ReviewThe gut microbiota in anxiety and depression – A systematic review
Graphical abstract
Introduction
Anxiety and depressive disorders are ubiquitous and debilitating psychiatric conditions that collectively affect close to 10% of the global population every year (World Health Organization, 2017). The World Health Organization (2019) estimates the global loss in productivity due to anxiety and depressive disorders amounts to $1 trillion USD annually – a trajectory expected to rise (Doran & Kinchin, 2019). Although engagement with psychotherapeutic and psychotropic treatments has increased over the past several decades (Olfson, Druss, & Marcus, 2015; Stephenson, Karanges, & McGregor, 2012), the prevalence and burden of anxiety and depressive disorders remains unchanged (Jorm, Patten, Brugha, & Mojtabai, 2017). Furthermore, there is substantial variation in response to existing treatments, which are overall efficacious in less than half of diagnosed patients (Casacalenda, Perry, & Looper, 2002; Cipriani et al., 2018). Accordingly, there is an urgent need to gain new insight into the underlying pathophysiology of anxiety and depressive disorders in order to develop more effective treatment targets. The high comorbidity between internalizing disorders has been cited as evidence for possible shared physiological processes, risk factors, and illness trajectories (Kotov et al., 2017). One such promising area of research is the microbiota-gut-brain axis, which may elucidate shared pathophysiology.
A growing body of research describes the bidirectional communication between the gut microbiota – the ecosystem of trillions of bacteria, viruses, archaea and fungi – with the host's central nervous system (CNS; Dinan and Cryan, 2015, Dinan and Cryan, 2017; Rieder, Wisniewski, Alderman, & Campbell, 2017). This biochemical signaling pathway, also known as the gut-brain axis, is thought to influence cognitive functioning and mood via neural, metabolic, hormonal, and immune-mediated mechanisms (Foster & McVey Neufeld, 2013). The gut microbiota is a key regulator within the gut-brain axis: bacterial species regulate the production of neurotransmitters and their precursors (e.g., serotonin, GABA, tryptophan), and can secrete and upregulate essential proteins and metabolites involved in neuropeptide and gut hormone release, such as short-chain fatty acids (SCFAs; e.g., Faecalibacterium prausnitzii and Clostridium leptum) and brain-derived neurotrophic factor (BDNF; e.g., Bifidobacterium; Bercik et al., 2010; O'Sullivan et al., 2011; Parada Venegas et al., 2019). Furthermore, vagal and spinal afferent pathways mediate neural communication between gut microbes and the CNS, and the gut microbiota modulates immune signaling from gut to brain, via cytokine induction (Dinan & Cryan, 2017; Foster, Rinaman, & Cryan, 2017).
The extant literature indicates that gut microbes may also be involved in the development and function of the hypothalamic-pituitary-adrenal (HPA) axis, which coordinates the adaptive stress response in the body (Foster et al., 2017; Sudo et al., 2004). Dysregulated HPA axis signaling is implicated in anxiety and depressive disorders, typically associated with higher levels of cortisol and inflammatory mediators that lead to a sustained proinflammatory state (Keller et al., 2017; Winter, Hart, Charlesworth, & Sharpley, 2018). Not only can the gut microbiota contribute to increases in cortisol and inflammation (Kamada, Seo, Chen, & Núñez, 2013), but proinflammatory states may also compound microbiota alterations via deleterious effects on gastrointestinal health. Excessive levels of circulating cortisol and inflammatory mediators increase intestinal permeability, thus allowing Gram-negative bacteria (i.e., bacteria which contain an additional lipopolysaccharide exterior membrane, associated with inflammation in high concentrations) to translocate into the bloodstream which may induce chronic CNS inflammation (Foster et al., 2017; Huang et al., 2019). This suggests that microbiota-driven inflammatory responses may contribute to affective disorders, due in part to increased intestinal permeability. Similarly, gastrointestinal conditions suspected to involve alterations in the gut microbiota and intestinal permeability co-occur at remarkably high rates with psychiatric disorders (e.g., irritable bowel syndrome; Simpson, Schwartz, & Simmons, 2020). Hence, the role of the gut microbiota in mood regulation and emotional processing, via the gut-brain axis, may be of particular relevance to anxiety and depression aetiology.
Given the role of gastrointestinal bacteria in the bidirectional communication between the gut and the brain, recent studies have focused on characterising gut microbiota composition in anxiety and depression. Preclinical models highlight gut microbiota disturbances in rodents exhibiting anxiety- and depressive-like behaviours, and report normalisation of both behavioural and microbial alterations after bacterial probiotic administration (Mayer, Knight, Mazmanian, Cryan, & Tillisch, 2014; Mayer, Tillisch, & Gupta, 2015). Extension of this research into humans has been relatively slow prior to the last several years. Reviews have highlighted gut microbiota alterations in clinical depressive disorders relative to healthy control groups (Cheung et al., 2019; Huang et al., 2019; Sanada et al., 2020); however, findings related to the diversity of microbial communities in depression are inconsistent, and it is unclear whether specific bacterial taxa drive group differences (Cheung et al., 2019; Huang et al., 2019; Sanada et al., 2020). Existing reviews have also inadequately considered research quality and the effects of confounders, particularly diet and psychotropic medication (Simpson, Schwartz, & Simmons, 2020).
