A cross-sectional study of gastrointestinal symptoms, depressive symptoms and trait anxiety in young adults

The GI tract and the brain are intimately connected via bidirectional neural, endocrine and immune pathways, commonly referred to as the gut-brain axis (GBA) [1]. This complex communication system not only ensures GI homeostasis but also influences motivation and higher cognitive functions. The GBA includes the central nervous system, the autonomic nervous system, the enteric nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, as well as signalling via gut peptides [2]. The role of the GBA is to integrate gut functions and link emotional and cognitive centres of the brain with peripheral intestinal functions and mechanisms such as appetite, satiety, immune activation, intestinal permeability, enteric reflexes and enteroendocrine signalling [1].

Functional gastrointestinal disorders (FGIDs) are a group of disorders affecting the GI tract, often causing considerable impact on health-related quality of life, but where there is no clear pathogenesis. The most common FGID is irritable bowel syndrome (IBS), which affects the lower GI tract [3]. Psychiatric co-morbidity is high in patients with FGIDs, suggesting shared or interacting disease mechanisms, possibly related to the proposed communication between the gut and brain, in which variations of the intestinal microbiome may play an essential role [4, 5]. Specifically, a recent review points out an alternative pathway from the gut (with its microbiome) via the vagus nerve and the mechanisms of the bidirectional communication between the gut and brain for the development of depression [6]. In another report, a high correlation between stress-related mental symptoms, including anxiety and IBS was brought forward, providing a basis for further studies of the vagus nerve and the GBA [5]. Furthermore, a model is emerging where uncontrolled sympathetic and poor vagus control interacts with the microbiome and immune system to predispose individuals for psychiatric and gastrointestinal disease [7, 8].

Approximately 60% of those who seek medical care for FGIDs suffer from psychiatric illness [9]. Depression and anxiety disorders are the most common psychiatric co-morbidities in patients with FGIDs [9, 10]. Correspondingly, patients with high levels of depression or anxiety have a two-fold risk of developing IBS and patients with major depressive disorder (MDD) more frequently meet the criteria for IBS than healthy controls [11, 12]. Anxiety levels appear to be related to the burden of gastrointestinal symptoms and co-morbidity in IBS is observed in patients with panic disorder and generalised anxiety disorder [13‐16]. High levels of anxiety might also be an independent predictor of developing FGIDs [17]. However, the same study also found higher levels of depression and anxiety at follow-up in patients with FGIDs at baseline, which is consistent with bidirectional brain-gut dysfunction.

Contradictory results have been found for subtypes of IBS in levels of depression compared with controls. One meta-analysis reported that patients with both diarrhoea-predominant IBS (IBS-D) and constipation-predominant IBS (IBS-C) showed higher levels of anxiety, whereas patients with only IBS-D appear to have higher levels of depression [18]. In contrast, another recent meta-analysis found that both depression and anxiety levels were higher in all subtypes of IBS as compared with controls, with the highest level of depression seen in patients with IBS-C [19].

IBS is characterised by unexplained chronic abdominal discomfort and pain associated with altered stool consistency and emptying [16, 20]. The prevalence of IBS varies widely in the general population because of regional and diagnostic differences, with a pooled global prevalence of 11.2%. Most studies show a higher prevalence in women than in men [21]. Because of the burden associated with abdominal and psychological symptoms, IBS can result in a profound reduction in health-related quality of life [3].

The complex aetiology of IBS remains elusive. Altered brain-gut interactions, increased gut permeability and immune activation may all be involved in the pathophysiology of IBS, at least in sub-populations of IBS patients [22, 23]. In addition, psychological, social and genetic factors may play a role in the development of IBS, with or without psychiatric comorbidity (e.g., through alterations of the HPA axis, increased visceral perception and psychological vulnerability) [10, 24]. The enigmatic influence of the bacterial flora on the brain and gut function remains an open question but may exert a major contribution to the brain-gut communication in IBS [25‐27].

Pharmacological management of IBS seeks to ameliorate the predominant symptoms and reduce pain and discomfort. Illuminating the mechanisms of IBS with or without psychiatric co-morbidities is crucial to understand the pathophysiology and identification of new therapeutic targets in IBS [24]. Importantly, psychotherapy and antidepressants (such as selective serotonin reuptake inhibitors, SSRIs and tricyclic antidepressants, TCAs) have shown efficacy in different subpopulations of IBS [22, 28].

