Introduction

Autism is a neurodevelopmental condition associated with increased rates of co-occurring medical conditions including gastrointestinal (GI) disorders [1]. In addition, several studies report higher rates of GI symptoms in paediatric [2, 3] and adult autistic populations [4]. Higher GI symptom rates in autism likely stem from a combination of multifactorial causes, involving genetic, environmental, and behavioural factors. Several gene mutations linked to autism are associated with GI symptoms including impaired motility, constipation and gastro-oesophageal reflux (e.g. CHD8, NOS1, FOXP1 and TCF4) [5]. Autistic traits, such as high levels of restricted and repetitive behaviours and interests, are also associated with less diverse diets in some autistic people [6], which could exacerbate GI issues and contribute to microbial dysbiosis [7]. GI issues interact with other conditions and may worsen sleep problems and increase rates of self-injurious and aggressive behaviours, particularly among non-verbal autistic children [8,9,10]. Higher rates of internalising symptoms, including anxiety and social withdrawal, which present at elevated rates in the autistic population, have a bidirectional relationship with GI problems such as constipation, diarrhoea, nausea, and stomach pain [11].

There has been little research examining whether these higher rates of GI symptoms are associated with dysregulated immune responses within the GI tract, prompting investigations into whether low-grade GI inflammation is present in the autistic population [12]. Epidemiological evidence from a recent meta-analysis suggests that autistic people are more likely to be diagnosed with inflammatory bowel disease (IBD) than non-autistic people highlighting the need to screen for GI inflammation in the autistic population [13]. Comparisons of endoscopic findings have been limited to small sample sizes and have found conflicting evidence as to whether GI inflammation is present in the autistic population [3, 14]. While endoscopy remains the gold standard to identify GI inflammation, inflammatory biomarkers measured in faecal samples are often used in research and clinical settings as non-invasive markers of GI inflammation to avoid the risks of endoscopy and general anaesthesia [15, 16]. The direct contact with mucosa of the GI tract makes faecal biomarkers a more direct, non-invasive marker of intestinal inflammation than plasma or serum biomarkers which could be elevated by non-GI causes of inflammation [17].

Biomarkers of interest include calprotectin and S100 calcium binding protein A12 (S100A12) which are released by neutrophils, monocytes and infiltrating macrophages in response to inflammation in the GI tract [17,18,19]. Other markers of interest include lactoferrin and secretory Immunoglobulin A (IgA) which are anti-inflammatory glycoproteins secreted by macrophages [1518]. Faecal measurements of the dimeric M2-isoform of pyruvate kinase (M2-PK), which is associated with increased cell turnover in the GI tract, is also used as a marker of GI inflammation [15, 19, 20]. Lysozymes are antimicrobial enzymes produced by neutrophils and neopterin which is released by activated T-lymphocytes, and macrophages have also been found to be upregulated in IBD [19]. Alpha1-antitrypsin (AAT), a serine protease inhibitor produced by a range of cells including: hepatocytes, neutrophils, monocytes-macrophages, enterocytes, and Paneth cells, and polymorphonuclear neutrophil elastase (PMN-E), a serine protease produced by neutrophils, are both upregulated in response to GI inflammation [19]. GI symptoms in autism have been explored in relation to the microbiome [21]; however, evidence of GI abnormalities as reflected in faecal biomarkers of inflammation has been conflicting. Given higher rates of GI symptoms in the autistic population and concerns of higher rates of inflammation-driven GI conditions, this paper sought to conduct a systematic review of markers of faecal markers of GI inflammation.

Materials and methods

The systematic review and meta-analysis were undertaken and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [22] and was pre-registered on PROSPERO (CRD42022369279).

Literature search

We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, PsycINFO, Web of Science Core Collection and Epistemonikos using strategies developed for each database (Additional file 1). Scopus and Web of Science were used to examine backwards and forwards citations of all studies included in this review.

Selection of studies

The titles and abstracts of all studies retrieved by the search were reviewed by two researchers (NM and DM). The full texts of relevant studies were then screened by NM to identify eligible studies that met the inclusion and exclusion criteria. The criteria for inclusion were (1) the measurement of inflammatory biomarkers in faeces (2) autism diagnoses confirmed by standardised diagnostic tools or by a medical professional in line with the criteria outlined in the DSM-III, IV or 5 or ICD-10 or 11. The exclusion criteria were (1) studies of biopsies and endoscopies, as the focus of this review is on biospecimens collected using minimally invasive sampling procedures, (2) studies that did not provide data as absolute concentrations (e.g. relative data reported by Western blots) or insufficient information regarding the method of data quantification, (3) studies that only report data from analyses of the microbiome, as the focus of this meta-analysis is on markers of GI inflammation.

