Probiotics Ameliorate Gut–Brain Dysbiosis in Autism Spectrum Disorder by Modulating Nrf2-Keap1 Signaling Pathway

Abstract

Autism spectrum disorder (ASD) involves deficient ability to socially interact and communicate, pervasive, and stereotypic behavior. It also involves co-morbidities such as anxious and aggressive nature and epilepsy. Apart from above, this disorder also involves physiological symptoms which co-exist with behavioral symptoms, such as dysfunction of immune system and mitochondria as well as gastrointestinal complications, which lead to oxidative stress and neuroinflammation, further worsening the behavioral complications. Twenty-three percent to 70% of patients suffering from ASD account for gastrointestinal complications and these correlate with behaviors which are relevant to autistic endophenotype. A strong gut–brain dysbiosis occurs in ASD patients in consequence to the enormous production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora which worsens the behavioral, neurochemical, and mitochondrial dysfunction. This further leads to the generation of free radical species responsible for the synthesis of pro-inflammatory cytokines, which cause microglia activation. The Nrf2-Keap1 signaling pathway in the brain might be a plausible therapeutic target in autism for targeting gut–brain dysbiosis responsible for worsening behavioral and biochemical alterations. Its activation can serve as a putative link in targeting oxidative stress as the delicate balance of the Nrf2-NFkB pathway is responsible for either protection by antioxidant genes and phase II enzymes or generation of pro-inflammatory cytokines. Probiotics are potential neurotherapeutics which can target the Nrf2-Keap1/ARE pathway and mitigate the neuroinflammatory cascade. Hence, it can prove to be utilized as an adjunct therapy for targeting the gut–brain dysbiosis generated inflammatory cascade.