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Gut–brain axis. Note: Bidirectional gut–brain communication includes both afferent and efferent pathways showing the role of different mechanisms involved.
Source publication
Autism spectrum disorder (ASD) is a genetically determined neurodevelopmental brain disorder presenting with restricted, repetitive patterns of behaviors, interests, and activities , or persistent deficits in social communication and social interaction. ASD is characterized by many different clinical endophenotypes and is potentially linked with ce...
Citations
... Among patients with ASD, gastrointestinal (GI) symptoms are frequently reported as more prevalent and severe. The occurrence of GI symptoms among children with ASD varies widely across studies, ranging from 9% to 84%, compared to 9-37% in children without ASD [70]. The most commonly reported symptoms include abdominal pain and discomfort, constipation, diarrhea, soiling, flatulence, nausea or vomiting, and gastroesophageal reflux (GERD) [71]. ...
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by challenges in social communication, restricted interests, and repetitive behaviors. It is also associated with a high prevalence of eating disorders, gastrointestinal (GI) symptoms, and alterations in gut microbiota composition. One of the most pressing concerns is food selectivity. Various eating disorders, such as food neophobia, avoidant/restrictive food intake disorder (ARFID), specific dietary patterns, and poor-quality diets, are commonly observed in this population, often leading to nutrient deficiencies. Additionally, gastrointestinal problems in children with ASD are linked to imbalances in gut microbiota and immune system dysregulation. The aim of this narrative review is to identify previous associations between the gut–brain axis and gastrointestinal problems in ASD. We discuss the impact of the “microbiome–gut–brain axis”, a bidirectional connection between gut microbiota and brain function, on the development and symptoms of ASD. In gastrointestinal problems associated with ASD, a ‘vicious cycle’ may play a significant role: ASD symptoms contribute to the prevalence of ARFID, which in turn leads to microbiota degradation, ultimately worsening ASD symptoms. Current data suggest a link between gastrointestinal problems in ASD and the microbiota, but the amount of evidence is limited. Further research is needed, targeting the correlation of a patient’s microbiota status, dietary habits, and disease course.
... It is known that low bowel frequency and disorders of gut-brain interactions including functional constipation are common in children with cognitive dysfunctions such as autism spectrum disorders. 36 None of the studies included in our metaregression have screened children for cognitive dysfunction using appropriate tools to understand the potential effects of cognitive dysfunction on bowel frequency in children. Furthermore, some studies scored low in quality assessment, potentially leading to under-or overestimating bowel frequency. ...
Objectives
Defecation disorders are a common pediatric problem and bowel frequency is crucial in identifying them. The aim of this analysis is to define normal bowel frequencies in healthy children ranging from newborns to adolescents.
Methods
A literature search was conducted using MEDLINE, SCOPUS, EMBASE, Cochrane Library, and Web of Science from their inception to February 2024, aiming to identify studies reporting bowel habits of healthy children (0–18 years). A Bayesian distribution modeling approach was adopted to pool the mean frequency of bowel opening using inverse‐variance weighing. A subgroup analysis and a meta‐regression were performed with Bayesian generalized additive mixed distributional models. The methodological quality of the articles was evaluated using the Newcastle–Ottawa Scale modified for cross‐sectional studies.
Results
Seventeen studies were included in the analysis, including 22,698 children aged from 0 to 18 years. The subgroup meta‐analysis showed mean bowel frequencies for newborns, 1–6 months, 6–12 months, 1–2 years, 2–5 years, and over 5 years are 3.24 (95% credible interval [CrI]: 2.83–3.63), 1.99 (95% CrI: 1.77‐2.19), 1.66 (95% CrI: 1.45–1.88), 1.53 (95% CrI: 1.37–1.7), 1.15 (95% CrI: 0.99–1.31), and 1.02 (95% CrI 0.88–1.18), respectively. Between studies, heterogeneity demonstrated a near‐normal distribution with a mean of 0.16 and a 95% CrI of 0.04–0.28. The variance of the distribution of mean bowel frequency reduced with age.
Discussion
In this Bayesian meta‐analysis, we found that younger children have a higher bowel frequency. The reported bowel frequencies for each age group could serve as normal values in clinical practice to differentiate health and disease.
