Autism symptoms alleviated by fecal microbiota transplantation

Relation

Kang DW, Adams JB, Gregory AC, et al. Microbiota transfer therapy alters the gut ecosystem and improves gastrointestinal and autism symptoms: an open study.Microbiome. January 23, 2017;5(1):10.

Draft

Prospective, open, uncontrolled pilot study

Participant

Eighteen children between the ages of 7 and 16 years with autism spectrum disorder (ASD) and moderate to severe gastrointestinal (GI) problems. Twenty age- and gender-matched neurotypical children without GI disorders were observed as a comparison group during this period.

Primary outcome measures

1. Der primäre Endpunkt war die Veränderung der GI-Symptome, gemessen von den Eltern anhand einer überarbeiteten Version der Gastrointestinal Symptom Rating Scale (GSRS). Das Ansprechen wurde als mindestens 50 %ige Reduktion des durchschnittlichen GSRS definiert.
2. Das sekundäre Ergebnis war die Veränderung der neuropsychosozialen Symptome, gemessen von einem professionellen Gutachter mit dem Autism Diagnostic Interview-Revised (ADI-R) und der Childhood Autism Rating Scale (CARS) und von den Eltern mit dem Parent Global Impressions-III (PGI-III), die Aberrant Behavior Checklist (ABC), die Social Responsiveness Scale (SRS) und die Vineland Adaptive Behavior Scale II (VABS-II).
3. Die Autoren untersuchten auch die bakteriellen Darmmikrobiome der ASD- und neurotypischen Kinder zu Studienbeginn und 10 weitere Male während des Experiments und das virale Mikrobiom an 2 Punkten.

Study medication and dosage

The intervention consisted of:

• Vancomycin 40 mg/kg oral jeden Tag in 3 aufgeteilten Dosen (
• Omeprazol 20 mg oral täglich für 62 Tage (beginnend am 12. Tag der Vancomycin-Behandlung bis zum 74. Tag, dem letzten Tag der FMT)
• Macrogol-Polyethylenglycol (variable Dosis je nach Körpergewicht) nur an Tag 15 (einen Tag nach der letzten Vancomycin-Dosis)
• Orale fäkale Mikrobiota-Transplantation (FMT). FMT-Material wurde hergestellt, indem gesiebter menschlicher Stuhl unter N2-Gas auf 250 Mikron filtriert und anschließend bei 6.000 xg zentrifugiert wurde, um ein Pellet zu erzeugen, das zu >99 % aus Bakterien besteht. Die Teilnehmer wurden quasi randomisiert in 1 von 2 Gruppen eingeteilt:
• Gruppe 1: Orale/orale Verabreichung: 2,5 Billionen aus Fäkalien stammende Zellen, suspendiert in Schokoladenmilch, Milchersatz oder Saft, oral verabreicht in 3 getrennten Dosen an Tag 16 und erneut an Tag 17, dann 2,5 Milliarden aus Fäkalien stammende Zellen, suspendiert in Schokolade Milch, Milchersatz oder Saft einmal täglich an den Tagen 18-74.
• Gruppe 2: Rektale/orale Verabreichung: 2,5 Billionen aus Fäkalien stammende Zellen, suspendiert in Glyzerin und normaler Kochsalzlösung, verabreicht rektal an Tag 16, dann 2,5 Milliarden aus Fäkalien stammende Zellen, suspendiert in Schokoladenmilch, Milchersatz oder Saft, einmal täglich oral verabreicht Tage 18-74.

Key insights

Population analysis

The ASD group included more individuals who were delivered by cesarean section, used non-standard formula in infancy, and suffered from food allergies and eczema, but there were no differences between the ASD group and the neurotypical group in age, sex distribution, body mass index, or antibiotic consumption in the first 4 years of life. Children with ASD had significantly shorter breastfeeding duration and slightly lower fiber consumption than neurotypical children. Mothers of children with ASD consumed an average of 6.2 grams of fiber per day (± 1.3 g), while mothers of neurotypical children consumed an average of 8.6 grams per day (± 1.3 g). This was a statistically significant difference (P<0.01)

Shipping method

There were no significant differences in clinical outcomes between initial oral FMT and initial rectal FMT.

