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Some research suggests that GI symptoms seen in children with ASD may relate to behavior problems. The objective of this pilot study was to assess the effect of the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet on GI and behavioral problems in children with ASD. At follow-up, the low FODMAP diet group had significant relief in some GI problems compared with both baseline in the group and control group. At baseline and at follow-up, there were no significant differences in behavioral problems between the low FODMAP diet group and the control group. Randomized controlled studies including larger sample sizes are needed to confirm the effects of low FODMAP diets in children with autism who have gastrointestinal problems.

Functional somatic syndromes (FSS) are common in adolescents, characterised by severe disability and reduced quality of life. Behavioural treatments such as acceptance and commitment therapy (ACT) has shown promising results in children and adolescents with FSS, but has focused on specific syndromes such as functional pain. The current study will compare the efficacy of group-based ACT with that of enhanced usual care (EUC) in adolescents with a range of FSS operationalised by the unifying construct of multiorgan bodily distress syndrome (BDS). A total of 120 adolescents aged 15-19 and diagnosed with multiorgan BDS, of at least 12 months duration, will be assessed and randomised to either: (1) EUC: a manualised consultation with a child and adolescent psychiatrist and individualised treatment plan or (2) manualised ACT-based group therapy plus EUC. The ACT programme consists of 9 modules (ie, 27 hours) and 1 follow-up meeting (3 hours). The primary outcome is physical health, assessed by an Short Form Health Survey (SF-36) aggregate score 12 months after randomisation. Secondary outcomes include self-reported symptom severity, symptom interference, depression and anxiety, illness worry, perceived stress and global improvement; as well as objective physical activity and bodily stress response measured by heart rate variability, hair cortisol and inflammatory biomarkers. Process measures are illness perception, illness-related behaviour and psychological flexibility. The study is conducted in accordance with Helsinki Declaration II. Approval has been obtained from the Science Ethics Committee of the Central Denmark Region and the Danish Data Protection. The results will be sought to be published according to the CONSORT statement in peer-reviewed journals. This is one of the first larger randomised clinical trials evaluating the effect of a group-based intervention for adolescents with a range of severe FSS. NCT02346071; Pre-results.

Gastrointestinal symptoms are highly prevalent, but many people who have them will have no organic explanation for their symptoms. Most of these people will be labelled as having a functional gastrointestinal disorder, such as irritable bowel syndrome, functional dyspepsia, or functional constipation. These conditions affect up to 40% of people at any one point in time, and two-thirds of these people will have chronic, fluctuating symptoms. The pathophysiology of functional gastrointestinal disorders is complex, but involves bidirectional dysregulation of gut–brain interaction (via the gut–brain axis), as well as microbial dysbiosis within the gut, altered mucosal immune function, visceral hypersensitivity, and abnormal gastrointestinal motility. Hence, nomenclature refers to the conditions as disorders of gut–brain interaction. Psychological comorbidity is common; however, whether or not this predates, or is driven by, symptoms is not clear. Patients with functional gastrointestinal disorders can feel stigmatised, and often this diagnosis is not communicated effectively by physicians, nor is education provided. Prompt identification and treatment of these conditions is crucial as they have a considerable impact on health-care systems and society as a whole because of repeated consultations, unnecessary investigations and surgeries, prescriptions and over-the-counter medicine use, and impaired health-related quality of life and ability to work. Symptom-based criteria are used to make a diagnosis, with judicious use of limited investigations in some patients. The general principles of treatment are based on a biopsychosocial understanding and involve management of physical symptoms and, if present, psychological comorbidity. In the future, treatment approaches to functional gastrointestinal disorders are likely to become more personalised, based not only on symptoms but also underlying pathophysiology and psychology.

Key Points Common gastrointestinal diseases, such as IBS, functional dyspepsia and IBD, are closely linked to psychological morbidity This link is driven in part through bidirectional signalling between the brain and gut, which reciprocally regulate each other Growing evidence implicates the importance of immune activation, which might be overt (IBD) or more subtle (IBS, functional dyspepsia) in pathological gut–brain interactions The composition of the intestinal microbiota affects behaviour and mood, which could in part rely on selective activation of distinct host cytokine responses Therapeutic targeting of gut microorganisms, host immunity or psychological symptoms could hold the key to uncoupling pathological interactions between the gut and brain Bidirectional gut–brain communications are proving key to both gastrointestinal and neurological diseases. This Review explores the role of the mucosal immune system as gatekeeper and master regulator of these brain–gut and gut–brain communications. Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota–gut–brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut–brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain–gut and gut–brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis.

