The Gut-Immune-Brain Axis in Autism Spectrum Disorders; A Focus on Amino Acids

Abstract

Autism spectrum disorder (ASD) is a range of neurodevelopmental conditions that affect communication and social behavior. Besides social deficits, systemic inflammation, gastrointestinal immune-related problems, and changes in the gut microbiota composition are characteristic for people with ASD. Animal models showed that these characteristics can induce ASD-associated behavior, suggesting an intimate relationship between the microbiota, gut, immune system and the brain in ASD. Multiple factors can contribute to the development of ASD, but mutations leading to enhanced activation of the mammalian target of rapamycin (mTOR) are reported frequently. Hyperactivation of mTOR leads to deficits in the communication between neurons in the brain and to immune impairments. Hence, mTOR might be a critical factor linking the gut-brain-immune axis in ASD. Pharmacological inhibition of mTOR is shown to improve ASD-associated behavior and immune functions, however, the clinical use is limited due to severe side reactions. Interestingly, studies have shown that mTOR activation can also be modified by nutritional stimuli, in particular by amino acids. Moreover, specific amino acids are demonstrated to inhibit inflammation, improve gut barrier function and to modify the microbiota composition. In this review we will discuss the gut-brain-immune axis in ASD and explore the potential of amino acids as a treatment option for ASD, either via modification of mTOR activity, the immune system or the gut microbiota composition.

Keywords: amino acids; autism spectrum disorder; gut-immune-brain axis; mammalian target of rapamycin; nutritional intervention.

Figure 1

In the first phase of allergy or type 1 hypersensitivity reactions sensitization to the food allergen takes place (sensitization phase). During this phase, allergens cross the intestinal mucosal barrier and are presented via MHC-II to naïve T cells that develop into type 2 helper T (Th2) cells. Th2 cells induce the plasma cells to produce IgE antibodies (37), after which IgE binds to the FcεRI receptor on mast cells. In the challenge phase, upon a second exposure to the same allergen, cross-linking of mast cell-bound IgE occurs. In turn, this leads to mast cell degranulation, a process resulting in the release of several mediators including histamine, cytokines and tryptases. The release of these mediators is the direct cause of most of the allergic intestinal symptoms, including nausea, vomiting, cramps, and diarrhea (38). With permission of Dr J. Wu.

Figure 2

Schematic representation of the mTOR-signaling pathway in ASD. Mutations in various components involved in the mTOR signaling pathway such as PTEN, Nf1, TSC, eIF4E, FMRP (indicated by red circles) affect the protein synthesis machinery, leading to the development of ASD. Adapted from Ehninger et al. (62, 65). With permission of Dr. J. Wu.

Figure 3

Schematic representation regarding the possible role of mTOR activity in the balance of T cell profiling in food allergy. Enhanced mTOR activity is required for Th1, Th2, and Th17 cell differentiation. Suppression of the mTOR activity induces the differentiation into Treg cells. Adapted from Delgoffe et al. (68) and Kim et al. (69). With permission of Dr J. Wu.

Figure 4

Schematic representation of the possible targets for dietary amino acids in the impaired gut-microbiome-immune-brain axis in ASD.