We conducted a literature search in Pubmed and OVID Embase (1910 to Present); MEDLINE(R) (1946 to Present with Daily Update, Epub Ahead of Print, In-Process & Other Non-Indexed Citations). The following keywords were used for literature search: "Anxiety," "Antibiotic," "Brain-Gut-Axis," "Crohn," "Depression," "Gastrointestinal Microbiome," "Inflammatory Bowel Diseases," "Microbiota," "Microbiota-Gut-Brain-Axis," "Mood Disorders," "Prebiotic," "Probiotic," "Stress" and "Ulcerative Colitis."
Psychiatric Symptoms or Co-morbidities in IBD
Psychiatric co-morbidities in IBD are common and repeatedly described. IBD patients are two to four times more likely to develop depression and three to five times more likely to develop anxiety disorders than the general population. Here, we describe the commonly reported psychiatric co-morbidities in IBD.
Anxiety and Depression. Up to 66% of IBD patients develop anxiety and up to 34% suffer from co-morbid depression during active disease, with slightly higher rates in CD than in UC. A lower prevalence of anxiety and depression has been described in paediatric IBD patients.[14,15] Studies in different populations have reported comparable rates of depression and anxiety in IBD, ranging from 15% to 30%.[16–25] The most prominent factor associated with anxiety and/or depression is active and complex disease.[26–28]
The negative impact of anxiety and depression on quality of life can be even more substantial than that of disease activity.[29,30] Most patients report a strong relationship between psychosocial stress and flares, and in recent years, the scientific evidence of a bidirectionality between psychiatric symptoms and the disease course is mounting.[31,32]
While the mechanisms are yet to be fully understood and may comprise direct and indirect influences, the presence of anxiety and depression is associated with increased risk of surgery, hospital readmissions, non-adherence to medical therapy and an overall increase in healthcare utilisation[33–40] as well as impaired work function. A recent Scandinavian population-based study showed that suicide was one of the three leading causes of mortality in IBD with paediatric onset. What remains largely unclear is whether psychiatric co-morbidities directly influence disease activity by exacerbating inflammation, or whether the negative outcomes are indirectly caused by medication, non-adherence to medication or a generally worse subjective feeling that is ascribed to IBD without the presence of objective inflammation (ie IBS-like symptoms).[31,43–50]
There is an association between depression and upregulated immune activity in IBD.[51,52] It has been shown that depression and anxiety can precede the onset of IBD and other immune-mediated diseases for years, which implies a common immune-mediated pathway for psychiatric and somatic inflammatory diseases.[53–55] Recent large population-based surveys have shown a protective role of anti-depressants against the onset of IBD and a potentially beneficial effect of anti-depressants on the disease course of IBD. A recent study evaluating data from genome wide association studies reported correlations between psychiatric and immune-mediated diseases highlighting common disease pathways. It is likely that depression and anxiety should not be seen as a mere psychological byproduct of a chronic somatic disease but rather an extra-intestinal inflammatory manifestation of IBD. This is consistent with the fact that symptoms of depression can precede the onset of IBD symptoms for years, and intestinal inflammation can be present long before the start of clinical symptoms.
Psychological Stress and Trauma. Perceived stress is among the most relevant factors associated with health-related quality of life in IBD patients.[59,60] Whether it has an independent influence on disease activity or onset is unclear.[32,61,62] Important psychological stressors in IBD include faecal urgency and the fear of losing bowel control. Stress from major life events has been reported to double the risk of symptom recurrence in IBD patients. Population-based studies have linked childhood maltreatment to an increased risk of development of UC and shown adverse childhood experiences to be more common in IBD than the general population.
Gut Microbiota in IBD, Psychiatric Disorders and Stress
For a summary of studies on associations between faecal/gut microbiota and IBD as well as psychiatric disorders, please refer to Table 1.