Although the link between anxiety, mood disorders and gastrointestinal symptoms has attracted attention, most studies have investigated the prevalence of psychiatric co-morbidity in patients with IBS. Regrettably, less research has been conducted from a psychiatric viewpoint, especially in young adult patients with a different disease panorama than older populations.

The study aimed to investigate the relationship between gastrointestinal symptoms, depressive symptoms and trait anxiety in a cohort of young adult patients seeking psychiatric care and to compare these patients with healthy controls. The main hypothesis was that there might be a positive association between the severity of subjective depressive and gastrointestinal symptoms in young adults seeking psychiatric care. Specifically, we aimed to i) compare the severity of gastrointestinal symptoms between psychiatric patients and healthy controls and between patients with and without current psychotropic medication, ii) investigate whether gastrointestinal symptom burden is related to depressive symptom severity and iii) explore the role of trait anxiety in this context.

The study was approved by the Regional Ethics Committee in Uppsala. All patients signed an informed consent form on recruitment to the study. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

This study examined the prevalence of gastrointestinal symptoms and their relationship to depressive symptoms and anxiety traits in young adults seeking outpatient psychiatric care. We found a larger burden of gastrointestinal symptoms in patients compared with healthy controls. Gastrointestinal symptom severity was positively associated with overall depressive symptom burden and the severity of individual depressive symptoms. Consistent with previous results [41], trait anxiety correlated with gastrointestinal symptom burden independent of the effects from depressive symptom severity, bulimia nervosa gender and BMI.

Patients with IBS are known to have a high psychiatric co-morbidity. This connection between IBS and psychiatric co-morbidity appears to be bidirectional, with a high prevalence of IBS diagnosis and IBS symptoms in psychiatric patients, especially in patients with mood and anxiety disorders [11, 29]. In this study, gastrointestinal symptom burden correlated with depressive symptom severity, a finding in accordance with previous evidence [42]. One large Korean study, however, reported that IBS was more common in patients with mild depression than in those with severe depression [43]. Our current study included only outpatients and therefore may not generalise to inpatients with severe depression. The correlation between the total MADRS-S score and the total GSRS-IBS score in our study showed a larger effect size in controls than in patients. Exaggerated gastrointestinal symptoms may cause a greater impact on mood and function in an otherwise healthy individual than in a psychiatric patient who also suffers from depression or anxiety.

We identified different subgroups within the studied patient population. One subgroup of patients (cluster 4) had a high level of gastrointestinal symptoms (fast and slow bowel and disturbed appetite) together with high trait anxiety and high levels of depressive symptoms. In contrast to cluster 4, patients in cluster 1 did not score high on any of the factors and thus they may constitute a different subgroup of patients, perhaps closer to remission, as it has been shown that patients in remission from recurrent depression do not have more symptoms of IBS than healthy controls [42].

In our study, personality traits reflecting anxiety and stress susceptibility significantly correlated with gastrointestinal symptom burden with the largest effect size for somatic trait anxiety, which is consistent with the proposed presence of somatisation in patients with IBS [44]. In animal models, central pathways mediating stress and anxiety have been linked to increased gut sensitivity [45]. In patients with IBS, visceral hypersensitivity is a result of several factors, including increased afferent signalling to the brain [46], abnormal descending modulation of pain, and dysfunction of the medial pain system, which is responsible for the emotional aspect of pain [47]. Immune activity in the intestinal mucosa or the central nervous system may play a role in the development of visceral hypersensitivity. However, the precise role of immune activity remains contentious [48, 49].

The pivotal question of the causation of disease is the temporal relationship of the onset of symptoms or the making of a classified diagnosis. The use of questionnaires does not focus on this relationship and the long-term observation time needed precludes conclusions as regards to the onset of disease or symptoms. Animal models may be useful to reveal possible etiological factors related to the onset of gastrointestinal symptoms [50‐52].