The present systematic review provides an essential update of the expanding literature characterising the gut microbiota in depressive disorders, and provides the first systematic review in anxiety disorders. This paper also aims to integrate evidence to examine whether these highly comorbid conditions share underlying microbial features, and to critically appraise the effect of methodological inconsistencies and confounding factors. A more nuanced understanding of the pathophysiology of anxiety and depressive disorders may inform future diagnosis and treatment options in these common and debilitating psychiatric conditions.
Section snippets
Search strategy
Systematic searches were conducted in March 2020 following PRISMA guidelines (Moher, Liberati, Tetzlaff, Altman, & Group, 2009). The MEDLINE (Ovid), Embase, PsycINFO, and PubMed databases were searched to capture human studies which i) assessed the gut microbiota composition in anxiety or depressive disorders, or ii) investigated associations between the gut microbiota and anxiety/depression symptom measures in healthy participants or relevant conditions (i.e., anxiety and depressive
Characteristics of included studies
Comprehensive screening yielded 1216 studies after duplicate removal (Fig. 1). A total of 26 studies met inclusion criteria, including 17 clinical case-control studies that compared the gut microbiota of controls to participants with a depressive disorder, two studies which compared individuals with generalised anxiety disorder (GAD) to controls, and one study which compared participants with depression, anxiety, or comorbid anxiety/depressive disorder and controls. The remaining six studies
Discussion
The present systematic review provides an essential update of studies characterising the gut microbiota in anxiety and depressive disorders, and captures the large number of studies published in recent years. Of note, the body of literature has nearly doubled since the last systematic review of the gut microbiota in depressive disorders (Cheung et al., 2019). This review also extends a recent summary focused on the gut microbiota in MDD-only (Sanada et al., 2020), by considering depressive
Declaration of Competing Interest
None.
Acknowledgments
Carra Simpson and Djamila Eliby are supported by the Australian Government Research Training Program. Authors thank Ryan Carceller for his assistance with figure design. Figures created with BioRender.com.
Role of funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Contributors
All authors provided scientific input, and edited and reviewed the manuscript content. All authors provided their final approval and agree to be accountable for all aspects of the work, ensuring integrity and accuracy.
Carra A. Simpson is a PhD Candidate at the University of Melbourne in the Faculty of Medicine Dentistry and Health Sciences (Melbourne School of Psychological Sciences). Her research seeks to bridge the arbitrary categorisation of “mental” and “physical” health. She is passionate about interdisciplinary human microbiome research, specifically the bidirectional relationships between the gut and oral microbiota with host gastrointestinal functioning and behaviour.
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Carra A. Simpson is a PhD Candidate at the University of Melbourne in the Faculty of Medicine Dentistry and Health Sciences (Melbourne School of Psychological Sciences). Her research seeks to bridge the arbitrary categorisation of “mental” and “physical” health. She is passionate about interdisciplinary human microbiome research, specifically the bidirectional relationships between the gut and oral microbiota with host gastrointestinal functioning and behaviour.
Carmela Díaz-Arteche is a Research Assistant at the University of Melbourne in the Faculty of Medicine Dentistry and Health Sciences (Melbourne Neuropsychiatry Centre). Her research interests include investigating associations between neurodevelopment and affective disorders.
Djamila Eliby is a PhD Candidate at the University of Melbourne in the Faculty of Medicine Dentistry and Health Sciences (Melbourne School of Psychological Sciences). Her research interests include investigating associations between the gut microbiome, mental health, and diet.
Orli S. Schwartz is a Clinical Psychologist and a Research Fellow in Mood Disorders at Orygen, the Centre for Youth Mental Health at the University of Melbourne Faculty of Medicine Dentistry and Health Sciences.
Julian G. Simmons is a Senior Research Fellow at the University of Melbourne in the Faculty of Medicine Dentistry and Health Sciences (Melbourne School of Psychological Sciences). His research focusses on how the environments we grow up in interact with our biology to influence risk (and protection) for mental health disorders, and particularly depressive and anxiety disorders.
Caitlin S. M. Cowan is a Post-Doctoral Research Fellow at the APC Microbiome Ireland, University College Cork. She is a clinically-trained psychologist and behavioural neuroscientist with a special interest in development. Her research explores the translational value of targeting the brain-gut axis to modulate behavioural and mental health outcomes.
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Joint senior authorship.