rexresearch.com
Rosa KRAJMALNIK-BROWN,
et al: Fecal Transplants vs
Autism
https://www.rt.com/news/456148-fecal-transplants-autism-breakthrough/
Fecal transplants yield MASSIVE
breakthrough for child autism, 50% reduction in severity
(VIDEO)
Scientists are celebrating a “world-first discovery” which shows the “highest improvement” in child autism patients, using fecal transplants to massively curtail symptoms and greatly reduce suffering.
The results of the initial study involving 18 children show great promise: 83 percent of the children had “severe” autism symptoms, but just two years later, only 17 percent had “moderate” symptoms, while 44 percent fell below the threshold for “mild” autism.
The team recorded a roughly 45-percent drop in language, social, and behavioural issues in the children over the course of the study.
The initial success of the microbiota or ‘fecal transfer’ therapy adds further weight to the theory this, and many other, neurological conditions may be strongly connected to the gut rather than the brain.
“We are finding a very strong connection between the microbes that live in our intestines and signals that travel to the brain,” Dr. Rosa Krajmalnik-Brown, a microbiologist at Arizona State University who jointly led the study, said, adding that, “Two years later, the children are doing even better, which is amazing.”
In the US, one in every 59 children is diagnosed with some form of autism, which is a spectrum disorder, a vast increase in diagnosis from just one in every 150 in 2000. This means that half a million people on the autism spectrum will become adults in the next decade, “a swelling tide for which the country is unprepared,” according to the researchers.
In children with autism, gastrointestinal symptoms such as constipation and diarrhoea can cause irritability, decreased attention span, and negatively impact behaviour, exacerbating other symptoms and making treatment and condition management far more difficult.
The regimen consists of pre-treatment with a bowel cleanse, administering a stomach acid suppressant and fecal transplants for between seven and eight weeks. The ‘donation’ of more diverse gut bacteria greatly boosts overall health and wellbeing in the patients.
Much larger trials are required before the treatment is officially approved by the US Food and Drug Administration.
The treatment was originally pioneered by Dr. Thomas Borody, an Australian gastroenterologist, who has hailed the results as a significant breakthrough.
“This is a world-first discovery... I would call it the highest improvement in a cohort that anyone has achieved for autism symptoms,” he said.
https://biodesign.asu.edu/news/autism-symptoms-reduced-nearly-50-two-years-after-fecal-transplant
Autism symptoms reduced nearly 50% two
years after fecal transplant
According to the Centers for Disease Control and Prevention, about one in every 59 children in the U.S. is diagnosed with autism, up from one in every 150 in 2000. They report that “about half a million people on the autism spectrum will become adults over the next decade, a swelling tide for which the country is unprepared.”
The apparent rise in autism spectrum disorder (ASD) and its stubborn resistance to treatment has spurred a legion of researchers to enter the field and explore the disability in innovative ways.
Currently, effective treatments for ASD include behavioral therapy, speech and social therapy, psychiatric medications, and dietary and nutritional approaches. However, no medical treatments have been approved to treat core symptoms of ASD such as social communication difficulties and repetitive behaviors.
One promising avenue of autism research involves the gut microbiome, which is the collection of microbes that lives in our intestines and helps us in many ways including digestion of our food, training our immune system and preventing overgrowth of harmful bacteria. Recent research suggests our gut microbiomes also affect brain communication and neurological health. Worldwide, interest is growing in the idea that changes in normal gut microbiota may be responsible for triggering a vast range of diseases.
In a new study, “Long-term benefit of Microbiota Transfer Therapy in Autism Symptoms and Gut Microbiota,” published in Scientific Reports, Arizona State University researchers Rosa Krajmalnik-Brown, Ph.D., James Adams, Ph.D, and lead author Dae-Wook Kang, Ph.D, demonstrate long-term beneficial effects for children diagnosed with ASD through a revolutionary technique known as Microbiota Transfer Therapy (MTT), a special type of fecal transplant originally pioneered by Dr. Thomas Borody, an Australian gastroenterologist. Remarkably, improvements in gut health and autism symptoms appear to persist long after treatment.