Although the gut microbiota has been postulated to play a role in the pathogenesis of IBD, it remains unclear whether IBD results from a normal immune response against an abnormal microbiota or from an abnormal immune response to a normal microbiota or whether both the systemic and/or gut immune response and the gut microbiota are aberrant. Animal studies have demonstrated both possibilities by showing that immune distortions can change the gut microbiota towards one with a colitogenic capacity.[67,68] Microbiota are required for the development and maturation of the immune system of the host, and a lack of microbial exposure in early life may predispose individuals to autoimmune diseases in later life, including IBD.[69,70] Altering the gut microbiota in the first year of life at a vulnerable time also predisposes to IBD. On the other hand, genetic susceptibility and the indigenous microbiota exert a combinatorial role in IBD pathogenesis, but the timing of onset likely depends on environmental factors such as exposure to viruses and chemicals. Structural imbalances of the gut microbiota occur in IBD and associate with inflammation. Whether microbial alterations contribute to the onset of IBD remains controversial.[75–78]
Several animal and human studies have reported alterations in the gut microbiota in psychiatric and neurological disorders including autism spectrum disorders, Parkinson's disease, Alzheimer's disease, and also mood disorders.[82–86]
Much of our knowledge on the interactions between the gut microbiota and mental health is based on experiments in animals born and raised in a sterile environment, known as gnotobiotic or germfree (GF) animals. GF mice have been shown to display less anxiety-like behaviour in several behavioural tests.[87,88] In human studies, analysis of faecal samples from individuals with major depression disorder (MDD) showed lower levels of Bifidobacterium and/or Lactobacillus compared with controls. Another study showed an overrepresentation of the order Bacteroidales, while Lachnospiraceae were underrepresented. On the genus level, clades within the Alistipes and Oscillibacter operational taxonomic units (OTUs) correlated with depression. Another group reported increased levels of Enterobacteriaceae and Alistipes and reduced levels of Faecalibacterium in faeces of patients with MDD. In this study, abundance of Faecalibacterium correlated negatively with the severity of depressive symptoms. A recent study involving more than 1000 individuals showed a relative depletion of Dialister and Coprococcus spp correlating with depressive symptoms.
To our knowledge, there is only one rather small study that addressed microbiome changes with regard to anxiety, which reported a lower bacterial alpha-diversity and a reduction in Firmicutes and Tenericutes phyla in 36 subjects with generalised anxiety disorder.
In animal studies on stress and microbiota, GF animals were found to have an exaggerated hypothalamic-pituitary-adrenal (HPA) axis response to stress.[87,89,90] In a mouse model for depression caused by chronic variable stress, distinct microbial and metabolic changes of gut bacteria were observed. Stress exposure early in life alters the gut microbiota composition, and these microbial changes may be capable of shaping an individual's stress response in adulthood.[92–95] The paucity of clinical human studies investigating how stress affects the gut microbiome is likely based on difficulties due to individual differences in stress perceptions and the challenge of "standardised" stress in experiments in human. However, psychological stress has been shown to increase intestinal permeability in the human gut which was mediated by the gut microbiota.[96,97]
The complex biological systems enabling communication between the gut, its microbiota and the brain, commonly termed the microbiota-gut-brain-axis, have increasingly attracted scientific interest over the last decade. Figure 1 illustrates biopsychosocial factors and mechanisms of interaction along the microbiota-gut-brain-axis.
Interactions between gut inflammation and mental health with a central mediating role of the gut microbiota. AHR, Aryl hydrocarbon receptor; BDNF, brain-derived neurotrophic factor; ENS, enteric nervous system; GABA, gamma-amino butyric acid; HPA, hypothalamic-pituitary-adrenal; IBD, inflammatory bowel disease; MAMPS, microbe-associated molecular patterns; SCFA, short-chain fatty acids; TMAO, trimethylamine-N-oxide
Again, most of our knowledge regarding the microbiota-gut-brain-axis is based on animal studies using GF or microbiota-depleted animals. Studies on GF animals have shown that bacterial colonisation of the gut is crucial for the development and maturation of both the enteric nervous system (ENS) and central nervous system (CNS).[98,99] The absence of microbial colonisation is associated with an altered expression and turnover of neurotransmitters in both nervous systems.