Different theories have been proposed to explain the high co-morbidity of IBS and psychiatric illness in which the GBA plays a central role in mediating this interaction. Alterations of the autonomic nervous system with increased sympathetic and decreased parasympathetic activity can influence perception from the gastrointestinal tract [53]. Local hormones and inflammation further influence the autonomic nervous system and the vagus nerve may provide a transport route for microbial and other metabolites to the CNS [7, 8]. Dysregulation of the HPA axis has also been observed in female IBS patients of which both basal levels of cortisol and stress-induced cortisol levels were elevated compared with healthy controls [54]. Moreover, alterations in the gut microbiome have been central in seeking to understand the complex relationship between depression and IBS [55]. Significant differences in microbiota composition have been demonstrated in patients with IBS compared with controls [56]. The intestinal microbiota can produce neurologically active substances (e.g., gamma-aminobutyric acid and short-chain fatty acids, SCFAs) that can influence immune regulation and the mucosal barrier, but their role in stress-induced behavioural and physiological alterations is poorly understood [57, 58]. In mice, administration of SCFAs was found to alleviate stress-induced anhedonia and increased responsiveness to acute stress as well as reversed changes in intestinal permeability caused by psychosocial stress [59]. Moreover, breakdown of the mucosal barrier in the gut wall, bacterial translocation and immune activation are believed to result in excessive cytokine production that can affect not only gut functions and the intestinal microflora, but also brain functions and behaviour [60, 61]. Elevated pro-inflammatory markers, especially interleukin-1, interleukin-6 and tumour necrosis factor-alpha are seen in patients with depression and we already know that inflammation may induce depression [62].

A limitation of this cross-sectional study is that the patient group is not delimited to a single diagnosis; rather, symptomatic measurements of depression and anxiety levels are analysed, which restricts the possibility to examine differences between individual diagnostic groups. Still, because of the overlap in concomitant diagnoses, specific psychiatric symptoms reflecting different underlying biological mechanisms are probably more relevant. For this reason, the MADRS-S total score, as a measure of the level of depressive symptoms, and the scales of the SSP were used rather than the diagnostic group affiliation to capture these symptoms or behaviours. Here, we wished to investigate the impact of trait anxiety, which is why individual diagnoses of anxiety were not further analysed in the context of gastrointestinal symptoms. Another limitation is that patients completed the SSP questionnaires with ongoing depressive symptoms and a possible state effect cannot be ruled out. Additionally, the control group was significantly older than the patient group, which may have influenced the results.

Gastrointestinal symptoms in this study are self-reported. The GSRS-IBS questionnaire was developed to evaluate treatment for IBS and in our study the total score is used as a measurement of symptom burden. This method is likely more inclusive, whereas when the actual diagnosis is used rather than reported symptoms, the propensity to seek medical care must be considered. While the GSRS-IBS total score reflects symptom burden, gastrointestinal symptoms may vary during each week (such as alternating diarrhoea and constipation), which influences the comparison of the total score between individuals. An attempt to visualise this issue is through the cluster analysis in which different groups with a diverse spectrum of symptoms were identified.

Studies have found ameliorated IBS symptoms with SSRI treatment, but also with tricyclic antidepressants [63, 64]. Of note, there were no differences in gastrointestinal symptom burden between patients with and without psychotropic medication (antidepressants, including SSRI’s). Indeed, treatment with SSRIs for IBS may not be a “one size fits all” solution, but rather a treatment that only a subpopulation of IBS patients benefits from. In fact, one study reported more IBS symptoms in patients with SSRI treatment [42]. The present study design did not allow for distinction from GI side effects from SSRI treatment, why possible benefits may have been cancelled out. Also, medication compliance could not be fully determined in this study, which could have influenced the results.

The prevalence of FGIDs is high in patients with eating disorders [65]. Patients who met the criteria for anorexia nervosa were excluded because this diagnosis constitutes a very special catabolic state due to starvation, making results difficult to interpret and generalise. Patients with ongoing bulimia were included, although they generally have a high level of self-starvation, but this potential confounder was adjusted for in the generalized linear model and did not influence the results.

Young adults seeking psychiatric care reported more gastrointestinal symptoms than controls, regardless of ongoing psychotropic medication. Gastrointestinal symptoms correlated positively with the severity of depressive symptoms and trait anxiety. Although we confirmed significant associations between gastrointestinal and psychiatric symptoms their aetiology is multifactorial, complex and not well understood. The cluster analysis revealed different groups with a diverse spectrum of symptoms. We believe this may be important for designing future studies focused on understanding biological factors where genetic vulnerability and disease mechanisms may differ between clusters. The high co-morbidity of mood and anxiety disorders and gastrointestinal symptoms and IBS in early adult life motivates further investigation to identify common denominators in the complex mechanisms underlying these disorders.