Data extraction and risk of bias

The means and standard deviations of the faecal biomarker levels in autistic and non-autistic cohorts were extracted if available. If means and standard deviations were not reported, they were derived from sample size, median, IQR, minimum, or maximum values [23]. Risk of bias in all included studies was assessed using a study specific adaptation of the Newcastle–Ottawa Scale (NOS) for case–control studies carried out by two researchers (NM and DM) (Additional file 1). We extracted the following data from all included studies: the age and sex of participants, measurement of concurrent psychiatric or medical conditions, country of publication and publication year, details of recruitment settings, any variables used to match participants, method of faecal biomarker quantification. As considerable interassay variability has been reported between different commercial calprotectin assays [24,25,26], details of the assays used by individual studies were also extracted. To examine the generalisability of the literature, the inclusion of autistic participants with limited verbal and/or cognitive abilities was also coded based on reports of communication ability, adaptive functioning or cognitive ability in line with the criteria developed by Stedman et al. [27].

Statistical analysis

Meta-analyses were performed when at least two studies that could be combined were identified. Random-effects meta-analyses were conducted in R 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria) using the metafor package. To control for the substantial variability in biomarker concentrations between laboratories and assays, the ratio of mean (RoM) faecal biomarker levels in autistic and non-autistic cohorts and standard errors were generated for each comparison, log transformed and pooled for meta-analysis [28]. Standardised mean differences were also calculated and pooled for all analyses. All major findings remained consistent with the analysis of RoM (Additional file 2: Figs. S1, S2). When multiple autistic cohorts were present within a single study, autistic cohorts were combined for the main analysis. When multiple control cohorts were present, individual ratios were generated. Heterogeneity was assessed using I2 [29].

Results

Systemic review of faecal biomarkers of inflammation

Many inflammatory markers used in studies of GI inflammation (e.g. M2-PK, S100A12, AAT) have not been examined in the autistic population. Single studies found lower faecal levels of lysozyme, particularly among those with higher probiotic usage [30], cortisol and glutamate metabolites [31] and comparable levels of PMN-E [30] among autistic participants relative to controls. A small Swedish study found that elevated rectal nitric oxide levels, defined as levels above < 250 parts per billion, were reported in 27% of surveyed autistic participants (6/22) and in 9% of surveyed controls (2/22) [32] (Fig. 1).

Fig. 1
figure 1

PRISMA flow diagram of search for faecal biomarkers in autism

Two studies examined the levels of secretory IgA in faecal samples, but the results of these studies could not be synthesised as one study reported results as optical densities rather than concentrations. Adams et al. found comparable levels of faecal IgA concentrations in 39 control children and adolescents and 58 autistic children and adolescents, (55 participants with a DSM-IV diagnosis of Autistic disorder and 3 with a diagnosis of Asperger’s disorder) [30]. Zhou et al. [

Availability of data and materials

All data used for the meta-analysis is available in Additional file 3.

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Funding

Nisha E. Mathew is funded by the Australian Government Department of Education, Skills and Employment Research Training Program and a Neuroscience Research Australia top up award. Delyse McCaffrey is the Christie Scholar and supported by the NeuRA PhD Pearls Program and funded by the Australian Government Department of Education, Skills and Employment Research Training Program. Adam K. Walker is supported by the Schizophrenia Research Institute and Neuroscience Research Australia (Grant#: GXX0049). Chee Y. Ooi is supported by a National Health and Medical Research Council Investigator Grant (Grant#: APP1194358) funded by the Australian government.

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NM extracted the data, carried out statistical analysis, and wrote the first draft. DM extracted the data. KM advised on the statistical analysis. AKW, KM, AM, MJM and CYO supervised the work, provided relevant input and critically reviewed the manuscript for important intellectual content. All authors read and approved the final manuscript.

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Correspondence to Chee Y. Ooi.

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Supplementary Information

Additional file 1.

Search strategy and study-specific adaptation of the Newcastle-Ottowa Scale for case-control studies.

Additional file 2.

Additional analyses.

Additional file 3.

 Meta-analysis dataset.

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Mathew, N.E., McCaffrey, D., Walker, A.K. et al. The search for gastrointestinal inflammation in autism: a systematic review and meta-analysis of non-invasive gastrointestinal markers. Molecular Autism 15, 4 (2024). https://doi.org/10.1186/s13229-023-00575-0

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