Leaky Gut Plays a Critical Role in the Pathophysiology of Autism in Mice by Activating the Lipopolysaccharide-Mediated Toll-Like Receptor 4–Myeloid Differentiation Factor 88–Nuclear Factor Kapp...
Fang Li1 · Haoran Ke2 · Siqi Wang3 · Wei Mao1 · Cexiong Fu4 · Xi Chen5 · Qingqing Fu6 · Xiaori Qin1 · Yonghua Huang1 · Bidan Li4 · Shibing Li7 · Jingying Xing8 · Minhui Wang9 · Wenlin Deng101 Department of Gastroenterology, Gastroenterology Endoscopy Center, Hainan General Hospital, Hainan Afliated Hospital of Hainan Medical University, Haikou 570311, China
2 Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
3 Department of Gastroenterology, First Afliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, China
4 Department of Hepatopancreatobiliary Surgery, Hainan General Hospital, Hainan Afliated Hospital of Hainan Medical University, Haikou 570311, China
5 Otolaryngology-Head and Neck Surgery, Hospital of Hainan Province, Department of Otorhinolaryngology, Head and Neck Surgery, Hainan General Hospital, Hainan Afliated Hospital of Hainan Medical University, Haikou 570311, China
6 Department of Radiology, Hainan General Hospital, Hainan Afliated Hospital of Hainan Medical University, Haikou 570311, China
7 Department of Pediatric Surgery, Hainan General Hospital, Hainan Afliated Hospital of Hainan Medical University, Haikou 570311, China
8 Department of Gastroenterology, Hainan General Hospital, Hainan Afliated Hospital of Hainan Medical University, Haikou 570311, China
9 Department of Nephrology, Department of Nephrology, Hainan Afliated Hospital of Hainan Medical College, Hainan General Hospital, Haikou 570311, China
10 Department of Pediatrics, The Sixth Afliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
Abstract
Increased intestinal barrier permeability, leaky gut, has been reported in patients with autism. However, its contribution to the development of autism has not been determined. We selected dextran sulfate sodium (DSS) to disrupt and metformin to repair the intestinal barrier in BTBR T+tf/J autistic mice to test this hypothesis. DSS treatment resulted in a decreased affinity for social proximity; however, autistic behaviors in mice were improved after the administration of metformin. We found an increased affinity for social proximity/social memory and decreased repetitive and anxiety-related behaviors. The concentration of lipopolysaccharides in blood decreased after the administration of metformin. The expression levels of the key molecules in the toll-like receptor 4 (TLR4)–myeloid differentiation factor 88 (MyD88)–nuclear factor kappa B (NF-κB) pathway and their downstream inflammatory cytokines in the cerebral cortex were both repressed. Thus, “leaky gut” could be a trigger for the development of autism via activation of the lipopolysaccharide-mediated TLR4–MyD88–NF-κB pathway.
Keywords
Autism; Gut; Lipopolysaccharide; Toll-like receptor 4; Metformin