At two years post-treatment, most of the initial improvements in gut symptoms remained. In addition, parents reported a slow steady reduction of ASD symptoms during treatment and over the next two years. A professional evaluator found a 45% reduction in core ASD symptoms (language, social interaction and behavior) at two years post-treatment compared to before treatment began.
“We are finding a very strong connection between the microbes that live in our intestines and signals that travel to the brain,” said Krajmalnik-Brown, a professor at the Biodesign Swette Center for Environmental Biotechnology at the Biodesign Institute and ASU’s School for Sustainable Engineering and the Built Environment. “Two years later, the children are doing even better, which is amazing.”
“Many kids with autism have gastrointestinal problems, and some studies, including ours, have found that those children also have worse autism-related symptoms,” said Krajmalnik-Brown. “In many cases, when you are able to treat those gastrointestinal problems, their behavior improves.”
Roughly 30-50% of all people with autism have chronic gastrointestinal (GI) problems, primarily constipation and/or diarrhea that can last for many years. That chronic discomfort and pain can cause irritability, decreased attention and learning, and negatively impact behavior.
An earlier study with only vancomycin (an antibiotic) had found major temporary improvements in GI and autism symptoms, but the benefits were lost a few weeks after treatment stopped despite use of over-the-counter probiotics.
So, the question at hand was what’s going on in the gut, and how does it affect both physical and behavioral symptoms of autism, and how can we develop a long-lasting treatment?
Krajmalnik-Brown, Kang and Adams have shown that by transferring healthy microbiota to individuals lacking certain gut bacteria, it is possible to “donate” a more diverse set of bacteria into the patient and improve gut health.
In Australia, Fecal Microbiota Transplantation (FMT) was initially developed by Borody. At his Centre for Digestive Diseases in Sydney, Borody has overseen more than 18,000 FMTs for various disorders since 1987. He pioneered in Australia the use of FMT for colitis and Clostridium difficile infection, and was the first to use oral FMT to treat children with ASD. Only one dose of FMT is usually enough to cure C. Difficile infections, but his patients with autism were far harder to treat. He discovered that three months of daily FMT was required to treat his autism patients, but eventually resulted in significant improvements in both GI and autism symptoms.
Based on his experience with his patients, Borody led the design of the clinical treatment used at ASU for this study. The MTT approach involves 10 weeks of treatment, including pre-treatment with vancomycin, a bowel cleanse, a stomach acid suppressant, and fecal microbiota transfer daily for seven to eight weeks.
The initial open-label study, led by Krajmalnik-Brown and Adams, and published in the journal Microbiome in 2017, concluded that “this exploratory, extended-duration treatment protocol thus appears to be a promising approach to alter the gut microbiome and improve GI and behavioral symptoms of ASD. Improvements in GI symptoms, ASD symptoms, and the microbiome all persisted for at least eight weeks after treatment ended, suggesting a long-term impact.” The present study now shows the benefits are extended beyond eight weeks to at least two years post-treatment.
The ASU team compared differences in the microbiome of children with autism compared to typically developing children. At the start of the study, children with autism were found to have lower diversity in their respective gut microbes and were depleted of certain strains of helpful bacteria, such as Bifidobacteria and Prevotella. “Kids with autism are lacking important beneficial bacteria, and have fewer options in the bacterial menu of important functions that bacteria provide to the gut than typically developing kids,” Krajmalnik-Brown said.
FMT treatment substantially increased microbial diversity and the presence of helpful bacteria in the gut, such as Bifidobacteria and Prevotella. After two years, diversity was even higher and the presence of beneficial microbes remained.
“We originally hypothesized that our therapy would be efficient to transform the dysbiotic gut microbiome toward a healthy one. In our original paper in 2017, we reported an increase in gut diversity together with beneficial bacteria after MTT, and after two years, we observed diversity was even higher and the presence of beneficial microbes remained,” Kang said. He added that this may be one of the reasons for success in improving the gut health, but further mechanistic studies are warranted to define specific roles of gut microbes in the context of autism.
The work done at ASU is not only about treating patients but also about learning from the treatment in order to develop better formulations and optimize dosing.
“Understanding which microbes and chemicals produced by the microbes are driving these behavioral changes is at the heart of our work,” Krajmalnik-Brown said. The team’s new publication reports that the study demonstrated that two years after treatment stopped the participants still had an average of a 58% reduction in GI symptoms compared to baseline. In addition, the parents of most participants reported “a slow but steady improvement in core ASD symptoms.”