... Food allergy, which is related to gastrointestinal symptoms (Rajani et al., 2020;Wasilewska & Klukowski, 2015), is also associated with autism. A meta-analysis study reported that the odds ratio (OR) for autistic individuals (children and young adults) with food allergy was 2.22 compared with the non-autistic group, confirming a strong relationship between food allergy and autism (Wang et al., 2021). ...
Autistic children often have comorbid somatic problems. However, in adulthood, this has been much less studied. We investigated the associations between autistic symptoms and irritable bowel syndrome, food allergy, pain, and fatigue in adulthood and examined sex and life-course differences herein. A total of 35,048 adults aged from 18 to 90 from the Lifelines Cohort Study reported autistic symptoms, irritable bowel syndrome, food allergy, pain, and fatigue. Associations between autistic and somatic problems were estimated by logistic and linear regression models. Higher autism scores were associated with more severe somatic problems with an odds ratio of 1.44 (95% confidence interval: (1.34, 1.55)) for irritable bowel syndrome, an odds ratio of 1.13 (95% confidence interval: (1.07, 1.20)) for food allergy, a regression coefficient (b) of 0.20 (95% confidence interval: (0.18, 0.22)) for pain and a regression coefficient (b) of 0.37 (95% confidence interval: (0.35, 0.39)) for fatigue. Associations were stronger in females than males for pain and fatigue. Associations declined with age for fatigue and food allergy and increased with age for irritable bowel syndrome and pain, in a subgroup with autism scores >98th percentile combined with symptom onset in childhood and high functional impairments. These findings are important for autistic adults and may aid in diagnosis, monitoring, and intervention.
Lay Abstract
What is already known about the topic?
Autistic children frequently often have accompanying physical health problems. However, this has been much less studied in autistic men and women during adulthood.
What does this article add?
This is one of the first studies to investigate the associations between autistic and somatic problems in adults from the general population. Using a continuous measure of autistic symptom scores and a categorical definition of autism (referred to below as probable autism) which considered symptom severity, childhood age of onset, and functional impairment, we found that autistic problems and irritable bowel syndrome, food allergy, pain, and fatigue were associated in adults. Sex differences were present for pain and fatigue, for which the associations with autistic symptom scores were somewhat stronger in females than males. Regarding age differences, the associations with fatigue and having food allergy were more pronounced in younger adults. Conversely, older individuals had a higher risk of developing irritable bowel syndrome or experiencing pain if they met the criteria for probable autism.
Implications for practice, research, or policy
There is a need for providing routine programs of screening, assessment, and treatment of autism-related somatic problems and developing evidence-based interventions for autistic individuals. These could be tailored to the needs of specific autistic populations. For example, autistic females could be given extra attention about the potential presence of pain and fatigue, younger adults about the potential presence of food allergy and fatigue, and older adults concerning the potential presence of irritable bowel syndrome and pain.
... Further, anxiety and pain often co-occur in people with complex needs. For example, there is a link between anxiety and gastrointestinal (GI) difficulties in autistic people, which may interact with one another, causing a cycle of heightened anxiety and heightened GI difficulties [24,[63][64][65]. Despite this, the pain subscale yielded promising results and therefore warrants further evaluation using more direct assessments. ...
Background
There is a critical need for the development of dependable and valid anxiety assessment tools suitable for people with moderate to severe intellectual disabilities, particularly those who speak few or no words. Distinguishing anxiety from distress caused by physical discomfort (pain) or characteristics associated with autism, prevalent in this population, necessitates specialised assessment tools. This study (a) developed a parent-report anxiety questionnaire tailored for individuals with severe to moderate intellectual disabilities, potentially with a co-diagnosis of autism, and (b) evaluated the psychometric attributes of this novel measure.
Methods
A comprehensive approach involving literature reviews, inspection of existing tools, and interviews with clinicians and parents guided the creation of the Clinical Anxiety Scale for People with Intellectual Disabilities. The tool was completed by parents or caregivers (N = 311) reporting on individuals aged 4 or older with intellectual disabilities.
