Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of pro-inflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia and anxiety, new research shows.
A meta-analysis of 59 studies, encompassing roughly 2600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions vs controls.
In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus — two types of bacteria that have an anti-inflammatory effect in gut — and higher levels of Eggerthella, a bacterium with pro-inflammatory effects.
"The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals," lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King's College London, London, United Kingdom, told Medscape Medical News.
"While it is still too early to recommend specific interventions, it's clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders," she said.
The study was published online September 15 in JAMA Psychiatry.
"Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers," the authors write.
However, "while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven't been any attempts to evaluate the specificity of this evidence — that is, if these changes are unique to specific disorders or shared across many," Nikolova said.
Previous research in individual disorders has identified "patterns that may be promising biomarker targets," with the potential to "improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response," the authors note.
"We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota," said Nikolova.
The researchers wanted to "evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers."
They identified 59 studies (64 case-control comparisons; n = 2643 patients, 2336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).
These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder, (OCD) posttraumatic stress disorder (PTSD), and attention deficit hyperactivity disorder (ADHD).
Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also "varied substantially."
The researchers conducted several analyses, with primary outcomes consisting of "community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance)."
Alpha diversity provides a "summary of the microbial community in individual samples," which "can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample."
Beta diversity, on the other hand, "measures interindividual (between samples) diversity that assesses similarity of communities compared with the other samples analyzed."
Control samples consisted of participants without the relevant condition.
The alpha diversity meta-analysis encompassed 34 studies (n = 1519 patients, 1429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference [SMD] = −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD = −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.
MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.
"These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls," the authors write.
However, "method of measurement and method of patient classification (symptom- vs diagnosis-based) may affect findings," they add.
When they focused on relative abundance, they found "little evidence" of disorder specificity, but rather a "transdiagnostic pattern of microbiota signatures."
In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were "consistently shared" between MDD, BD, psychosis and schizophrenia, and anxiety, "suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while pro-inflammatory genera are enriched."
"The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis," said Nikolova.
"We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota."
The authors highlighted potential confounders, including study region and medication use.
Conditions such as MDD, psychosis, and schizophrenia were "largely investigated in the East," while anorexia nervosa and OCD were primarily investigated in the West.
Moreover, comparing results from medication-free studies to those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.
In light of these confounders, the findings should be considered "preliminary," the investigators note.
Greater Standardization Needed
Commenting on the study for Medscape Medical News, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA in Los Angeles, said it is "intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date."
In addition, the study "lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function," cautioned Mayer, who was not involved in the research.
Future studies "with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses," asserted Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.
Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London.
Nikolova has disclosed no relevant financial relationships. The other authors' disclosures are listed on the original paper. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
JAMA Psychiatry. Published online September 15, 2021. Abstract
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