Neuronal Signalling. One of the most obvious ways by which the gut and the brain communicate is via the vagus nerve, which conveys information from peripheral organs in the gastrointestinal tract to the CNS and vice versa. The vagus nerve and other parasympathetic nerves have been shown to have a protective effect on murine models of colitis.[101,102] Animal studies also showed a bidirectional relationship between the vagus nerve and bacteria in the gut. For example, treatment of wild-type mice with the bacterium Lactobacillus rhamnosus decreased stress-induced anxiety- and depression-like behaviour. After vagotomy, this effect was abolished. Another study showed that increased anxiety-like behaviour in experimental colitis could be ameliorated by treatment with Bifidobacterium longum, but again not in vagotomised mice. Animal studies also suggest that sympathetic efferents of the autonomic nervous system are involved in intestinal bacterial homoeostasis, as changes of noradrenaline signalling after brain injury led to changes in caecal microbiota in mice and spinal cord injury was shown to cause significant changes in gut microbiota composition.
Neuroendocrine Pathways, Neurotransmitters, Neuropeptides and Other Neuroactive Substances. Multiple microorganisms (eg Lactobacillus, Bifidobacterium, Escherichia, Enterococcus and Trichuris ) produce neurotransmitters and neuropeptides or other substances (eg metabolic products) that have the ability to influence neural activity.[107–109]Lactobacillus and Bifidobacterium have been shown to produce gamma-aminobutyric acid (GABA) and acetylcholine, and L rhamnosus can modulate the central expression of GABA receptors in key brain regions in mice. Among others, species of Escherichia and Enterococcus commonly found in the gut, metabolise tryptophan and mediate the production of serotonin, a neurotransmitter long associated with depression. Intestinal microbiota have also been shown to increase the levels of hippocampal brain-derived neurotrophic factor (BDNF) in specific pathogen free (SPF) mice after treatment with antimicrobials and faecal transplants. In mice infected with Trichuris muris, a decreased level of hippocampal BDNF was observed, which normalised after treatment with B longum. Decreased levels of BDNF have been associated with depression and treatments for depression have been shown to increase the expression of BDNF in the brain.
Other microbial metabolites that have been shown to interact with the brain are short-chain fatty acids (SCFA). For example, valeric acid, a SCFA produced by Oscillibacter, structurally resembles GABA and has been shown to bind the GABAa receptor. Other SCFA such as acetate and propionate have been linked to autism spectrum disorders[113,114] and sodium butyrate was associated with depression- and anxiety-like behaviour in mouse models.
Psychological/Behavioural Effects of gut Microbiota Modulation
Probiotics. Several randomised controlled trials (RCTs) have examined the effects of probiotics on depression and anxiety. Most RCTs studied multispecies probiotics containing Lactobacillus and Bifidobacterium. However, results are heterogeneous. Some RCTs reported positive effects of probiotics on mood,[116,117] cognitive and affective functioning, anxiety and stress, while others showed no significant differences. Contrary to human studies, the vast majority of animal studies report that treatment with probiotics leads to reduced anxiety- and depression-like behaviour. Those behavioural changes in animals are induced by germfree upbringing, early life stress such as maternal separation,[122–124] other forms of stress-like immobilisation/restraint,[125,126] chronic unpredictable mild stress, social defeat, or diet changes and inflammation. Almost all studies used different species of either Lactobacilli, Bifidobacteria or a combination thereof. Of note, one recent study examined the potential of Faecalibacterium prausnitzii to diminish the deleterious behavioural effects of chronic unpredictable mild stress in rats and showed that administration of F prausnitzii prevented stress-induced anxiety- and depression-like behaviour.
The behavioural outcomes are measured by tests like the forced swim test, light preference test, tail suspension test or open field test, among others. These models for anxiety and depression are controversial and their translatability to humans is questionable. They do, however, still represent the current state-of-the-art in behavioural research, and regardless of their extent of relevance for human trials, highlight the effects of microbial perturbation on behaviour.