“Every family completed the study, and every family returned two years later for a follow-up evaluation,” said Adams, citing the families’ dedication to the research. “The treatment was generally well-tolerated with minimal adverse effects.”
"This is a world-first discovery that when we treated the gut bacteria in these children during our clinical trial two years ago to reset their microbiome with FMT, positive results are still continuing to be improving two years from the original treatments. I would call it the highest improvement in a cohort that anyone has achieved for autism symptoms,” said Borody.
Professional evaluation revealed a 45% decrease in ASD symptoms compared to baseline. Researchers note that although there may be some placebo effect, much of that effect appears to be real. At the start of the study, 83% of participants were rated as “severe” autism. At the end of the study, only 17% were “severe,” 39% were “mild/moderate,” and 44% were below the cut-off for mild ASD.
Greg Caporaso, at Northern Arizona University, a leading expert in microbiome data science and a co-author on these studies, helped to analyze the microbiome data to better understand bacterial changes as a result of MTT.
“Drs. Krajmalnik-Brown, Kang and I are excited about the results, but we want to caution the public that we need larger clinical trials for this to become an FDA-approved treatment,” said Adams. Professional expertise is required for safe and effective treatment.
MTT improves GI distress by introducing key strains of beneficial bacteria and helping to raise levels of biodiversity within the gut, boosting health overall.
Adams has both professional and personal reasons for doggedly pursuing ways to help children with autism because he knows the situation first-hand. His daughter was diagnosed with autism just before her third birthday. Adams, a President’s Professor at ASU’s School for Engineering of Matter, Transport and Energy, and the chair of Materials Sciences, is also president of the Autism Society of Greater Phoenix, the largest parent support group in Arizona.
“Dr. James Adams is the reason why I started working on autism,” Krajmalnik-Brown said. “I had the methods to do all of the measurements and assessments in the microbiome part of the work, and he had the autism knowledge.”
Adams recruited patients, supervised clinical work and ASD assessments, and guided the patients through the trials, and Krajmalnik-Brown led the microbiome evaluations and helped plan the study.
All of the participants in the study exhibited chronic GI symptoms from infancy, including chronic constipation and/or chronic diarrhea. The treatment benefits extended beyond their physical symptoms, even causing some parents to note how much their children’s behavior had improved over time.
“It is very unusual to see steady gradual improvement after the conclusion of any treatment,” said Adams. “We only conducted the long-term follow-up study after several families told us that their child was continuing to improve significantly.” Krajmalnik-Brown stated that the data suggests that the MTT intervention transformed the gut environment into a healthier status, leading to long-term benefit on both GI and ASD symptoms.
Adams said many of the participants in the trial shared common traits, including birth by C-section, reduced breastfeeding, increased antibiotics, and low fiber intake by the mother and child, all of which lead to limited biodiversity in their gut bacteria. Due to the open label nature of the study and the small sample size used, more research is needed in order to verify the usefulness of MTT as a therapeutic.
The initial study involved a “first-generation” estimate as to optimal dose and duration of treatment, and it was enough for 90% of the children to have substantial benefit. The team is now working on optimizing the dosing and duration to try to improve benefits even more, and to determine if booster doses may be needed in some cases.
Krajmalnik-Brown and Adams are working now on a larger placebo-controlled trial in adults with ASD to verify their results. More information on that study is available at autism.asu.edu. They also hope to do another study for children with ASD pending future funding...
https://www.youtube.com/watch?v=UEOtCT8cohE
The Gut Microbiome: Opening new
possibilities for autism treatment
Professors Rosa Krajmalnik-Brown and James Adams discuss their research that may change the way we treat symptoms of autism in the future.
https://www.nature.com/articles/s41598-019-42183-0
Scientific Reports, volume 9, Article number: 5821 (2019)
Long-term benefit of Microbiota Transfer
Therapy on autism symptoms and gut microbiota
Dae-Wook Kang, James B. Adams, Devon M.
