Is there a causal link between psychological disorders and functional gastrointestinal disorders?

Abstract

Psychological disorders, most notably anxiety and depressive disorders, somatization and catastrophizing, often precede or exacerbate functional gastrointestinal disorder (FGID) symptoms and correlate with symptom severity and health outcomes. Mounting evidence shows that psychological distress alters gut immunity, in particular mast cell activation, leading to a potentiation of sensory nerves and aberrant visceral pain perception. On the other hand, psychological stressors modulate the processing of incoming sensory signals by the brain, thereby contributing to FGID symptom development. A better understanding of the molecular mechanisms underlying stress-induced changes in the immune system or brain processing is crucial for the development of novel beneficial therapeutic strategies.

KEYWORDS:

• Anxiety
• depression
• functional dyspepsia
• irritable bowel syndrome
• psychological disorder

Functional gastrointestinal disorders (FGIDs) manifest as chronic or recurrent symptoms arising from the GI tract for which clinical and laboratory investigations do not reveal any evident organic abnormalities. FGIDs are very common, affecting up to one-third of the population. The main characteristics include increased sensitivity to luminal stimuli, also defined as visceral hypersensivity, motor dysfunction (nausea, vomiting, bloating, diarrhea, constipation, difficult passage of food or feces, or any combination of these) and increased central perception.[1] Currently, the diagnosis of FGIDs relies on meeting Rome III inclusion criteria and exclusion of other illnesses based on history, physical exam and laboratory testing.

Comorbid psychiatric disorders such as major depression, anxiety and somatoform disorders are highly prevalent in FGID patients, and can affect up to 50–94% of irritable bowel syndrome (IBS) patients.[2] In addition, psychosocial difficulties, such as a history of physical or sexual abuse, maladaptive coping and “catastrophizing,” predict poorer health outcomes as reflected by greater pain scores, psychologic distress and poorer daily function, more days spent in bed, and more frequent physician visits and surgeries. When using the standardized Functional Bowel Disorder Severity Index, patients classified as severe are distinguished from moderates by greater depression and psychological distress, indicating that psychosocial factors can predict symptom severity and clinical outcome.[3] In contrast, although patients with severe illness report more pain, there is no difference compared to patients with moderate illness in terms of visceral sensation threshold.[3]

Over the years, a biopsychosocial model has been developed in order to explain FGID pathogenesis, involving aberrant interactions between biological/physiological, psychological and social factors. Biological factors contributing to the risk and severity of FGID symptoms include genetic predisposition, female gender, immune dysfunction, altered hypothalamic–pituitary–adrenal axis, gastrointestinal infection or inflammation, altered microbiota composition and childhood environmental factors. Epidemiological studies indicate a combined contribution of genetic and environmental factors in the risk for FGIDs. Several genetic variants have been associated with FGIDs, including single-nucleotide polymorphism (SNP) in genes involved in neuronal function, mucosal barrier integrity and immune regulation.[4] In parallel, meta-analyses of genome-wide association studies indicate a genetic predisposition for psychological disorders.[5] Studies assessing the risk variants for psychological disorders in FGIDs are crucial to provide insight into the pathophysiological mechanisms of FGIDs, but are currently completely lacking. In addition, early life severe stress or trauma can lead to lifelong molecular changes in the form of epigenetic DNA modifications and potentially lead to disease. Also, these studies are in their infancy but of utmost importance to elucidate the role of gene–environment interactions in the development of FGIDs. Much attention has recently been given to the gut microbiome, as mounting evidence shows that the gut microbiome is capable of modulating the brain–gut axis, thereby influencing behavior such as anxiety and depression. Further research is, however, needed to identify the underlying mechanisms. Finally, the development of IBS, but not functional dyspepsia, was associated with childhood environmental factors, such as a shorter duration of breast-feeding, sharing a bedroom, exposure to a herbivore pet and hygiene factors.[6] Psychological factors such as anxiety, depression, panic, posttraumatic stress and somatization disorders often precede or exacerbate FGID symptoms. A 12-year prospective population-based study by Koloski et al. [7] elegantly demonstrated the bidirectional communication between the central nervous system and the gut. Among people who did not have elevated levels of anxiety and depression at baseline, those with an FGID at baseline had significantly higher levels of anxiety and depression at follow-up. In contrast, among individuals free of an FGID at baseline, higher levels of anxiety at baseline was a significant independent predictor of developing new onset FGIDs 12 years later. More recently, in a Swedish population-based follow-up study, anxiety at baseline increased the risk for the development of functional dyspepsia by 7.6-fold in the next 10 years.[8] We are only just beginning to understand how psychological factors, including stress, anxiety and fatigue, may increase the risk to develop FGIDs and in the next few paragraphs, we will elaborate on the current knowledge of the field and how it may implicate therapeutic strategies.

