Editorial – Fecal Microbiota Transplantation and Autism

Over the past several years, Fecal Microbiota Transplantation (FMT) has become the subject of growing interest in the autism community due, at least in part, to the increased awareness of the gut-brain relationship. Along with its possible significance, however, there are concerns regarding its safety and the need for evidence-based research to establish its effectiveness. This editorial discusses the various aspects of FMT, describes potential benefits, and outlines critical issues that must be addressed.

Gastrointestinal Disease in Autism

In 2010, a consensus report on gastrointestinal (GI) disorders in individuals with autism spectrum disorder (ASD) was published in Pediatrics, sparking widespread research focused on causes and treatment (1). GI problems found to be common in individuals on the autism spectrum include chronic constipation, diarrhea, abdominal pain, and gastroesophageal reflux disease (GERD) (2). The causes of these disorders are multifaceted, and numerous studies have documented some commonalities, including reduced bacterial diversity and dysbiosis (3,4). Moreover, many of these GI disturbances have been found to be associated with co-occurring conditions such as anxiety, sleep disturbances, and various behavioral disorders, such as aggressive, repetitive, and self-injurious behaviors. (5).

Fecal Microbiota Transplantation

FMT involves the transferring of fecal microbes from a healthy donor into the GI tract of a patient. This procedure is often beneficial in treating recurrent Clostridioides difficile infections (CDI) (6) and is being investigated in clinical trials for other gut conditions, including ulcerative colitis (7).

The lack of standardization in the preparation and delivery of fecal microbes and in donor selection poses significant challenges (8,9). The microbes are obtained from donor fecal material. The preparation process involves meticulous screening of donors for past and current GI issues, chronic illnesses, and infectious diseases such as HIV and hepatitis. In addition, the donor’s fecal microbes may be tested to ensure a diverse and healthy gut microbiota. The fecal material is administered to a suitable patient via oral capsules, liquid solutions, nasogastric tube, enema, or direct placement in the colon or upper GI tract via endoscopy (10). The American Gastroenterological Association is currently developing guidelines for the use of FMT (11).

It is important to understand that CDI is fundamentally different from most other disorders that may be associated with an altered gut microbiota. CDI is a complication of antibiotic therapies, and the disorder is also treated with antibiotics. Many patients develop recurrent CDI because antibiotics cannot eliminate C. difficile spores from their intestines. Repeated antibiotic treatments result in an altered gut microbiome, which can then be restored with FMT. A single administration of donor microbiota is typically sufficient. This is not the case in most other conditions, where a single FMT dose will not achieve a significant and lasting change in the gut microbial composition. Modification of the gut microbiome in non-CDI conditions typically requires antibiotic conditioning and repeated dosing of donor microbiota. The precise protocols are still being investigated.

Safety Concerns and FDA Regulations

In 2019, the FDA issued a safety warning about the potential risk of serious adverse effects using FMT due to the transmission of harmful organisms (12). Two individuals had contracted extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli); one died, while the other recovered. They both received stool samples from the same donor. The New England Journal of Medicine later published a detailed description of each case (13). In 2020, the FDA issued another safety warning with regard to two individuals who contracted Shiga toxin-producing Escherichia coli (STEC) infection as the result of FMT and subsequently died (14). These patients had both received the STEC infection from the same donor. Both patients were at risk of bacterial infections because of weakened immune systems. Additionally, four other individuals were hospitalized due to an infection with enteropathogenic Escherichia coli (EPEC), which they acquired from two different donors. All six patients had undergone FMT from fecal matter provided by OpenBiome (15).

In a 2022 review and meta-analysis that examined data from 61 studies involving nearly 5,100 patients, researchers found that serious adverse effects of FMT were relatively rare, occurring in less than 1% of the cases (16). These serious effects included sepsis or sepsis-like conditions (0.19%), aspiration pneumonia (0.27%), and bowel perforation (0.20%). More common, although less severe, adverse effects included constipation (1.03%), abdominal pain (1.66%), nausea (0.92%), vomiting (0.34%), flatulence (0.70%), and febrile episodes (0.33%).