Coleman, Elena L. Pollard, Juan Maldonado, Sharon
McDonough-Means, J. Gregory Caporaso & Rosa
Krajmalnik-Brown
Abstract
Introduction
The human gut and brain interact in complex ways, and abnormal conditions in the gut may predispose individuals to neurodevelopmental disorders1,2. Individuals with Autism Spectrum Disorders (ASD)3, Parkinson’s disease4, 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.6 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 children7,8,9,10,11. Moreover, multiple mouse studies have reported that gut microbes and their metabolites can impact behavior through the gut-brain axis, including for ASD12,13,14.
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 ASD15, 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 infection16 and has shown varying levels of success for treating other GI disorders17, which has drawn attention to the method for use beyond GI-associated disorders18. 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 problems19. 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 MTT19. 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.
Results and Discussion
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. S2a) as well as for all sub-categories of DSR (no stool, hard stool, and soft/liquid stool, Supplementary Fig. S2b), 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 S2). 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. 1b–f. 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. 2a). 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. 2a). 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 (Fig. 2b), 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. 1d). 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. 1f), 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).
Overall, the most substantial improvements observed were on the CARS assessments, which was conducted by a professional evaluator and is less susceptible to placebo-effect20. CARS is a stable and consistent diagnostic tool with high predictive validity21 and has been used to evaluate participants before and after therapeutic interventions in multiple studies20,22,23. For the follow up CARS, the evaluator collected current information based on each question’s unique criteria. After the interview was complete for each question, the evaluator reviewed the information initially collected at baseline and used it for calibrating the final evaluation.
Improvements in GI and ASD symptoms were significantly correlated
We performed statistical analyses to assess whether improvements in GI and ASD severity were correlated. As shown in Fig. 2c–e, percentage changes in CARS, SRS, and ABC scores were positively correlated with percent changes in GSRS scores (Spearman correlation test, 2-tailed p?<?0.005 and r?>?0.7), implying that GI relief provided by MTT may ameliorate behavioral severity in children with ASD, or vice versa, or that both may be similarly impacted by another factor. Another GI assessment, DSR, however, showed that there was no significant correlation. Although the direction of the influence is not clear, a potential clinical link between GI and behavior severity is consistent with what previous studies have reported24,25.
ASD fecal bacterial diversity was higher two years after the MTT stopped
16 out of 18 original ASD participants provided an additional fecal sample two years after the open-label trial. Based on 16S ribosomal RNA (rRNA) gene amplicon sequencing analysis, most participants maintained higher gut microbiota diversity two years after treatment relative to baseline. Interestingly, for many individuals, the bacterial diversity was higher at two years than at the week 18 follow up as measured by Faith’s Phylogenetic Diversity (Fig. 3a and Supplementary Fig. S4a) and Observed OTUs (Supplementary Fig. S5a). Considering low gut bacterial diversity in individuals with ASD26 and other human disorders27,28,29, an increase in diversity after MTT may reflect that MTT intervention successfully transformed gut environment into a healthier status and led to a long-term benefit on GI and behavior symptoms
Upon completion of the original MTT treatment, we observed that the unweighted UniFrac distance30 between the gut microbiota of MTT recipients and their corresponding donors was smaller than before treatment, suggesting some engraftment of the donor microbiome into the recipients by MTT19. Interestingly, two years after the trial, the recipients were as different from the donor microbiome as they were pre-treatment as measured by unweighted UniFrac distance (Fig. 3b, Supplementary Fig. S4b) and several other metrics of community dissimilarity (Supplementary Fig. S5b–e). This suggests that the recipients didn’t retain completely the donated microbiome, but rather retained some features of it such as increased overall diversity, and increase in some important microbes such as Prevotella, while finding a new state.
