Association between autism spectrum disorder and inflammatory bowel disease: A systematic review and meta‐analysis

Abstract

Children with autism spectrum disorder (ASD) are frequently diagnosed with co‐occurring medical conditions including inflammatory bowel disease (IBD). To investigate the association, we conducted a systematic review registered in PROSPERO (ID:CRD42021236263) with a random‐effects meta‐analysis. We searched PubMed, Embase, and PsycInfo (last search on January 25, 2021), and manually searched relevant publications. We included observational studies measuring the association between ASD and IBD. The primary outcome was the association (odds ratio, OR) between ASD and later development of IBD. Sensitivity analyses were conducted by quality, confounding adjustment, and study design. We performed meta‐regression analyses and assessed heterogeneity, publication bias, and quality of studies with the Newcastle‐Ottawa Scale. Overall, we included six studies consisting of eight datasets, including over 11 million participants. We found that ASD was significantly associated with subsequent incident IBD (any IBD, OR = 1.66, 95% confidence interval[CI] = 1.25–2.21, p < 0.001; ulcerative colitis, OR = 1.91, 95%CI = 1.41–2.6, p < 0.001; Crohn's disease, OR = 1.47, 95%CI = 1.15–1.88, p = 0.002). ASD and IBD were also associated regardless of temporal sequence of diagnosis (any IBD, OR = 1.57, 95%CI = 1.28–1.93, p < 0.001; ulcerative colitis, OR = 1.7, 95%CI = 1.36–2.12, p < 0.001; Crohn's disease, OR = 1.37, 95%CI = 1.12–1.69, p = 0.003). Sensitivity analyses confirmed the findings of the main analysis. Meta‐regression did not identify any significant moderators. Publication bias was not detected. Quality was high in four datasets and medium in four. In conclusion, our findings highlight the need to screen for IBD in individuals with ASD, and future research should identify who, among those with ASD, has the highest risk of IBD, and elucidate the shared biological mechanisms between ASD and IBD. Lay Summary This systematic review and meta‐analysis of eight observational datasets found that individuals with autism spectrum disorder (ASD) are more likely to develop any inflammatory bowel disease, ulcerative colitis, or Crohn's disease. Our findings highlight the need to screen for inflammatory bowel disease in patients with ASD and elucidate the shared biological mechanisms between the two disorders.

Investigating Causal Relationships between Inflammatory Bowel Disease and Autism Spectrum Disorder: A Bidirectional Two-sample Mendelian Randomization Study

“…In another retrospective study from the TRICARE Management Activity Military Health System database involving over 48,000 ASD cases, researchers identify an enhanced risk of IBD diagnosis in children with ASD (OR = 1.67, 95% CI = 1.31-2.13) (Lee et al, 2018). A meta-analysis involving over 11 million participants confirms that ASD is epidemiologically associated with incident IBD (OR = 1.66, 95% CI = 1.25-2.21), including CD (OR = 1.47, 95% CI = 1.15-1.88) and UC (OR = 1.91, 95%CI = 1.41-2.6) (Kim et al, 2022). Researchers assumed a temporal order of IBD diagnosis subsequent to ASD diagnosis, indicating that ASD might increase the risk of IBD (Kim et al, 2022).…”

“…A meta-analysis involving over 11 million participants confirms that ASD is epidemiologically associated with incident IBD (OR = 1.66, 95% CI = 1.25-2.21), including CD (OR = 1.47, 95% CI = 1.15-1.88) and UC (OR = 1.91, 95%CI = 1.41-2.6) (Kim et al, 2022). Researchers assumed a temporal order of IBD diagnosis subsequent to ASD diagnosis, indicating that ASD might increase the risk of IBD (Kim et al, 2022). Among patients with IBD, based on a Northern California cohort, it is observed that the risk of ASD is increased (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.22-1.40) (Alexeeff et al, 2017).…”

“…Among the patients with IBD, a national Swedish cohort study observes a 40% increased risk of developing ASD (Butwicka et al, 2019). For the patients with ASD, a recent meta-analysis involving over 11 million participants indicates that the risk of subsequently developed IBD is increased by approximately 66% (Kim et al, 2022). Interactions between gut microbiota and the brain also indicate the possible involvement of altered gut microbiome in the pathogenesis of ASD (Bundgaard-Nielsen et al, 2020).…”

Integrative Functional Genomic Analysis in Multiplex Autism Families from Kazakhstan

“…The central role in maintaining the balance between the gut microbiota and the host immune response to control inflammation [76] makes NOD2 one of the most important sus-ceptibility genes for inflammatory bowel diseases [77][78][79][80][81][82]. At the same time, a number of studies confirm that autistic children are at higher risk for this disorder [83][84][85][86][87][88]. Moreover, there is evidence of an association between maternal inflammatory bowel disease and ASD in children [89,90].…”

Autism spectrum disorders pathogenesis: Toward a comprehensive model based on neuroanatomic and neurodevelopment considerations

“…The gut microbiome drives immunoregulation (in particular during the first 3 years of life) and faulty immunoregulation, as well as inflammation, predispose to psychiatric disorders, including autism, while psychological stress drives further inflammation via pathways that involve the gut microbiome ( Kostic et al, 2015 ). Thus, while ASD is significantly associated with subsequent incidence of inflammatory bowel disease ( Kim et al, 2022 ), contrary to many psychological and psychiatric diseases there is a lack of evidence for systemic low-grade inflammation in association with ASD affected individuals ( Prosperi et al, 2019 ).…”