The presence of Th17 cell-inducing bacteria in the maternal gut promote autism-like phenotype in offspring
Sangdoo Kim1*, Hyunju Kim1*, Yeong Shin Yim2, Soyoung Ha1, Koji Atarashi3, Tze Guan Tan4, Randy S. Longman5, Kenya Honda3, Dan R. Littman6,7, Gloria B. Choi2 & Jun R. Huh1† 1Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA; 2The McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 3Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; 4Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA; 5The Jill Roberts Institute for Research in IBD, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York 10021, USA; 6The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA; 7Howard Hughes Medical Institute, New York, New York 10016, USA †Present address: Division of Immunology, Department of Microbiology and Immunobiology and Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA *These authors contributed equally to this work
Several epidemiological studies have suggested that viral infection of women during pregnancy correlates with an increased frequency of autism spectrum disorder (ASD) in children. In the rodent maternal immune activation (MIA) model of this phenomenon, offspring from pregnant mice injected with poly(I:C), a mimic of viral infection, exhibit behavioral abnormalities as well as cortical abnormalities in offspring. Previously we demonstrated that interleukin-17a (IL-17a) produced by T helper 17 (Th17) cells in pregnant mothers promotes behavioral and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. In this study, we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote Th17 cell differentiation. For example, pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria (SFB) or human commensal bacteria that induce Th17 cells are more likely to produce offspring with MIA-associated phenotypes. Overall, our data suggest that gut microbial communities in women during pregnancy that promote excessive Th17 cell differentiation may be more likely to bear children with autistic spectrum disorder in the event of uncontrolled inflammation.