Safety and tolerability

All subjects in the ASD group completed the 18-week treatment and observation period. The only adverse reaction noted was a transient increase in hyperactivity and aggression at the start of vancomycin treatment.

Change in gastrointestinal symptoms

There were significant (P<0.001) Improvement in abdominal pain, indigestion, diarrhea, and constipation according to the parent-rated GSRS. These improvements remained significant even 8 weeks after stopping treatment. Sixteen of the 18 (89%) children with ASD achieved a reduction in mean GSRS of more than 50%, which was the cutoff point for response.

Change in neuropsychosocial symptoms

There was a significant (P<0.001) 22% decrease in professionally assessed CARS score from baseline to end of treatment, with no regression in the 8 weeks post-treatment.

GI and neuropsychosocial symptoms improved slowly over the 10-week FMT period and were sustained throughout the 8-week follow-up.

There were significant changes in parent-rated PGI-III (P<0.001), SRS (P<0.001), ABC (P<0.01) and VABS-II (P<0.001) points. VABS-II, which assesses communication, daily living and socialization skills, found that the average developmental age increased by 1.4 years across all subdomain areas.

Stool analysis

At baseline, the ASD group had a significantly less diverse fecal microbiome than the neurotypical group, but at the end of the study the two groups were statistically indistinguishable: 15/16 responders and 1/2 non-responders in the ASD group had fecal microbiomes as diverse as those in the neurotypical group.

Fecal samples from the ASD group at the end of treatment and 8 weeks after the end of treatment showed at least partial engraftment of the donor bacterial community. Changes in the ASD group's fecal microbiome included a fourfold increaseBifidobacteriumand significant increases inPrevotellaandDesulfovibri.BifidobacteriumandPrevotellahave long been considered possible mutualists in the ASD population, butDesulfovibriis generally considered commensal or pathogenic; the significance of this increase is unknown.

Practice implications

In a previous open-label study of 8 vancomycin for ASD children, neuropsychosocial symptoms according to CARS and other scales improved. However, the improvement was lost 2 weeks after the end of treatment.¹In contrast, in the study reviewed here, gastrointestinal and neuropsychosocial symptoms improved slowly over the 10-week FMT period and were sustained throughout the 8-week follow-up. This sustained benefit compared to a similar study makes it less likely that the benefit observed in this open-label study was placebo or regression to the mean.

Legal guidelines regarding FMT limit North American clinicians to providing FMT only to patients with aClostridium difficileInfection that does not respond to standard therapies. An oral FMT solution such as the one used here is expensive, time-consuming, and requires a certain degree of scientific and technical skill to produce at home, which was an insurmountable obstacle for all of my patients, except for a few who were also physicians and were willing and able to properly filter, centrifuge, and preserve screened donor stool for the benefit of a family member.

On the other hand, home FMT retention enemas are much cheaper, less time consuming, and require little more scientific or technical know-how than many food recipes. Home FMT enemas are performed approximately 10,000 times at home each year in the United States alone.²

Improper FMT screening or preparation techniques can potentially lead to harm, but communicating safe home FMT technique and facilitating FMT donor screening can lead to safe home FMT.³I have helped facilitate hundreds of home FMT storage enemas in my practice, and the types and frequencies of side effects I have observed are no different than the types and frequencies of side effects reported in clinical trials.

The results of this study are fascinating and promising. Families of ASD patients, particularly those with regressive autism, are understandably often willing to try anything that can help without harming their child. You may encounter families who want to try to improve GI and neuropsychosocial pathology in their ASD child with FMT. It is important that practitioners who come into contact with these patients are familiar with techniques to facilitate safe home FMT with screened donors or know how to properly refer the patient if this is not the case.