Bifidobacterium and Prevotella relative abundances remained higher in feces of participants with ASD two-years after MTT stopped
Three taxa that were noticeably enhanced in MTT recipients at the conclusion of the original clinical trial19 were revisited during the two-year follow-up. Notably, compared to baseline, median relative abundances of Bifidobacteria and Prevotella increased 4-fold and 712-fold at week 10, and 5-fold and 84-fold at two years, respectively (Fig. 4a,b). Desulfobivrio relative abundance decreased since week 18 (Fig. 4c), but at the two-year follow-up was still marginally higher compared to baseline (two-tailed Wilcoxon signed-rank test, p?=?0.07) and higher than neurotypical controls (two-tailed Mann-Whitney U test, p?<?0.05). An increase in Prevotella after MTT is noteworthy, since its lower abundance in feces of children with ASD compared with neurotypical children has been confirmed in two different cohorts26,31. A recent study also found reduced levels of Prevotella in the oral microbiome of children with ASD32. Prevotella may be involved in butyrate production33, a key nutrient for the intestinal epithelial cells34. In addition, its co-occurrence with Desulfovibrio may reflect a synergistic advantage to outcompete other commensal microbes that utilize mucin as nutrients35, although more research is needed on how their ecological niche in mucin desulfation could contribute to an integrity of gut epithelial cells36 as well as to the improvement on GI and behavior symptoms we observed. Further mechanistic studies with multi-omic approaches are warranted to define the roles of Prevotella and Desulfovibrio in the context of autism.
To the best of our knowledge, long-term follow-up studies are rare for medical treatment of individuals with ASD. In treatments with vancomycin37 or phytochemical sulforaphane38, benefits were lost within two or four weeks, respectively, of the treatments being discontinued. Thus, the long-term benefits observed here two years after MTT stopped are very encouraging, and MTT-driven gut microbiota transformation seems robust and long-lasting for the treatment of ASD. Despite steady and continuous improvement in behaviors over two years, we must underscore that the original clinical trial and current follow-up study are open-label trials without a control for placebo effect. Autism symptoms are relatively stable over time without a major intervention: for example, a trajectory study with 345 children with ASD showed that more than 80% of participants with ASD retained unexpectedly stable core symptoms severity over 8 to 12 years39. The VABS observations indicate that the improvements in adaptive behaviors observed here were substantially more than expected for children with ASD over two years. A limitation of this study is that 12 out of 18 participants made one or more changes to their medications, nutritional supplements, and diets between the end of the original MTT trial and the two-year follow-up since the treatment stopped (Supplementary Table S1). As described in detail in the methods section, participants were asked to rate the perceived effectiveness on GI and ASD symptoms (on a scale of 0–4) caused by changes in medications, diet, or nutritional supplements. Although the scale on the perceived effectiveness is still subjective and difficult to interpret, low scores received (1.1 for GI and 0.8 for ASD symptoms) suggest that these treatments on average could have only “slight effect”. Thus, it appears that most of the changes observed were probably due to the MTT, although we still need follow-up studies to understand whether the improvement by MTT were solely from vancomycin, MoviPrep, Prilosec, Standardized Human Gut Microbiota (SHGM), or a combination of these individual factors. For example, some participants in our study could have GI symptoms that were acid-peptic in nature, and their improvements on GI symptoms might be solely attributed to the administration of stomach-acid suppressant (Prilosec)40. We hypothesize that MTT may also be beneficial for children with ASD who do not have obvious GI symptoms but have low diversity of gut bacteria, as our previous study26 found that most children with ASD had low gut bacterial diversity, regardless of whether they have GI problems.
Here, we also would like to address a potential study limitation interpreting the improvement on GI symptoms after MTT, since these heterogeneous GI symptoms could reflect a wide range of underlying etiological GI pathologies. Although we reviewed medical histories to exclude children with known gastrointestinal diagnoses (such as ulcerative colitis, Crohn’s Disease, celiac disease, eosinophilic gastritis, or similar conditions)19, we did not conduct additional GI diagnostic evaluations, which is a limitation of this study. Thus, we want to underscore need of follow-up studies embracing more thorough examination of participants’ GI pathologies in order to better understand effectiveness of MTT.
Conclusions
In summary, all 18 participants with ASD were re-evaluated two years after MTT treatment stopped, and we observed significant improvements both in GI and behavior symptoms as compared with baseline measurements collected at the beginning of the original open-label trial. GI benefits were mostly maintained from the end of treatment, and autism symptoms were reported to have improved significantly since the end of treatment. Changes in gut microbiota persisted at two years, including in overall community diversity and relative abundances of Bifidobacteria and Prevotella. These encouraging observations demonstrate that the intensive MTT intervention is a promising therapy for treating children with ASD who have GI problems. We recommend future research including double-blind, placebo-controlled randomized trials with a larger cohort...