While there are numerous medical comorbidities associated with ASD, gastrointestinal (GI) issues have a significant impact on quality of life for these individuals. Recent findings continue to support the relationship between the gut microbiome and both GI symptoms and behavior, but the heterogeneity within the autism spectrum requires in-depth clinical characterization of these clinical cohorts. Large, diverse, well-controlled studies in this area of research are still needed. Although there is still much to discover about the brain-gut-microbiome axis in ASD, microbially mediated therapies, specifically probiotics and fecal microbiota transplantation have shown promise in the treatment of GI symptoms in ASD, with potential benefit to the core behavioral symptoms of ASD as well. Future research and clinical trials must increasingly consider complex phenotypes in ASD in stratification of large datasets as well as in design of inclusion criteria for individual therapeutic interventions.

UNDERLYING MECHANISMS FOR GI SYMPTOMS IN COVID-19 The pathophysiology of GI symptoms in COVID-19 is not well understood; however, evidence points to a role of angiotensin-converting enzyme 2 (ACE2) cell-surface receptors and to a severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2)–induced inflammatory process in the digestive tract (3). POSTVIRAL-FUNCTIONAL GI DISORDERS Initially, postinfection (PI)-IBS was reported after acute bacterial gastroenteritis (8) (e.g., Shigella, Salmonella, and Campylobacter); however, later studies reported that protozoa (e.g., Giardia lamblia), as well as viruses (e.g., Norwalk-like viruses, Rotavirus, and Norovirus), were also associated with PI-IBS (10) (Table 1). [...]the time period since the onset of the pandemic may be yet too short for diagnosing PI-FGIDs/DGBI after COVID-19. [...]as gastroenterologists, we need to be aware of the possibility of PI-FGDs/DGBI in patients who suffered from COVID-19, especially among those who had GI symptoms (Table 2). [...]the authors of the current study have already started to consult patients likely to have symptoms of post–COVID-19 FGIDs/DGBI.

Eating disorders involve irregularities in eating behavior that may cause gastrointestinal (GI) symptoms. Consequently, many patients with eating disorders seek gastroenterological healthcare at some point in their illness, with many seeking this care even before they seek treatment for and/or diagnosed with their eating disorder. As such, the gastroenterology provider is in a unique position to identify, manage, and facilitate treatment for an eating disorder early in the course of the illness. Although assessing eating disorders is already a difficult task, the identification of eating disorders in patients with GI disease represents an even greater challenge. In particular, common GI symptoms, such as nausea, vomiting, and bloating, may disguise an eating disorder because these symptoms are often viewed as a sufficient impetus for dietary restriction and subsequent weight loss. In addition, the focus on identifying an organic etiology for the GI symptoms can distract providers from considering an eating disorder. During this prolonged diagnostic evaluation, the eating disorder can progress in severity and become more difficult to treat. Unfortunately, a misconception that hinders eating disorder detection is the notion that the rate or method of weight loss is associated with an eating disorder. Regardless of whether weight loss is slow or rapid, purposeful or accidental, eating disorder behaviors and thought patterns may be present. Unidentified eating disorders are not only dangerous in their own right but also can interfere with effective management of GI disease and its symptoms. As such, it is imperative for the GI provider to remain well versed in the identification of these diseases.

Key Points Placebo response rates in randomized controlled trials in gastroenterology are of similar size, and mediators and moderators are of similar type to those in other medical subspecialties Some trends found in other medical subspecialties—for example, an increase of the placebo response over time and high placebo responses with unbalanced randomization—have been avoided in gastroenterology Experimental gastroenterology has shown that the placebo response (for example, in visceral pain and nausea) follows established rules and mechanisms (learning, expectations) Brain imaging studies have demonstrated that the placebo response is not merely a response bias, but exhibits neurobiological and psychobiological properties along the gut–brain axis With improved doctor–patient communication, it might be possible to boost the efficacy of drug treatment by utilizing the placebo mechanisms in daily practice Striking placebo responses seen in randomized clinical trials have generated an interest in investigating this phenomenon in gastroenterology. Sigrid Elsenbruch and Paul Enck discuss general aspects of the placebo response relating to gastroenterology and aspects that are unique to gastrointestinal disease. This Review provides a fascinating insight into placebo research and how this phenomenon could be exploited in the future for better patient care. Placebo effects in clinical trials have sparked an interest in the placebo phenomenon, both in randomized controlled trials (RCTs) and in experimental gastroenterology. RCTs have demonstrated similar short-term and long-term placebo response rates in gastrointestinal compared to other medical diagnoses. Most mediators and moderators of placebo effects in gastrointestinal diseases are also of similar type and size to other medical diagnoses and not specific for gastrointestinal diagnoses. Other characteristics such as an increase in the placebo response over time and the placebo-enhancing effects of unbalanced randomization were not seen, at least in IBS. Experimental placebo and nocebo studies underscore the 'power' of expectancies and conditioning processes in shaping gastrointestinal symptoms not only at the level of self-reports, but also within the brain and along the brain–gut axis. Brain imaging studies have redressed earlier criticism that placebo effects might merely reflect a response bias. These findings raise hope that sophisticated trials and experiments designed to boost positive expectations and minimize negative expectations could pave the way for a practical and ethically sound use of placebo knowledge in daily practice. Rather than focusing on a 'personalized' choice of drugs based on biomarkers or genes, it might be the doctor–patient communication that needs to be tailored.

