The Role of Microbes and Autoimmunity in the Pathogenesis of Neuropsychiatric Illness

Mady Hornig


Curr Opin Rheumatol. 2013;25(4):488-495. 

In This Article

Microbes, Autoimmunity and Neuropsychiatric Disease: A Unifying Framework

Recent evidence suggests that both pathogenic and commensal microbes play a role in the pathogenesis of a subset of neuropsychiatric disorders through induction of brain-reactive autoantibodies. Whereas infection with certain pathogens can trigger autoantibody production through molecular mimicry,[73] commensal bacteria that comprise the gastrointestinal microbiota probably set the stage for the development of autoimmune responses by skewing immune responses toward overproduction of Th17 cells[74] and reduction in numbers and function of Tregs.[75] Failed uptake of antioxidant precursors in the terminal ileum, influenced by differences in tryptophan degradation capacity of the microbiota and related factors, may also contribute to a skew toward autoimmunity by reducing levels of Tregs and increasing levels of autoimmunity-provoking Th17 cells (Fig. 1).[76,77]

Figure 1.

Autoimmune disturbances may result from failed uptake of dietary precursors of antioxidants in the terminal ileum. Cysteine and selenocysteine uptake in the terminal ileum regulates autoimmunity. The excitatory amino acid transporter 3 (EAAT3), encoded by the SLC1A1 gene, transports diet-derived cysteine (CYS) and selenocysteine (Sel-CYS) into gastrointestinal (GI) epithelial cells in the terminal ileum. Within the cell, CYS is directed to glutathione (GSH) synthesis and Sel-CYS is incorporated into the selenoproteins that maintain GSH in its reduced state. EAAT3 activity is regulated by multiple factors, including intracellular redox status, Nrf2-dependent transcription, growth-factor-dependent translocation to the cell surface and the inhibitory effects of casein and gluten-derived opiate peptides. Systemic availability of CYS and GSH depends upon these terminal ileum events, as does the local mucosal environment. Immune cells in the terminal ileum can be a source of autoantibodies, including antibodies targeting the folate receptor (FR). Anti-FR antibodies are frequently present in individuals with autism.76 Under oxidative stress conditions, EAAT3-mediated uptake of CYS by Treg cells is impaired, limiting the ability of Tregs to suppress naive CD4+ T cells. Autoimmune responses to antigens present locally, including the FR, are thus increased. Data from Waly et al. 77

There is now a great deal of evidence to suggest that serologic responses to Toxoplasma gondii are increased in schizophrenia.[78] There is also evidence that the microbial infection itself is not likely to be as important in pathogenesis as the presence of antibodies to the microbe, as well as the isotype and binding characteristics (cross-reactivity, affinity and avidity) of these antibodies. Anti-toxoplasma antibodies may also be more prevalent in individuals with bipolar disorder, type 1.[79] In individuals with schizophrenia, antibodies directed against food antigens, including bovine milk casein and wheat-derived gluten, are correlated with the presence of antibodies to T. gondii.[78] This association has also been demonstrated in a mouse model, with more prominent effects in female mice.[80] In a separate study,[81] increased levels of anti-gliadin antibodies were found in individuals with schizophrenia. Furthermore, the interactomes of nine neuropsychiatric disorders, including multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, ADHD and ASD, but not anorexia nervosa or myalgic encephalomyelitis/CFS, showed significant overlap with the interactome of T. gondii,[82] and has been closely associated with a number of autoimmune diseases.

The relationship of anti-toxoplasma antibodies to anti-gliadin antibodies in some neuropsychiatric disorders may relate to reduced antioxidant capacity in the terminal ileum. Gliadin, a major protein component of wheat that is associated with celiac disease, also appears able to dysregulate redox balance in peripheral blood mononuclear cells, triggering allergic-type responses that include specific enhancement of IL-4-mediated IgE production.[83] Consistently with a role for redox status in the development and maintenance of autoimmunity, other immunoglobulin isotypes, such as IgM, exhibit an increase in carbonyl content and greater immunoreactivity against autoantigens after oxidation.[84] Similar findings were described earlier for IgG.[85] A clearer understanding of these processes may uncover unique strategies for intervention with less potential for toxicity, including antioxidants, prebiotics, probiotics and transplantation of fecal microbiota.