Ankita Brahmaroutu

Introduction. Autism spectrum disorders (ASDs) are a range of pervasive neurodevelopmental disorders, with autism at the center of the spectrum. ASDs include impairments in social interaction, communication, restricted interests, and repetitive behavior with no definitive etiology. Children with autism are more than twice as likely to develop gastrointestinal (GI) complaints that begin at 6 months and persist. This is around the same period that neurodevelopmental features of autism start¹. There are bacterial metabolic by-products that may contribute to the pathogenesis of ASDs and associated GI complaints. One of these neurotoxic by-products is propionic acid (PPA) and related short-chain fatty acids (SCFAs). PPA and SCFAs are metabolized by human mitochondria via beta oxidation and the citric acid cycle. PPA leads to defects in intestinal permeability by loosening tight junctions². High volumes of PPA are then able to enter the blood stream and are selectively transported into the central nervous system³. Thus, there may be a link between bacteria in the gut that produce high amounts of PPA, which is considered toxic in neurodevelopment, and ASDs. Methods. In a rat study, toxic doses of PPA (250 mg/kg body weight/day for 3 days) were given. Levels of serotonin, IFN-γ, and glutathione-s-transferase in the brain were measured. Oral N-acetyl-cysteine (NAC) was then given to potentially reverse the effects of PPA on neurotoxicity³. Another study sequenced fecal microflora in children with autism and control children using bacteria tag-encoded FLX amplicon pyrosequencing to link PPA-producing bacteria to autism⁴. Results. Data showed evidence of brain toxicity from PPA by the depletion of serotonin, an increase in IFN-γ, and inhibition of glutathione-s-transferase (a 41% decrease compared to controls). NAC can be given early as a therapy to reduce neuroinflammation caused by PPA, specifically by reducing IFN-γ (p <0.001)³. Sequencing the microbiota of children with autism demonstrated higher amounts of Desulfovibrio, Clostridia, and Bacteroidetes bacteria than controls, which are all implicated in producing PPA⁴. Fecal transplants to correct this imbalance and increase amounts of Bifidobacterium, Prevotella, and Desulfovibrio phyla showed reversal of ASD-like behavior by 80%⁵. Conclusions. New evidence provides an association between gut bacteria that produce PPA and ASDs. Amino acid therapy and fecal transplants are promising treatments for ASDs. Species within the Desulfovibrio phylum need to be investigated further as to its role in pathogenesis. With this synthesized information, we can invest more time into developing treatments for the virulence factors that predispose hosts to ASDs.

1. Bresnahan M, Hornig M, Schultz AF, Gunnes N, Hirtz D, Lie KK, Magnus P, Reichborn-Kjennerud T, Roth C, Schjølberg S, Stoltenberg C, Surén P, Susser E, Lipkin WI. Association of Maternal Report of Infant and Toddler Gastrointestinal Symptoms with Autism Evidence from a Prospective Birth Cohort. JAMA Psychiatry. 2015;72(5):466-474. doi:10.1001/jamapsychiatry.2014.3034. Accessed March 20, 2017.
2. MacFabe DF. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microbial Ecology in Health & Disease. 2012;23:19260. http://dx.doi.org/10.3402/mehd.v23i0.19260. Accessed March 16, 2017.
3. Aldbass AM, Bhat RS, El-Ansary A. Protective and therapeutic potency of N-acetyl-cysteine on propionic acid-induced biochemical autistic features in rats. Journal of Neuroinflammation. 2013;10:42. doi:10.1186/1742-2094-10-42. Accessed April 20, 2017.
4. Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, Youn E, Summanen PH, Granpeesheh D, Dixon D, Liu M, Molitoris DR, Green JA. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010 Aug;16(4):444-53. doi: 10.1016/j.anaerobe.2010.06.008. Accessed April 20, 2017.
5. Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, Khoruts A, Geis E, Maldonado J, McDonough-Means S, Pollard EL, Roux S, Sadowsky MJ, Schwarzberg Lipson K, Sullivan MB, Caporaso JG, Krajmalnik-Brown R. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017;5:10. doi: 10.1186/s40168-016-0225-7. Accessed March 21, 2017.