Anxiety and depression occur frequently in patients with functional gastrointestinal disorders (FGIDs), but their precise prevalence is unknown. We addressed this issue in a large cohort of adult patients and determined the underlying factors. In total, 4,217 new outpatients attending 2 hospitals in Hamilton, Ontario, Canada completed questionnaires evaluating FGIDs and anxiety and depression (Hospital Anxiety and Depression scale). Chart review was performed in a random sample of 2,400 patients. Seventy-six percent of patients fulfilled Rome III criteria for FGIDs, but only 57% were diagnosed with FGIDs after excluding organic diseases, and the latter group was considered for the analysis. Compared with patients not meeting the criteria, prevalence of anxiety (odds ratio (OR) 2.66, 95% confidence interval (CI): 1.62-4.37) or depression (OR 2.04, 95% CI: 1.03-4.02) was increased in patients with FGIDs. The risk was comparable to patients with organic disease (anxiety: OR 2.12, 95% CI: 1.24-3.61; depression: OR 2.48, 95% CI: 1.21-5.09). The lowest prevalence was observed in asymptomatic patients (OR 1.37; 95% CI 0.58-3.23 and 0.51; 95% CI 0.10-2.48; for both conditions, respectively). The prevalence of anxiety and depression increased in a stepwise manner with the number of co-existing FGIDs and frequency and/or severity of gastrointestinal (GI) symptoms. Psychiatric comorbidity was more common in females with FGIDs compared with males (anxiety OR 1.73; 95% CI 1.35-2.28; depression OR 1.52; 95% CI 1.04-2.21). Anxiety and depression were formally diagnosed by the consulting physician in only 22% and 9% of patients, respectively. Psychiatric comorbidity is common in patients referred to a secondary care center but is often unrecognized. The prevalence of both anxiety and depression is influenced by gender, presence of organic diseases, and FGIDs, and it increases with the number of coexistent FGIDs and frequency and severity of GI symptoms.

Autism spectrum disorder (ASD) is a complex neurological and developmental disorder, and a growing body of literature suggests the presence of autonomic nervous system (ANS) dysfunction in individuals with ASD. ANS is part of the “gut brain axis”, which consists of an intricate interplay between the gut microbiome, mucosal immune system, enteric nervous system, ANS, and central processes receiving input from the vagus nerve. Measurements of the gut microbiome and the autonomic indices can serve as non-invasive markers of the status of the gut-brain axis in ASD. To our knowledge, no previous studies have explored the relationship between ANS and gut microbiome in individuals with ASD. Furthermore, while previous studies investigated the use of autonomic indices and gut microbiome independently as markers of ASD-related comorbidities, such as anxiety, cardiovascular issues, and gastrointestinal dysfunction, the use of combined autonomic indices and gut microbiome factors to classify ASD and control subjects has not been explored. In this study, we characterized autonomic function of a group of individuals with ASD in comparison to their paired, first-degree relative controls. Second, we explored the ASD gut-brain-axis through the relationship between gut microbiome markers and autonomic indices, as well as the correlation between the gut-brain-axis and clinical presentation of ASD. Lastly, this study explores the predictive capability of gut-brain-axis biomarkers (including autonomic and microbiome indices) in subtyping ASD cases, serving as a starting point to investigate the possibility of assisting in ASD screening and diagnosis that still heavily relies on psychological testing, which may be based on highly subjective standards.