Results
Exploratory factor analysis indicated a four-factor structure encompassing anxiety, pain, low energy/withdrawal, and consolability. The anxiety factor explained the most variance in scores (26.3%). The anxiety, pain, low energy/withdrawal subscales demonstrated robust internal consistency (α = 0.81-0.92), and convergent, divergent, and discriminant validity. Robustness of these subscales was further evidenced by test-retest reliability (ICC = 0.79-0.88) and inter-rater reliability (ICC = 0.64-0.71). Subgroup analyses consistently demonstrated strong psychometric properties among individuals diagnosed with non-syndromic autism (N = 98), children (N = 135), adults (N = 175), and across diverse communication abilities within the sample. Moreover, individuals diagnosed with both autism and anxiety exhibited significantly higher scores on the anxiety subscale compared to those without an anxiety diagnosis, while showing no difference in autism characteristic scores.
Conclusions
The findings indicate that the Clinical Anxiety Scale for People with Intellectual Disabilities is a promising measure for use across diverse diagnostic groups, varying communication abilities, and with people with moderate to severe intellectual disabilities.
... This behavior can be also considered a manifestation of the rigid behavior and restricted interests that characterize autism spectrum disorders [11]. Evidence also shows that GIT problems are common among children with ASD and this was linked to the existence of the gut-immune-brain pathways [12]. Common symptoms include constipation, diarrhea, nausea, and abdominal pain [13]. ...
Background
The nutritional status and growth of children with Autism spectrum disorders (ASD) is influenced significantly by two factors; food selectivity behaviors due to their consumption of a limited variety of food and the high incidence of gastrointestinal (GIT) disorders.
Aim
This study aimed to assess the nutritional adequacy and growth pattern of ASD children aged three to twelve years compared to their healthy developing peers.
Methods
A national comparative, facility-based cross-sectional study was conducted in eight Egyptian governorates on 285 Egyptian children diagnosed with ASD and 224 children who are their relatives as healthy developing peers. Anthropometric measurements were obtained, including weight, height, head circumference, and mid-upper arm circumference. Body Mass Index (BMI) was calculated and all numbers were plotted on WHO growth charts. Assessment of food preferences, and nutrient intake adequacy of children was done using the Food preference questionnaire, and the Dietary Reference Intakes (DRIs) of Egyptian children.
Results
Calorie-dense food and sugar intake were higher among ASD children than their healthy developing peers. ASD children omit some important protein sources such as dairy (COR = 5.2, 95% CI:2.7–9.9), meat, and poultry (COR = 2.7, 95% CI: 1.6–4.7), and a lower intake of fruits and vegetables than their healthy developing peers. For children with ASD in all age groups, a deficiency in the range of 50–60% was detected for vitamins (C, D, B6, thiamine, riboflavin, niacin) and minerals (iron). A deficiency in the range of 60–70% was detected for folate and calcium. A deficiency of vitamin C calcium and iron was also detected for both children with ASD and their healthy developing relatives aged 6 to 12 years. GIT disorders were common among ASD children compared to healthy developing peers (COR = 2.8 to 10.3). Children with ASD had four-fold higher odds of stunting (COR = 4.1, CI: 1.7–10.1), threefold higher odds of being overweight (COR = 3.3, CI: 1.48–7.32), and nearly eleven-fold higher odds of obesity (COR = 11.4, CI: 4.05–32.17) compared to their healthy developing peers.
Conclusion
ASD children are prone to overweight and protein malnutrition. Their intake of fruits and vegetables is inadequate and hence their intake of vitamins and minerals is insufficient, contributing to stunting.
... GI problems commonly occur in patients with ASD, with up to 70% of patients being affected [4]. Generally, GI problems in ASD mainly include diarrhea, constipation, and abdominal pain [5]. Moreover, GI problems in ASD children with ASD are associated with the severity of behavioral ASD symptoms [6]. ...
BACKGROUND
Autism spectrum disorder (ASD) is a developmental disorder characterized by social deficits and repetitive behavior. Gastrointestinal (GI) problems, such as constipation, diarrhea, and inflammatory bowel disease, commonly occur in patients with ASD. Previously, GI problems of ASD patients were attributed to intestinal inflammation and vertical mother-to-infant microbiome transmission.
AIM
To explore whether GI problems in ASD are related to maternal intestinal inflammation and gut microbiota abnormalities.
METHODS
An ASD rat model was developed using valproic acid (VPA). Enzyme-linked immunosorbent assay and fecal 16S rRNA sequencing were used to test GI changes.
