The overall finding of the MR analysis showed that genetic susceptibility to IBD was linked to an elevated risk of ASD (OR = 1.028; 95%CI = 1.001–1.056; P = 0.042). For the IBD subtypes, a relationship was present for UC and ASD (OR = 1.036; 95%CI = 1.004–1.069; P = 0.027) but none was found for CD. The opposite direction research, however, showed that there was no genetic link between ASD and IBD.
A number of epidemiological studies have suggested a relationship between IBD and ASD. In the systematic review and meta-analysis, which included six studies with eight datasets and over 11 million individuals, it was discovered that people with ASD are more likely to develop any IBD (OR = 1.66, 95%CI = 1.25–2.21, p < 0.001), UC (OR = 1.91, 95%CI = 1.41–2.6, p < 0.001), and CD (OR = 1.47, 95%CI = 1.15–1.88, p = 0.002) than people without ASD15. A retrospective case-cohort study involving children with ASD (N = 48,762) and normal controls (N = 243,810) in the United States confirmed that children with ASD have a 67% increased risk of IBD compared to normal controls. The researchers also proposed that children with ASD are more likely to have severe IBD or disease resistant to traditional first-line treatments than children without ASD14. In addition, according to Krigsman et al, patients with ASD had an increased incidence of chronic ileitis or colitis than healthy people24.
It is challenging to identify a biological connection between ASD and IBD because the biological connection of illness for both have not been thoroughly explained thus far, however various plausible theories have been proposed. Firstly, neuroimmune pathways may contribute to ASD symptoms by the gut-brain associations25. It has been proposed that due to the damage of the mucosal barrier and increased intestinal permeability in IBD disease26, bacteria, chemokines, and cytokines may access to the circulation and traverse the blood-brain barrier (BBB), thereby influencing the brain and behavior of ASD patients25. Secondly, there was evidence that neurotensin (NT), a neuropeptide found both in the brain and gastrointestinal tract, were elevated in the serum of children with ASD27; furthermore, NT plays a key role in the pathogenesis of IBD. NT might initiate and/or amplify the intestinal inflammatory reaction by stimulating neurons and immune cells, including mast cells, in the lamina propria to release proinflammatory mediators and other neuropeptides28. Thirdly, there are genetic and molecular biological similarities between ASD and IBD. Somekh et al. found that ASD and IBD share a similar genetic architecture at the pathway level autophagy. Specifically, they supposed that one ASD-related gene (ATG7) may play a role in IBD, and that two IBD-related genes (ATG16L1 and GABARAPL1) may contribute to ASD29. In addition, Molecular studies discovered overlapped gene expression from the GI tracts of ASD patients and IBD patients by comparing the transcriptome profiles of gut biopsies from children with ASD, UC and CD30. Lastly, there is increasing evidence on the links between diagnoses of IBD, CD, and UC in parents and ASD in their offspring31,32. In a population-based cohort of 7,348 United Kingdom mothers, polygenic risk score analyses found connections between maternal genetic liability to CD and UC and ASD traits in their children33.
Our study is the first known MR study to evaluate the relationship between ASD and the prevalence of IBD. The study has several strengths, the first of which is that MR analyses are less susceptible to confounding and reverse causality not observed in observational studies. Secondly, through various sensitivity analyses using different MR methods and different model assumptions, the results are consistent, indicating that the results are robust and persuasive.
There are some limitations to our study. Our sample data were all derived from European ancestry, and while this may reduce the potential bias due to demographic stratification, our findings may not be extrapolated to other populations. For example, several gastrointestinal involvements (such as IBD) were often identified in Chinese patients with ASD34; therefore, further research on the causal association between IBD and ASD in the Asian population would be particularly significant.