The differences in efficacy between animal and human studies are, as described above, likely caused by the differences between behavioural test results in animals and the more complex human pathophysiology of anxiety and depression. Whether it will be possible in the future to treat specific psychiatric symptoms in humans with a specific microbe or a set of microbes remains uncertain, as individual differences in baseline microbiota composition and individual psychodynamics vary. Furthermore, the types and optimal doses of probiotics remain to be determined.
Antibiotics. Perturbation of the gut microbiota by antibiotics can also cause behavioural changes in mice. In humans, a small trial reported improvements in sleep and mood after a 6-day course of antibiotic treatment with erythromycin in patients with chronic fatigue syndrome. A pilot study of healthy controls showed that rifaximin reduced negative feelings caused by social stress. Conversely, psychiatric side effects including depression and suicidal ideations have been described during the treatment with fluoroquinolones. These effects are possibly mediated by microbial changes in the gut.
Faecal Microbiota Transfer. Faecal microbiota transfer (FMT) is an established and highly effective therapy for recurrent Clostridium difficile infection (CDI). Several RCTs have investigated the efficacy of FMT in UC, and meta-analyses show that FMT is associated with higher combined clinical and endoscopic remission when compared to placebo (risk ratio UC not in remission: 0.80; 95% CI: 0.71–0.89). Emerging evidence also suggests its potential in patients with Parkinson's disease, autism, and other extra-intestinal disorders.[133,135] Recent studies have demonstrated that anxiety- and depression-like behaviours can be transferable through FMT. An anxiety-like phenotype caused by chronic stress was transferrable from stressed mice to decolonised recipient mice via FMT. Similarly, GF mice which received faecal microbiota from patients with major depressive disorder developed depression-like behaviours[137,138] and mice that received faecal transplant from patients with irritable bowel syndrome and anxiety displayed higher anxiety-like behaviour. Besides anxiety and depression, one study also addressed inter-species transferability of alcohol dependence, which showed that decolonised mice which received FMT from patients with chronic alcoholism developed a predilection for alcohol. In contrast, transfer of stool from healthy donors to mice with chronic alcohol exposure resulted in decreased alcohol-induced anxiety- and depression-like behaviour in the mice.
Considering these manifold effects and the accompanying potential safety issues, FMT still has to be seen as a highly experimental procedure, and the role of microbiota modulation in the treatment or prevention of mental disorders requires extensive further research.
Linking the gut Microbiota and Psychiatric Symptoms With gut Inflammation
While there is mounting preclinical and clinical evidence on the effects of microbial perturbation on psychiatric symptoms (Table 2 and Table 3) and preliminary observational data addressing a relationship between the microbiota and psychiatric symptoms in IBD, interventional studies examining the tri-directional relationship between the gut microbiota, inflammation and behaviour are still restricted to preclinical work (Table 4).
It is widely accepted that DSS-induced colitis in mice results in anxiety-like behaviour at the peak of inflammation, which diminishes with decreasing inflammation. This inflammation has also been shown to be associated with gut microbial changes, and administration of probiotics to mice prior to DSS initiation prevented the behavioural deficits elicited by DSS,[104,142] reduced colonic disease and partially restored the microbiota. Similar effects could also be achieved with a prebiotic.
Mice which experienced chronic stress had increased inflammation and changes in the gut mucosa-adherent mucosa.[144,145] This effect might be host dependent, as some animal strains were more vulnerable to stress-induced colitis than others. Administration of probiotics was shown to mitigate the colitogenic effect of stress. Transferring microbiota from stressed mice to unstressed mice facilitated DSS-induced colitis in the recipients which highlighted the important role of gut microbiota in the relationship between chronic stress and inflammation. GF mice with a maternal separation model for depression exhibited increased susceptibility to experimental colitis and more anxiety- and depression-like behaviour compared to control GF mice after colonisation with microbiota from SPF mice, and these changes were accompanied by different microbiota profiles in the recipient mice despite identical donor microbiota. A recent study reported a protective effect of Lactobacillus and Bifidobacterium extracted from human faeces on the chronic stress and development of colitis as well as anxiety- and depression-like behaviour in mice. Interestingly, as described above, F prausnitzii, a species repeatedly associated with IBD, specifically in the form of a reduced abundance in active IBD, was able to prevent anxiety- and depression-like behaviour in rats subjected to stress.