RESULTS
VPA exposure during pregnancy led to pathological maternal intestinal changes, resulting in alterations in maternal gut microbiota. Additionally, the levels of inflammatory factors also increased. Moreover, prenatal exposure to VPA resulted in impaired duodenal motility in the offspring as well as increased levels of inflammatory factors.
CONCLUSION
GI problems in ASD may be associated with maternal intestinal inflammation and microbiota abnormality. Future research is required to find more evidence on the etiology and treatment of GI problems in ASD.
... Epilepsy and co-occurring psychiatric conditions such as anxiety and mood disorders are more frequently experienced in autistic people than their neurotypical peers (Khachadourian et al., 2023). Autistic children and adults are at risk of having gastrointestinal issues such as constipation, diarrhea, and abdominal pain, with suggestions that the associated pathways in the gut-brain axis contribute to alterations in both behaviour and cognition (Wasilewskal & Klukowski, 2015). Sleep disorders are also commonly experienced by autistic people, which can have an impact on social interaction, day to day life and academic achievement, with evidence suggesting that increased oxidative stress may play a major role in the pathogenesis of these symptoms (Devnani & Hedge, 2015). ...
Complementary and Alternative Medicine (CAM) is a therapeutic option currently used by autistic people with continued interest and uptake. There remains limited evidence regarding the efficacy of CAM use in autism. The aim of this systematic review is to comprehensively review published clinical trials to explore the efficacy of CAM in autism. A systematic literature review of available research published from June 2013 to March 2023 was conducted. Our literature search identified 1826 eligible citations, and duplications removed (n = 694) with 102 articles eligible for title/abstract screening. After full text review, 39 studies were included. The results of this systematic review identified that for autistic people, vitamin and mineral supplements may only be of benefit if there is a deficiency. The results also found that the main interventions used were dietary interventions and nutraceuticals, including targeted supplements, vitamins and minerals, omega 3 s and prebiotics, probiotics and digestive enzymes. The evidence does not support some of the most frequently utilised dietary interventions, such as a Gluten Free Casein Free (GFCF) diet, and the use of targeted nutraceutical supplements may be of benefit, but more conclusive research is still required to direct safe and effective treatment.
... Most research on food hypersensitivity in ASD individuals have been focused on type I hypersensitivity [1,3,8,11,29,30], as non-IgE-mediated hypersensitivities (and their associated GIS) often go unnoticed not only by caregivers but even by clinical pediatricians [8,9,29]. For instance, a cow's milk protein allergy is probably the most common type IV food hypersensitivity in ASD children affected by food protein-induced enterocolitis syndrome (FPIES; known as "autistic enterocoli-tis") [32,33]. Although the clinical diagnosis (including serologic testing) of both types of hypersensitivities is feasible in neurotypical children with sufficient verbal communication capacity, in those with ASD, it can be challenging and, therefore, could be underestimated, particularly type IV hypersensitivities [9,10,33], such as those detected here. ...
... For instance, a cow's milk protein allergy is probably the most common type IV food hypersensitivity in ASD children affected by food protein-induced enterocolitis syndrome (FPIES; known as "autistic enterocoli-tis") [32,33]. Although the clinical diagnosis (including serologic testing) of both types of hypersensitivities is feasible in neurotypical children with sufficient verbal communication capacity, in those with ASD, it can be challenging and, therefore, could be underestimated, particularly type IV hypersensitivities [9,10,33], such as those detected here. Lastly, the dual humoral response (IgA+/IgG+) against BMC observed in 23% of all ASD patients studied here, suggests a strong MALT activation in the Lamina propia due to an increased mucosal permeability (known as leaky gut) [34,35]. ...
Severe gastrointestinal symptoms (GIS) and food hypersensitivity are tightly associated in young individuals with autism spectrum disorders (ASD). Here, we explored the relationship of GIS (gastrointestinal severity index, ROMA IV criteria, Bristol scale), ASD-like behaviors (Childhood Autism Rating Scale), and certain sociodemographic/clinical traits (epidemiological survey) with serum immunoreactivity (IgG, IgA, IgE titers) towards bovine milk caseins (BMC; by ELISA) and subfractions (by immunoblotting) in thirty-one pediatric patients (~3-15 y, 77% male) with mild-to-severe GIS and ASD-like behaviors. In total, 42%, 25%, and 23% of all participants exhibited no (IgG−/IgA−), mono (IgG+/IgA−), or dual (IgG+/IgA+) immunoreactivity to BMC, respectively; the trend was significantly associated with the severity of the GIS and ASD-like behaviors, regurgitations, and self-reported allergies (OR: 1 → (1.9-3.1) → 13.5-16.0)]. No IgE+ response to BMC was found. Dual responders were α > κ > β-casein, though nonspecific reactivity to other protein fractions was also observed. The IgA+ > IgG+ but not IgE+ response to BMC (mainly α-casein) seems to be related to the severity of GIS and ASD-like behaviors, although a larger number of ASD patients are needed to draw a causal association.
