Risk factors for anxiety and depression in patients with gastrointestinal disorders—the role of the gut-brain axis

In the past decade the acknowledgement of the importance of the gut-brain axis for the etiology of diverse pathologies such as mental illnesses has increased significantly (1). The association of changes in the dynamic bi-directional connection between gut and brain with the development of mental and gastrointestinal diseases has become more evident in the last years (2). The gut-brain axis with its diverse neural, endocrine and immune signaling pathways (3) might explain the numerous observations of high prevalence of mood disorders, such as anxiety and depression, in the presence of gastrointestinal abnormalities, which gave rise to the examinations that were very recently published by Wu et al. under the title “The status and risk factors for anxiety/depression in patients with atrophic chronic gastritis: a cross-sectional study” (4).

Interestingly, mood disorders do not only pose a risk factor for gastrointestinal disturbances of a functional type, e.g., irritable bowel syndrome, but also somatic gastrointestinal disorders with more ‘somatic’ pathogenesis such as inflammatory bowel disease (5). Conversely, pathologies of the gut, such as ulcerative colitis or advanced gastrointestinal cancer increase the risk for psychological distress and depressive mood (6) as well as manifest psychiatric diseases such as anxiety and depression (5,7). This double-sided association between mood and gastrointestinal disorders are in line with the observations of Wu et al. reporting a high prevalence of anxiety and depression in patients suffering from chronic gastritis (4). In detail, using the Generalized Anxiety Disorder-7 and Patient Health Questionnaire-9 36.4% of the study’s population had anxiety, 25.4% had depression, and 21.2% had both anxiety and depression.

Although the understanding of the gut-brain axis has enormously advanced in the recent years, gaps in knowledge still remain (2), e.g., why certain patients with gastrointestinal diseases suffer from mood disorders and others do not. This question about risk factors for the development of anxiety and depression in the setting of gut disorders was addressed by Wu et al. in a population of 66 male and 52 female patients with a mean age of 52 years ranging from 25 to 77 with atrophic chronic gastritis (4). This work was able to identify, among others, poor sleep quality, high salt diet and abdominal pain as risk and exercise as protective factors for the presence of mood disorders in these patients (Figure 1) (4). It is to note that underlying mechanisms responsible for these associations were not identified; however, the involvement of the gut-brain axis in their mediation is highly probable.

Figure 1 Risk and protective factors for depression and anxiety in patients with gastrointestinal disorders. Data presented with a * symbol are based on Wu et al. (4); +/red color indicates an OR >1.0/positive association with anxiety or depression; −/green color indicates an OR <1.0/negative association with anxiety/depression; text presented in grey is based on hypothetical considerations and needs confirmation from future research. OR, odds ratio; CRF, corticotropin-releasing factor.

In the most recent years the microbiota and its metabolites, as an integral component of the connection between gut and brain, have deservedly earned enormous attention as they are implicated in the modulation of intestinal motility and permeability, mucosal immune functions and enteric nervous system activity (8). Gut microbiota composition is greatly impacted by diet, consequently it is not surprising that high salt diet induces modifications of gut permeability and immune homeostasis associated with increased vulnerability to inflammatory stress by microbiome alteration (9). Noteworthy, changes in microbiota, e.g., induced by probiotics, antibiotics or pathogens are associated with anxiety and depression (8), possibly explaining why Wu et al. observed an odds ratio of 6.94 for depression and 6.81 for both depression and anxiety in patients consuming excess salt with their diet (4). In contrast, weekly exercise time was negatively associated with the risk of anxiety (4). Here again, the microbiota could pose the underlying basis for this interaction, since moderate exercise has been associated with changes in microbiota resulting in increased intestinal permeability, preservation of mucous thickness, reduced bacterial translocation and anti-inflammatory effects (10), possibly affecting signaling to central behavior-regulating areas. Alterations or even dysfunctions of the gut microbiota, representing a direct link between gastrointestinal and brain functions, may be responsible for pathologies connecting gut and behaviour; this interaction should be further elucidated.

Wu et al. also found abdominal pain to be a risk factor for depressive symptoms in gastritis associated with an odds ratio of 4.44 (4). Visceral pain is mediated via the enteric nervous system, which is greatly modulated by intestinal peptides, representing a crucial component of the gut-brain axis (11). In detail, several peptides, including ghrelin, nesfatin-1, peptide YY, cholecystokinin, secreted from specialized enteroendocrine cells along the gastrointestinal tract e.g., in response to food intake, not only signal locally but their receptors are additionally found in regions of the central nervous system, enabling a direct mediation of the state of the gastrointestinal tract to the brain (11). Since many of those peptides such as ghrelin and nesfatin-1 are implicated also in mood regulation, the direct peptidergic communication between the gastrointestinal tract and brain represents an additional pathway linking the gut and mental functions (12), thus possibly gastrointestinal and mood disorders. Noteworthy, an increase of circulating nesfatin-1 was associated with heightened visceral hypersensitivity (13), giving rise to the hypothesis that intestinal peptides may be involved in the correlations observed by Wu et al. between abdominal pain and depression (4). Additionally, the increased risk of depression with high salt intake could be linked, besides microbial changes, also to altered peptidergic signaling, since high salt intake is associated with increased circulating ghrelin (14) and ghrelin was shown to exert both, anxiogenic and anxiolytic effects (15). Elucidating the peptide-dependent mechanisms responsible for alterations in mental health due to gut disorders and vice versa requires more investigations in the future.