In that same year, and in response to these safety concerns, the FDA published guidelines and regulations to improve safety, including screening for STEC and EPEC infections. Subsequently, in November 2022, the FDA approved the first fecal microbiota product for rectal administration to treat CDI (17), followed by an oral version of a subset of bacteria specifically tailored for CDI (18). These approvals were specific to individuals aged 18 years and older and were not explicitly extended to autistic individuals. These products involve 1 to 2 doses, which is sufficient for treating CDI. However, daily dosages for 8 weeks have been used for treating GI problems in autism. Moreover, the FDA’s approval of FMT was confined to the treatment of CDI and did not encompass other gut disorders.

A national registry has now been established to gather clinical and patient-reported outcomes with the primary goal of evaluating the safety of FMT over both short-term and long-term periods (19). This registry is sponsored by the American Gastroenterological Association (AGA) Institute in collaboration with the Crohn’s and Colitis Foundation of America, the Infectious Diseases Society of America, and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

The potential risk of bacterial infection can be drastically reduced with adequate donor selection and the testing of donor stool prior to administration to patients. Donor selection criteria are now very rigorous in their exclusion criteria and are needed to ensure that donors do not have any health conditions that may be associated with gut microbiota dysfunction. This means donors are metabolically fit, take no medications, and have no risk factors for autoimmunity, cancer, atopic disorders, or neuropsychiatric problems.

Research on FMT and Autism

Although research into the effectiveness of FMT in treating GI disease in autistic individuals is still in its early stages, several non-blinded studies involving autistic children have been carried out (20-24). Because these studies are open-label, which means both the researchers and participants know about the treatment being given, there is an increased possibility of bias.

In one study involving 18 autistic children with moderate to severe GI disease, as well as a control group of 20 neurotypical children without GI issues, autistic participants exhibited improvements in gut bacterial diversity (20,21) and a reduction in GI symptoms, as well as improvements in social interaction and adaptive behaviors (20). In this study, adverse effects of FMT were limited. One child developed a long-term rash during vancomycin treatment prior to receiving FMT. Additionally, 12 children experienced mild hyperactivity or tantrums for 1 to 3 days. FMT was generally well-tolerated in both rectal and oral forms, with the exception of one child who vomited during high-dose oral administration and was subsequently switched to the rectal route. Overall, the study observed only temporary and minor adverse effects. A follow-up study two years later suggested continued benefits from the initial FMT trial (22).

More recently, a separate independent research team conducted a study, utilizing similar assessment measures, that largely replicated the findings described above (23). This included a larger sample size of 40 autistic children, all experiencing GI issues, and a comparison group consisting of 16 age- and sex-matched neurotypical children without GI problems. Short-term adverse effects were noted, including fever (3.7%), hyperactivity (11.4%), and tantrums/aggression (3.7%). This study observed that the benefits from FMT began to diminish within a few weeks after the therapy ended, leading the authors to suggest the potential need for additional treatment.

Another study explored the possible long-term benefits of FMT over a five-year period (24). This retrospective study examined 328 autistic children without a control group and utilized assessment tools similar to those used in the earlier studies. The findings indicated that improvements were sustained for approximately four years but returned to baseline by the five-year follow-up. These data suggest the lack of prolonged benefit.

Concluding Remarks

While open-label studies suggest the potential for FMT to benefit autistic individuals with GI disorders, double-blind, multi-site trials are critical to definitively assess efficacy and safety. Some of these trials are already underway (25). Additionally, immune (26,27) impairments, occasionally observed in autistic individuals, may require special attention when providing FMT. Should FMT ever be approved for the treatment of autism, meticulous adherence to FDA-approved preparation and administration procedures by physicians will be critical to ensure patient safety and treatment efficacy.

Moreover, there are only a limited number of studies, both with and without autistic participants, to assess whether periodic doses throughout an individual’s lifetime are necessary. This necessity may depend on various factors, such as age, GI condition, and the route of administration, among others.

In summary, FMT holds promise as an effective intervention for some autistic individuals, but the treatment remains experimental and without proven efficacy. Dosage, standardization, and safety have yet to be established. As more is learned, it is essential to weigh the potential efficacy of a new treatment for autistic individuals with these GI issues against concerns about safety.

Stephen M. Edelson, Ph.D.
Executive Director, Autism Research Institute

References are available at www.ARRIReferences.or

This editorial originally appeared in Autism Research Review International, Vol. 38, No. 2, 2024