI health (Supplementary Table ). The families generally reported that ASD-related symptoms had slowly, steadily improved since week 18 of the Phase 1 trial, and this was consistent with the data reported in Fig. Based on the Childhood Autism Rating Scale (CARS) rated by a professional evaluator, the severity of ASD at the two-year follow-up was 47% lower than baseline (Fig. 1b), compared to 23% lower at the end of week 10. At the beginning of the open-label trial, 83% of participants rated in the severe ASD diagnosis per the CARS (Fig.. At the two-year follow-up, only 17% were rated as severe, 39% were in the mild to moderate range, and 44% of participants were below the ASD diagnostic cut-off scores (Fig.. The parent-rated Social Responsiveness Scale (SRS) assessment revealed that 89% of participants were in the severe range at the beginning of the trial, but the percentile dropped to 47% at the two-year follow-up (Fi. ), with 35% in the mild/moderate range and 18% below the cut-off for ASD. For the parent-rated Aberrant Behavior Checklist (ABC), total scores continued to improve, and were 35% lower relative to baseline (versus 24% lower at the end of treatment, relative to baseline; Fig.. The Parent Global Impressions-III (PGI-III) scores remained similar to the scores at the end of treatment (week 10) of the open-label (Fig. 1e). The Vineland Adaptive Behavior Scale (VABS) equivalent age continued to improve (Fig. , although not as quickly as during the treatment, resulting in an increase of 2.5 years over 2 years, which is much faster than typical for the ASD population, whose developmental age was only 49% of their physical age at the start of this study. Moreover, we observed improvement in behaviors in most sub-categories (Supplementary Figs S2c,d, and S3 for ABC, SRS, and VABS, respectively).