Update on Wellcome LEAP's $50 million program on autism and the microbiome

Exactly five months ago, I blogged about a program entitled Foundations of a Resilient Microbiome (FORM) that Wellcome LEAP was funding to the tune of $50 million. I had major reservations about the foundations of the research program, which seemed based on flaky research.

By coincidence, the 2025 funding call for FORM came out a couple of weeks before publication of a review that I co-authored with Kevin Mitchell and Darren Dahly, entitled "Conceptual and methodological flaws undermine claims of a link between the gut microbiome and autism". We'd done a fair bit of reading for that review, and featured the work of two of the luminaries of the field, James B. Adams and Sarkis Mazmanian.

The list of successful applicants to the FORM program was recently announced, and, yup, these two guys were on it. I could not find any details of the specific projects that were funded, but I think that on the basis of track record, this is not a good investment of valuable research funds. Here I explain why.

James B. Adams is President's Professor at the School for Engineering of Matter, Transport and Energy at Arizona State University. His degrees are in physics and materials engineering. His interest in autism was prompted by having a child with a diagnosis. He has authored a parent guide to biomedical treatments for autism which lists him as an adjunct professor at Southwest College of Naturopathic Medicine - a branch of alternative medicine that can be practiced by those with no medical qualifications. 

Adams was Principal Investigator (as stated in the trial registration) of two highly-cited articles that we featured in the Mitchell et al review, reporting the immediate and long-term outcomes of an open label study of "microbiota transfer therapy" in 18 children with autism. In the trial registration, it was stated that "This is an open-label clinical trial to evaluate the safety, tolerability, and feasibility of a combination therapy to treat gastrointestinal problems in children with autism spectrum disorders."(my emphasis) The initial report by Kang et al (2017), however, stated that "The goals of the study were to follow gut microbiota in healthy and treated children with ASD longitudinally as well as to evaluate an investigational new treatment, MTT, for its effectiveness in children with ASD in treating both GI symptoms (primary outcome) and ASD-related symptoms (secondary outcomes), and to determine the effect of MTT on the gut microbiome." This change in wording is misleading because it implies that the trial could assess effectiveness of the intervention, which it was not designed to do. In places it is clear that the authors are aware of this limitation, noting that a randomized controlled trial would be needed to estimate the effect of the treatment. Readers of the study might be puzzled by the fact that a control group is mentioned. However, this is not the kind of control that is needed to demonstrate a genuine effect of intervention - instead it is a comparison group of typically-developing children. It is argued that the microbiome of the treated autistic children becomes more similar to that of the typical children after intervention, but one needs to interpret that with caution, because we know that the microbiome is highly variable both within and between children, and there are no solid, replicable microbiome "biomarkers" for autism (Mitchell et al, 2025).

It is worth reproducing the full protocol here, to appreciate what is involved in MTT intervention. I doubt an Institutional Research Board would have approved such a trial had they been aware of how shaky the evidence is for microbiome abnormalities as a causal factor in autism,

The treatment began with 14 days of oral vancomycin, a non-absorbable broad spectrum antibiotic that stays in the GI tract. A 14-day course of vancomycin was used to ensure that pathogenic bacteria were profoundly suppressed. Prilosec (an acid pump inhibitor) was administered starting on the 12th day of vancomycin, and continued until the end of the lower dosage of SHGM [Standardized Human Gut Microbiota] in order to reduce stomach acidity and increase the survival rate of SHGM through the stomach. 

On day 15, parents administered MoviPrep, a drink that flushes the bowels, to remove most remaining gut bacteria and vancomycin. To enhance its effectiveness, a fasting period of 1 day was implemented during which participants were only allowed to consume clear liquids (children under 12 years were allowed a light breakfast), and then at 4 pm and 8 pm, parents administered the two doses of MoviPrep. 

On day 16, the participants began either oral administration of SHGM (2.5 × 1012 cells/day) mixed in a chocolate milk, milk substitute, or juice for 2 days (divided into three daily doses), or a single rectal dose of SHGM (2.5 × 1012 cells), given similar to an enema. The rectal dose was administered slowly over 1 h, and participants remained prone for at least several hours, and delayed defecation for at least several hours. The rectal dose was administered under the direct supervision of the study physician, and the first oral dose was similarly administered in the presence of the physician. 

Participants were randomly assigned to either the oral or rectal route of administration. If one administration route was not tolerated, or if the family preferred the other route, then participants had the option of trying the other route. 