Taken together, these preclinical data highlight the tri- or multidirectional relationship between mental health, inflammation and the gut microbiota.
The link between gut microbiota and psychiatric symptoms in gastrointestinal disorders in humans has been under investigation for some time in patients with irritable bowel syndrome (IBS), which is considered to be at least in part modulated by a dysregulation of the microbiota-gut-brain-axis and associated with low level or no gut inflammation and a high prevalence of psychiatric co-morbidities. GF mice receiving FMT from IBS patients with diarrhoea and anxiety, but not from healthy controls, demonstrated faster gastrointestinal transit, innate immune activation and anxiety-like behaviour, suggesting a direct link between immune responses, inflammation and mood. In addition, the potential of microbiota modulation in the treatment of psychiatric symptoms in IBS has already been addressed in RCTs.[153,154] One of these studies showed that B longum could reduce depression but not anxiety in patients with IBS and these changes were associated with changes in brain activation pattern, suggesting that probiotics could reduce limbic reactivity.
One study already applied a machine learning algorithm which was able to define a "microbial signature" of psychological distress in IBS patients, involving a higher abundance of Proteobacteria.
Comparable studies in IBD are still scarce. One small study indicated that patients with IBD and anxiety showed a significant increase in Collinsella and Coriobacteriales and a decrease in Streptococcaceae, Parabacteroides and phylum Firmicutes compared to IBD patients without anxiety. Recently, a larger study of the Swiss IBD cohort investigated the relationship between mucosa-adherent intestinal microbiota and mental health and showed that the presence of psychological distress in IBD patients who were in remission was negatively associated with the abundance of Clostridia, Bacilli, Bacteroidia and Beta-and Gamma-proteobaceteria in colonic mucosa. In Crohn's disease, the relative abundance of Bifidobacterium in colonic mucosa was associated with depression while in UC, relative abundance of Desulfovibrio was associated with depression.
These studies provide preliminary evidence to imply that the gut microbiota are involved in the emergence of psychological distress in IBD, and interventional studies examining the microbiota-brain-gut-axis in IBD are increasingly found in trial registries.
One possible mechanism by which psychiatric symptoms in IBD could be mediated through gut microbiota is via tryptophan metabolism.[157,158] Gut microbiota are known to metabolise tryptophan to different end products including serotonin, and a lack of tryptophan has been associated with both depression and IBD disease activity. One study assessed anxiety and depression in IBD patients and correlated higher depression scores and higher disease activity with lower tryptophan levels. However, altered tryptophan metabolism alone may not be sufficient to account for the differences in prevalence of depression among IBD patients with the same levels of disease activity.
Other microbial metabolites (eg bile acids, SCFA) that are influenced by inflammation-associated dysbiosis may also influence mood and behaviour. SCFA can mediate the serotonin production in enterochromaffin-like cells in the gut[162,163] and as described above, specific SCFA like valeric acid structurally resemble neurotransmitters and bind their receptors in the central nervous system.
As a normal function of gut microbiota is essential for development and homoeostasis of the mucosal immune system, it is also possible that immunological processes mediate between intestinal dysbiosis and psychiatric symptoms. For example, depression has been associated with Th17 cells, which are assumed to be crucial in the pathogenesis of IBD, and other proinflammatory cytokines like IL-6, TNF alpha and CRP, which are used as biomarkers or therapeutic targets in IBD treatment.
It has also been shown that gut microbiota influence normal neuronal development. Changes in brain structure and function have been reported in IBD,[166–169] and include possible IBD-associated changes in brain development. This development takes place in the prenatal phase and first years of life, and thus parallels the shaping of the gut microbiome and immune system of an infant.
One might speculate that brain changes could be associated with early-life microbiota changes that have also been described to predispose to IBD. Studies on the effect of microbiota modulation on brain structure and function have been conducted in IBS, but are still lacking in IBD.