Corticotropin-releasing factor (CRF), a major mediator in the hypothalamic-pituitary-adrenal (HPA) axis mainly secreted from the hypothalamus, is greatly implicated in gastrointestinal functions (16). In addition to its central expression, both CRF and its receptors are also expressed in the gastrointestinal tract (16) and involved in gastrointestinal secreto-motor functions, intestinal permeability and visceral hypersensitivity (16), besides being a crucial mediator in the body’s stress reaction and therefore being strongly involved in the pathogenesis of depression and anxiety (17). CRF may be involved in the association between abdominal pain and both depression and anxiety (odds ratio of 5.42) identified by Wu et al. (4) as CRF elevations are related to mood abnormalities and CRF receptor 1 activation is involved in the induction of visceral hypersensitivity (16,17). CRF has pleotropic actions and is additionally, besides its role in mood disturbances, implicated in sleep regulation (18). Briefly, poor sleep causes overdrive of CRF signaling (18), which may be the reason why poor sleep quality in the study by Wu et al. was associated with both anxiety and depression in patients with gastritis (4); however, this hypothesis needs to be examined in further investigations.

As commonly known, novel insights, as presented by Wu et al. in their recent publications, raise new questions, particularly on the underlying mechanisms responsible for the associations between gastrointestinal and mood disorders and the involvement of the gut-brain axis herein. These gaps in knowledge should be addressed in the future and the above-mentioned hypothetical considerations of the importance of microbial and peptidergic gut-brain signaling connecting gut and mental (dys)functions need further prove. A better understanding of these interrelations may pave the way for future therapeutic approaches in the treatment of not only gastrointestinal but also mental disorders.

Acknowledgments

Funding: This work was supported by funding of the German Research Foundation (No. STE 1765/3-2).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1190/coif). MAS reports that this work was supported by funding from the German Research Foundation (No. STE 1765/3-2). AS has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dinan TG, Cryan JF. Brain-Gut-Microbiota Axis and Mental Health. Psychosom Med 2017;79:920-6. [Crossref] [PubMed]
2. Dinan TG, Cryan JF. Gut-brain axis in 2016: Brain-gut-microbiota axis - mood, metabolism and behaviour. Nat Rev Gastroenterol Hepatol 2017;14:69-70. [Crossref] [PubMed]
3. Morais LH, Schreiber HL 4th, Mazmanian SK. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol 2021;19:241-55. [Crossref] [PubMed]
4. Wu H, Liang G, Kong M, et al. The status and risk factors for anxiety/depression in patients with atrophic chronic gastritis: a cross-sectional study. Ann Palliat Med 2022;11:3147-59. [Crossref] [PubMed]
5. Shah E, Rezaie A, Riddle M, et al. Psychological disorders in gastrointestinal disease: epiphenomenon, cause or consequence? Ann Gastroenterol 2014;27:224-30. [PubMed]
6. Takeoka A, Tayama J, Kobayashi M, et al. Psychological effects of Helicobacter pylori-associated atrophic gastritis in patients under 50 years: A cross-sectional study. Helicobacter 2017;22. [PubMed]
7. Chung J, Ju G, Yang J, et al. Prevalence of and factors associated with anxiety and depression in Korean patients with newly diagnosed advanced gastrointestinal cancer. Korean J Intern Med 2018;33:585-94. [Crossref] [PubMed]
8. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest 2015;125:926-38. [Crossref] [PubMed]
9. Rinninella E, Cintoni M, Raoul P, et al. Food Components and Dietary Habits: Keys for a Healthy Gut Microbiota Composition. Nutrients 2019;11:2393. [Crossref] [PubMed]
10. O'Sullivan O, Cronin O, Clarke SF, et al. Exercise and the microbiota. Gut Microbes 2015;6:131-6. [Crossref] [PubMed]
11. Schalla MA, Taché Y, Stengel A. Neuroendocrine Peptides of the Gut and Their Role in the Regulation of Food Intake. Compr Physiol 2021;11:1679-730. [Crossref] [PubMed]
12. Weibert E, Stengel A. The X/A-like cell revisited - spotlight on the peripheral effects of NUCB2/nesfatin-1 and ghrelin. J Physiol Pharmacol 2017;68:497-520. [PubMed]
13. Jia FY, Li XL, Li TN, et al. Role of nesfatin-1 in a rat model of visceral hypersensitivity. World J Gastroenterol 2013;19:3487-93. [Crossref] [PubMed]
14. Zhang Y, Li F, Liu FQ, et al. Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity? Nutrients 2016;8:323. [Crossref] [PubMed]
15. Chuang JC, Zigman JM. Ghrelin's Roles in Stress, Mood, and Anxiety Regulation. Int J Pept 2010;2010:460549. [Crossref] [PubMed]
16. Taché Y, Larauche M, Yuan PQ, et al. Brain and Gut CRF Signaling: Biological Actions and Role in the Gastrointestinal Tract. Curr Mol Pharmacol 2018;11:51-71. [Crossref] [PubMed]
17. Rana T, Behl T, Sehgal A, et al. Exploring the role of neuropeptides in depression and anxiety. Prog Neuropsychopharmacol Biol Psychiatry 2022;114:110478. [Crossref] [PubMed]
18. Steiger A, Dresler M, Kluge M, et al. Pathology of sleep, hormones and depression. Pharmacopsychiatry 2013;46:S30-5. [Crossref] [PubMed]