For participants who received the major initial rectal dose, they waited for 1 week (so the effect of the rectal dose could be evaluated by itself) and then received a lower oral maintenance dose (2.5 × 109 cells) for 7 weeks. In contrast, for participants who received major initial oral doses, they received a lower oral maintenance dose (2.5 × 109 cells) for 8 weeks, directly after the major initial oral dose. The lower maintenance SHGM doses were self-administered orally every day up to the end of week 10. 

After treatment was stopped, participants were monitored for another 8 weeks.

 The study reported improvements in measures of gut health and autistic symptoms as assessed by parental report. However, there was no control for placebo effects, maturation or regression to the mean. Nevertheless, the study received widespread media attention, focusing on the promise of the intervention as a treatment for autism. To date it has had 1282 citations.

In 2019, Kang et al reported a two-year follow-up study entitled "Long-term benefit of microbiota transfer therapy on autism symptoms and gut microbiota". As I noted in this PubPeer comment this suffered from the same problems as the initial report, namely it stated that the results showed benefit of the intervention, when the lack of controls limited the conclusions that could be drawn. In addition, there was a misinterpretation of one of the outcome measures, which showed changes that could readily be explained by the passage of time.

Both studies included Competing Interests statements stating that Adams had received research funds and acted as consultant for Crestovo, which is a "clinical-stage biopharmaceutical company developing Full-Spectrum Microbiota that harnesses the human gut microbiome". The 2019 study also noted he had pending/approved patents for use of fecal microbiome transplantation and/or probiotics in the treatment of autism and other conditions.

As it typical for those involved in naturopathic medicine, Adams' interests extend beyond the microbiome. Since 2003 he has published on a range of nutritional, metabolic and environmental causes of autism, including various metals, and has also written on the use of hyperbaric oxygen therapy. In a newspaper article he linked his daughter's autism to the "massive amounts of mercury" in vaccines she had received. He has co-authored articles with others who have promoted controversial approaches to intervention such as Richard E. Frye, Dan Rossignol and David Geier.

The profile of Sarkis Mazmanian, the other person funded by on the Wellcome FORM programme, is very different. While Adams' work is largely funded by charities or small enterprises, Mazmanian has had solid funding from NIH. The gut microbiome has been a central feature of his research, and he has used mouse models to investigate links to a range of disorders, including autism.

A particularly dramatic result was reported by his research group in 2019, claiming that fecal transplants from autistic boys could induce autistic behaviours in mice. As noted in the Transmitter  soon after publication, serious statistical criticisms were raised by several readers, undermining confidence in the findings. It seems that the authors did not accept that the analysis was faulty, and no correction has been made to the published article.

Last week, there was a new report in the Transmitter, concerning another article by Mazmanian and colleagues. This was a landmark mouse study (over 3000 citations) on the microbiome in Parkinson's disease. The study attracted some critical commentary on PubPeer soon after publication in 2016, but it was only last month that problems with the study were found by Markus Englund, in the course of evaluating software that he had developed to automatically flag blocks of duplicated data in datasets deposited in the Dryad repository.  Although the occasional repeated block may occur naturally, if multiple places in a spreadsheet are affected, then it indicates something is wrong. Similar issues were noted for an article published in Nature in 2022, reporting how the microbiome affected anxiety in mice.

Competing Interests statements note that Mazmanian has financial interests in Axial Biotherapeutics. In 2023, this company completed a Phase 2b randomised controlled trial (TAPESTRY Autism Study), "a first-in-class oral gut-targeted small molecule therapeutic designed to treat irritability associated with autism". I was not able to find a report of the results, and as noted here, "Axial never publicized its topline clinical data, which were due in the first quarter of 2024, and went quiet after disclosing its participation in investor conferences at the start of last year." It is concerning that the results of the TAPESTRY trial have not been reported. One can only assume that the trial results were disappointing and commercially damaging to the company, but negative results provide important information, and we'll never make progress if we don't learn what doesn't work. It does a disservice to the families and clinicians who took part in this big multicentre effort to hide the results. The company has now rebranded as Vertero, a company focused on neurodegenerative diseases.

I guess that both Adams and Mazmanian fit well with Wellcome LEAP's focus on "unconventional" projects with potential for commercialisation, but I will be surprised if they end up delivering the desired "seemingly impossible results on seemingly impossible timelines". 

 

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