An epidemiological observation that supports the hypothesis of the role of gut microbiota in IBD with psychiatric co-morbidities is that the prevalence of IBD is high in the western world, but dramatically increasing in the developing and newly industrialised countries in recent years accompanied by an increase in the prevalence of anxiety and mood disorders.[173,174] One possible explanation for this phenomenon is the concept of urbanisation, which is accompanied by significant changes in the gut microbiota and associated with an increased incidence in IBD[175,176] as well as anxiety and depression disorders.[177–179]
The link between childhood trauma and IBD[65,180] could also be mediated by the gut microbiota, since childhood is a critical phase for the development of several neuro- and immunobiological systems relevant for IBD, that is, the mucosal immune system, the intestinal microbiota, and immune tolerance in the gut. Childhood trauma may contribute to dysfunctions in the interplay between these factors which may increase the risk for IBD and impact on mental health.
Taken together, there are sufficient arguments to promulgate a mediating role of the gut microbiota in the link between inflammatory bowel disease and psychiatric symptoms, but a lack of evidence thus far.
Current Limitations and Future Directions for Research
Increasing research highlights the pivotal role of gut microbiota in IBD and psychiatric co-morbidities. In recent years, animal studies have begun to unravel the role of gut microbiota in these two conditions. However, proving causality remains challenging. The effects of modulating the microbiome on behavioural tests in preclinical studies may not be easily translated to humans, as the aetiology of anxiety and depression in patients is usually multifactorial.
Currently existing studies investigating the relationship between microbiota and mental health are mostly observational and include limited sample sizes and cross-sectional designs. Moreover, most studies regarding the gut microbiota in somatic as well as mental disorders rely on findings from 16S-rRNA-amplicon sequencing and focus solely on changes in the bacterial components, whereas metagenomic and functional data or studies regarding changes in the gut fungi or virome are still emerging.
The lack of human studies investigating the association between gut microbiota, psychiatric co-morbidities and IBD prompt further research which likely includes the use of "omics" analyses of large IBD patient cohorts with and without mental disorders with detailed genetic, epigenetic, microbial, sociodemographic and clinical assessments. Besides, potential confounding factors altering our gut microbiome, like childhood diet, trauma, home environment and early environmental exposure should be taken into account. Longitudinal studies to assess how changes in behavioural symptoms in IBD affect the gut microbiome and vice versa are warranted.
Comparable to the extant clinical trials in IBS patients, the potential of microbiota modulation to relieve anxiety and/or depression should be addressed specifically in RCTs.
Translational approaches may investigate the transferability of psychiatric phenotypes via FMT from IBD patients with anxiety or depression into GF mice.
Moreover, prospective clinical trials with psychological interventions (eg psycho- or hypnotherapy) using changes in the gut microbiota composition or metabolic functions as well as changes in brain structure and/or function as outcomes will provide a deeper understanding of the involved mechanisms beyond mere associative descriptions.
Given the impact of mental well-being on quality of life in IBD, we believe that it is essential to assess mental health and implement "psychological remission" as a future endpoint in IBD-related clinical trials. This will inevitably exponentiate our knowledge of the course of these symptoms during newly developed therapies, possibly helping to unravel mechanisms by which anti-inflammatory drugs can influence mental health. As many clinical trials already include assessment of gut microbiota-related parameters, this will also help to shed light on microbiota-gut-brain-axis interactions.
Taken together, investigations of the gut microbiome and the microbiota-gut-brain-axis in IBD and psychiatric symptoms will help to unveil factors which are central to the etiopathogenesis of psychiatric co-morbidities in IBD.
Detecting key microbial biomarkers leading to the development of both mental illness and IBD and individual differences in microbiota-gut-brain-axis interactions will eventually help to identify patients i) whose psychiatric symptoms are resolved by finding the right anti-inflammatory drug, ii) where psychotherapy can possibly reduce inflammation, and iii) where the right pre-, pro- or post-biotic or potentially FMT-related approach can treat or possibly even prevent inflammation and psychiatric co-morbidities in IBD.
Aliment Pharmacol Ther. 2020;52(2):247-266. © 2020 Blackwell Publishing