Psychological stressors, in particular anxiety, can modulate the intestinal immune system. Indeed, although acute stress accelerates the resolution of an infection by increasing both cellular and humoral immunity, prolonged periods of stress have the opposite effect and dampen immune responses to invasive pathogens, thereby increasing the vulnerability to infections.[9] A recent study by our group on a large cohort exposed to contaminated drinking water revealed that individuals with increased anxiety scores are at greater risk to develop postinfectious irritable bowel syndrome (PI-IBS), an effect that was partly the result of increased susceptibility to develop infectious gastroenteritis.[10] Increased anxiety scores before the outbreak were associated with a reduction in interleukin-2-expressing CD4+ T cells at the time of infection, cells that are involved in Th1 cytokine production and immune homeostasis. In addition, a more Th2-skewed immune response during the infectious challenge was predisposing to progression to PI-IBS.[10] Besides immune modulation, stress has been shown to induce exaggeration of the neuroendocrine response in IBS, potentially leading to increased sensitivity to rectal balloon distension rectal balloon distension.[11] Others reported a lower pituitary and adrenocortical activity in patients with FGIDs. The observed pituitary–adrenal reactivity in these patients is discussed as a possible consequence of lower adrenocortical activity, possibly resulting in a disinhibition of corticotrophin-releasing hormone in the brain.[12] Clearly, more extensive prospective studies are required to identify the exact molecular mechanisms and cells involved in stress-induced changes in the immune system and the subsequent increased susceptibility to post-infectious functional dyspepsia and PI-IBS.

One of the potential mechanisms by which psychological stress may directly affect gut function and thus trigger FGID is via mast cell activation. The latter seems to play a key role in FGID pathogenesis: mast cell numbers are increased in the duodenum of functional dyspepsia patients, while the colon of IBS patients shows increased mast cell numbers and mast cell mediator release (e.g., histamine, tryptase and prostanoids).[13] These mast cell mediators interact with nerves supplying the gut leading to altered gut physiology and increased sensory perception. In a recent study, we found that submucosal neurons from IBS patients show a potentiated response to capsaicin, the natural ligand of the nociceptor TRPV1, compared to healthy volunteers. This effect was mimicked in healthy volunteers by preincubation with histamine and was dependent upon histamine 1 receptor activation.[14] In parallel, in a mouse model, Cenac et al. showed that mast cell mediators, histamine and serotonin, can induce visceral hypersensitivity by potentiation of TRPV4 signaling.[15] These data underscore the importance of mast cell mediators in increased neuronal sensitivity by potentiating transient receptor potential channels, thereby leading to increased visceral pain perception. Of note, mast cell mediators also interact with epithelial cells, disrupting tight junction proteins and leading to increased permeability followed by an influx of luminal antigens, microbial products or even bacteria that can induce inappropriate immune responses and further activate mast cells. For example, in healthy subjects, psychological stress, evoked by cold pain stress or public speech, increases gut permeability in a mast cell–dependent manner.[16,17] The triggers that lead to persistent mast cell activation are not known, but are crucial in our understanding of the pathophysiological mechanisms underlying FGIDs.

Finally, psychological comorbidities may lead to altered brain processing of incoming sensory signals, thereby contributing to FGID symptom development. Functional MRI and positron emission tomography studies have been pivotal in elucidating the brain areas and networks activated during pain, discomfort and cognition-related tasks in health and FGID.[18] In studies of rectal distension, pain or discomfort, patients with IBS have fairly variable differences in activated brain regions compared with controls, generally comprising divisions of the prefrontal cortex, anterior cingulate cortex, mid-cingulate cortex, insula, amydala, hypothalamus and brainstem nuclei. Many of these areas are implicated in pain processing as well as in cognitive and emotional processing. On the other hand, increased anxiety during expectation of a rectal distension correlated with an absence of deactivation in arousal network regions, especially the dorsal brainstem, thereby potentially leading to increased pain perception in IBS patients. Unfortunately, current mechanistic studies do not delineate distinct facilitatory and inhibitory pathways but merely indicate that the balance of modulation is regulated largely within the same circuits. More systematic studies are required to identify the pathways involved in abnormal central processing of sensory information.

Altogether, there seems to be a close link between psychological factors and the risk to develop FGIDs. Psychological stressors contribute to the initiation and course of FGIDs, potentially via mechanisms involving immune modulation and altered brain processing of incoming nociceptive signals. The stress-induced release of the mast cell mediators, histamine, tryptase and serotonin, trigger sensitization of afferent nociceptive neurons, thereby leading to aberrant visceral pain perception.

How then can this insight contribute to patient management? As clinical practice clearly supports the notion that stress and psychological factors are important risk factors and triggers for symptoms or exacerbation of FGIDs, centrally acting agents such as antidepressants have been widely used to treat FGID. Recent meta-analyses, indeed, reveal the benefits of antidepressant therapy, with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors.[19] Clearly, antidepressants may have an antinociceptive effect, but the exact mechanism of action is still to be determined. For example, changes in brain processing during treatment with amitriptyline have been reported as a potential underlying mechanism.[20] Alternatively, as stress triggers mast cells leading to symptoms, stabilization of mast cells or blockade of the interaction of mast cell mediators with their respective receptors on afferents may have therapeutic potential. We have previously shown an improvement in IBS symptoms and visceral pain in a small proof-of-concept study with ketotifen, a mast cell stabilizer and histamine 1 receptor antagonist.[21] This benefit appeared to result from the histamine 1 receptor antagonistic properties of ketotifen rather than its action as a mast cell stabilizer. In a more recent proof-of-concept study, treatment of IBS patients with the histamine 1 receptor antagonist ebastine reduced visceral hypersensitivity, improved symptom relief and reduced abdominal pain scores.[22]

The most pressing question that future research needs to address is the extent to which stress-induced changes in the immune system or brain processing have meaningful implications for disease susceptibility in otherwise healthy humans. A better understanding of the interactions between the brain, enteric nervous system and the (enteric) immune system is crucial to gain insights into the pathophysiologic mechanisms underlying functional disorders. The latter will also lead to a better pathophysiologic definition of patient subcategories that are currently lumped under the broad umbrella of FGID.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Notes on contributors

M.M. Wouters

G.E. Boeckxstaens