... Os estudos ainda não são conclusivos quanto à relação de causa e efeito entre a restrição de alguns componentes nutricionais como o glúten e a caseína e melhoria dos sintomas do TEA. Sem prejuízo, há muito a comunidade científica reconhece a interligação do eixo intestino-cérebro no comportamento humano e cognição (Wasilewska & Klukowski, 2015). ...
O Transtorno do Espectro do Autismo (TEA) é um distúrbio do neurodesenvolvimento humano que acarreta prejuízo na comunicação e na interação social. Os indivíduos com TEA apresentam padrões de comportamentos repetitivos e restritivos, com repercussão na área da nutrição, uma vez que é recorrente entre os portadores a seletividade alimentar e a presença de problemas gastrointestinais. Esta revisão bibliográfica teve por objetivo analisar a seletividade alimentar e transtorno ou alteração no processo sensorial em crianças com TEA. Foram utilizados estudos em inglês e português das bases de dados SCIELO, CAPES, APA, Periódicos Internacionais EBSCO host. Após a análise de estudos que relatam sobre os hábitos e o estado nutricional de crianças que desenvolveram seletividade ou recusa alimentar, verificou-se que a terapia nutricional tem sido uma estratégia eficaz no tratamento da seletividade alimentar em crianças autistas. Constatou-se que até o momento, não há uma dietoterapia concretizada. As diferentes características do transtorno no comportamento e na parte sensorial demandam um olhar individualizado e o respeito de cada caso de forma única e particular. A literatura científica tem mostrado, com relação à alimentação, que os três aspectos mais marcantes são: seletividade, recusa e indisciplina.
... Specific modifiable environmental and lifestyle risk factors for ASD include exposure to environmental toxicants [45][46][47], poor diet [29,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63], disruption of the gut microbiota [64][65][66][67][68][69][70][71][72][73][74], excessive exposure to non-native electromagnetic fields (EMFs) [75][76][77][78][79][80][81][82][83][84], and accumulation of heavy metals. There are limited FDA-approved pharmacological options at present to treat ASD. ...
The prevalence of autism has been increasing at an alarming rate. Even accounting for the expansion of autism spectrum disorder diagnostic (ASD) criteria throughout the 1990’s, there has been an over 300% increase in ASD prevalence since the year 2000. The often debilitating personal, familial, and societal sequelae of autism are generally believed to be lifelong. However, there have been several encouraging case reports demonstrating the reversal of autism diagnoses, with a therapeutic focus on addressing the environmental and modifiable lifestyle factors believed to be largely underlying the condition. This case report describes the reversal of autism symptoms among dizygotic, female twin toddlers and provides a review of related literature describing associations between modifiable lifestyle factors, environmental exposures, and various clinical approaches to treating autism. The twins were diagnosed with Level 3 severity ASD “requiring very substantial support” at approximately 20 months of age following concerns of limited verbal and non-verbal communication, repetitive behaviors, rigidity around transitions, and extensive gastrointestinal symptoms, among other common symptoms. A parent-driven, multidisciplinary, therapeutic intervention involving a variety of licensed clinicians focusing primarily on addressing environmental and modifiable lifestyle factors was personalized to each of the twin’s symptoms, labs, and other outcome measures. Dramatic improvements were noted within several months in most domains of the twins’ symptoms, which manifested in reductions of Autism Treatment Evaluation Checklist (ATEC) scores from 76 to 32 in one of the twins and from 43 to 4 in the other twin. The improvement in symptoms and ATEC scores has remained relatively stable for six months at last assessment. While prospective studies are required, this case offers further encouraging evidence of ASD reversal through a personalized, multidisciplinary approach focusing predominantly on addressing modifiable environmental and lifestyle risk factors.
