- Awarded: 2014
- Award Type: Targeted: Innate Immune System
- Award #: 322839
There is growing support for the idea that both genetic and environmental risk factors contribute to autism. One environmental risk is maternal infection, as validated by large epidemiological studies showing links between infection during pregnancy and autism in the child. Similar associations were found with elevated immune responses in maternal serum or amniotic fluid. Also consistent with an immune pathophysiology are findings of activated microglia — immune cells within the brain — in people with autism, as well as dysregulation of immune-related genes in the brain, cerebral spinal fluid and periphery.
In addition, a significant proportion of individuals with autism have gastrointestinal abnormalities, including immune activation, constipation, bloating, abdominal cramps and diarrhea, and a high incidence of intestinal barrier dysfunction. Consistent with these non-neurologic features, recent studies have shown that the composition of gut bacteria (the intestinal microbiome) is altered in children with autism compared with controls. However, the potential connections between gastrointestinal and brain inflammation, intestinal bacteria and abnormal behavior have not been rigorously investigated.
Building on previous work by the late Paul Patterson, Sarkis Mazmanian and his team at the California Institute of Technology showed that activation of the maternal immune system in mice results in pups with behavioral deficits, immune dysregulation and neuronal abnormalities reminiscent of autism1. They have discovered that Bacteroidesfragilis, a probiotic from the human microbiome, can ameliorate immune activation and autism-related behavioral defects in mice2.
This same probiotic provides behavioral improvements in two genetic mouse models of autism. Mazmanian’s project aims to explore how maternal immune activation in genetic models of autism alters innate immunity in the gut and the brain, affecting behavior and neuronal function. The researchers also plan to test a probiotic therapy in preclinical models, with the long-term goal of validating novel approaches to ease the medical and social burden of autism.