Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study

Ning Li, Hongyan Chen, Yi Cheng, Fenghua Xu, Guangcong Ruan, Senhong Ying, Wen Tang, Lu Chen, Minjia Chen, LinLing Lv, Yi Ping, Dongfeng Chen, Yanling Wei, Ning Li, Hongyan Chen, Yi Cheng, Fenghua Xu, Guangcong Ruan, Senhong Ying, Wen Tang, Lu Chen, Minjia Chen, LinLing Lv, Yi Ping, Dongfeng Chen, Yanling Wei

Abstract

Autism spectrum disorder (ASD) is a severe brain development disorder that is characterized by deficits in social communication and restricted, repetitive and stereotyped behaviors. Accumulating evidence has suggested that gut microbiota disorders play important roles in gastrointestinal symptoms and neurodevelopmental dysfunction in ASD patients. Manipulation of the gut microbiota by fecal microbiota transplantation (FMT) was recently shown to be a promising therapy for the treatment of various diseases. Here, we performed a clinical trial to evaluate the effect of FMT on gastrointestinal (GI) and ASD symptoms and gut microbiota alterations in children with ASD. We found that there was a large difference in baseline characteristics of behavior, GI symptoms, and gut microbiota between children with ASD and typically developing (TD) control children. FMT could improve GI symptoms and ASD symptoms without inducing any severe complications. Similarly, FMT significantly changed the serum levels of neurotransmitters. We further observed that FMT could promote the colonization of donor microbes and shift the bacterial community of children with ASD toward that of TD controls. The abundance of Eubacterium coprostanoligenes pre-FMT was positively correlated with high GSRS scores, whereas a decrease in Eubacterium coprostanoligenes abundance induced by FMT was associated with the FMT response. Our data suggest that FMT might be a promising therapeutic strategy to improve the GI and behavioral symptoms of patients with ASD, possibly due to its ability to alter gut microbiota and highlight a specific microbiota intervention that targets Eubacterium coprostanoligenes that can enhance the FMT response. This trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) (trial registration number ChiCTR1800014745).

Keywords: autism spectrum disorders; clinic trial; fecal microbiota transplantation; gut microbiota; microbiome-gut-brain axis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Li, Chen, Cheng, Xu, Ruan, Ying, Tang, Chen, Chen, Lv, Ping, Chen and Wei.

Figures

Figure 1
Figure 1
Study design timeline. The trial consisted of a 4-week period of FMT and an 8-week follow-up observation period after the end of treatment. The time schedule of sample collection and GI/behavioral assessments.
Figure 2
Figure 2
The change in GI symptoms and ASD symptoms after FMT. Children were treated with FMT for 4 weeks and underwent follow-up evaluation for 8 weeks after treatment ended. (A) Changes in average GSRS scores after FMT. (B) Bristol stool scores. (C) Results of ABC assessment at different time points. (D) CARS scores before treatment, after treatment, and 8 weeks after treatment. (E) Total SAS scores before treatment, after treatment, and 8 weeks after treatment. (F) Total SRS scores before treatment, after treatment, and 8 weeks after treatment. The two-tailed Wilcoxon signed-rank test was used to determine the significance. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, ns, no significance.
Figure 3
Figure 3
The change in neurotransmitter levels after FMT. (A–C) Changes in 5-HT, GABA, and DA levels at before treatment, after treatment, and 8 weeks after treatment. The Wilcoxon signed-rank test was used to determine the significance. **P < 0.01, ****P < 0.0001, ns, no significance.
Figure 4
Figure 4
Gut microbiota changes after FMT. (A) Changes in alpha diversity were determined using Shannon indices in stool samples from children with ASD collected at different time points. The two-tailed Wilcoxon signed-rank test was used to analyze the difference. *P < 0.05. ns, not significant. (B) Unweighted UniFrac distance between ASD children treated with FMT at each timepoint and TD controls. (C) Unweighted UniFrac distance between ASD children treated with FMT at each timepoint and donors. The two-tailed Wilcoxon signed-rank test was used to analyze the difference. *P < 0.05, **P < 0.01, ***P < 0.0001. ****P < 0.00001. NS, not significant.
Figure 5
Figure 5
Specific microbial changes are associated with the response to FMT. (A) OPLS-DA analysis of the responder group and nonresponder group pre-FMT. (B) Variable influence on projection (VIP) for OPLS models. (C) Correlation between the abundance of Eubacterium and GSRS scores post-FMT in the FMT recipients. (D) Correlation between the change in the relative abundance of Eubacterium after FMT and the change in GSRS scores after FMT.

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