Anxiety and depression intestinal flora

Anxiety and depression intestinal flora-a systematic review

Anxiety and depression are widespread and debilitating mental illnesses that affect nearly 10% of the world’s population each year.

The World Health Organization (2019) estimates that the world’s annual productivity loss due to anxiety and depression is $1 trillion, and it is on the rise.

Although the number of people receiving psychotherapy and psychotropic medication has increased in the past few decades, the prevalence and burden of anxiety and depressive disorders have remained unchanged.

In addition, there are significant differences in response to existing treatments, which are generally effective in less than half of the confirmed patients.

Therefore, there is an urgent need to gain new insights into the underlying pathophysiology of anxiety and depression in order to develop more effective therapeutic targets.

The high comorbidity between internalization disorders has been cited as evidence of possible common physiological processes, risk factors, and disease trajectories. One of the promising research areas is the microbiota-brain-gut axis, which may shed light on the common pathophysiology.

Introduction

On November 29, 2020, Caitlin SM Cowan and his team from University College Cork, Ireland published a systematic review of The gut microbiota in anxiety and depression – A systematic review in Clin Psychol Rev (IF: 10.255) [1 ].

This systematic review updates a large amount of literature describing the characteristics of the gut microbiota in depression, and provides the first systematic review of anxiety disorders.

This article aims to integrate the evidence to examine whether these highly comorbid diseases have potential common microbial characteristics, and to critically exclude the influence of methodological differences and confounding factors.

A more detailed understanding of the pathophysiology of anxiety and depression may provide a basis for the diagnosis and treatment of these common and debilitating mental diseases in the future.

Main method

In March 2020, a systematic search was conducted in accordance with the PRISMA guidelines. Searched the MEDLINE (Ovid), Embase, PsycINFO and PubMed databases to capture human studies

1) assessed the composition of the gut microbiota in anxiety or depressive disorders,

2) investigated gut microbiota and measurement of anxiety/depressive symptoms The value is the association between healthy controls or related diseases (ie anxiety and depression disorders).

Through literature review, various sequencing workflows were used to assess the composition of the gut microbiota.

Most studies (n=20) used amplicon 16S rRNA gene sequencing, one of which also included shotgun metagenomics, and two studies used qPCR to verify the 16S rRNA gene sequencing results.

Two other studies used shotgun metagenomics to comprehensively sample all microbial genes.

Among the remaining four technologies, one study used RT-qPCR to quantify bifidobacteria and lactobacillus counts and bifidobacteria oligonucleotide probes, and the other study used to quantify Lactobacillus species.

One study carried out single nucleotide polymorphism genotyping and microbiota-related gene set enrichment analysis, and one study carried out a comparative analysis of metagenomics.

In addition to comparisons between groups (n=17), most studies included self-reported symptom scales, although only six studies included case-control studies that clearly assessed the association between microbial population abundance and persistent levels of internalization symptoms.

Five studies used the self-report scale as the only measure of anxiety or depression.

A few case-control studies also focused only on the diagnostic level (n=4). Eleven different self-report scales were used to quantify anxiety and depression symptoms.

Among them, the 17-item and 21-item versions of the Hamilton Depression Scale (n=10) and the Beck Depression Scale (n=6) were the most common.

Main results:

Features of included studies

After eliminating duplicates, comprehensive screening resulted in 1216 studies (Figure 1).

A total of 26 studies met the inclusion criteria, including 17 clinical case-control studies comparing the gut microbiota of subjects with depression, 2 studies comparing individuals with generalized anxiety disorder (GAD) and controls, and 1 comparing depression , Anxiety or anxiety/depressive disorder comorbidity subjects and controls.

The remaining six studies evaluated the general population (n=1), patients with major depressive disorder (MDD) without a control group (n=1), mothers from two lower socioeconomic groups (n=1), and healthy community samples (n=3) the correlation between anxiety or depression symptoms and gut microbiota.

Figure 1 describes the screening process, and Table 1 provides a summary of the included studies.

Figure 1. PRISMA flow chart describing the screening process for incorporating research into qualitative synthesis

Definitions of microbial indicators used in existing literature

In most studies, the characterization of the gut microbiota involves a variety of methods, usually including the measurement of alpha and beta diversity.

Alpha diversity provides summary statistics of microbial communities, where higher alpha diversity indicates more species (ie “richness”), more uniform expression (ie “uniformity”), and/or according to species The ancestral dissimilarity of is indicative of greater biodiversity (ie “physical diversity”, Figure 2).

The calculation of α diversity index (for example, Shannon, Simpson, and Faith’s phylogenetic diversity) considers and weights these factors differently, but in general, α diversity is usually used as a representative of community stability and function .

Figure 2.

A. Conceptual representation of α diversity, used to measure complexity within a sample.

Different metrics give different emphasis to the various components of α diversity: richness (i.e. the number of members of different communities), uniformity (i.e. equal representation of these members) and phylogenetic diversity (i.e. Relevance).

B. In order to assess the relationship between α diversity and clinical symptoms, bioinformatics analysis can be performed to perform statistical tests on differences between groups or the correlation with symptom scores

Although alpha diversity is estimated separately for each subject, beta diversity is an inter-individual measure that examines the similarity of the community relative to other analyzed samples (Figure 3).

Use data dimensionality reduction techniques to visualize data on a smaller number of axes (for example, using principal coordinate analysis [PCoA]) so that the microbiological composition of closer samples is more similar.

This can be used to check whether subjects in the same group (eg suffering from depression) are clustered together in a multidimensional space by their microbiota, but separated from another group (eg, control group).

Like alpha diversity, different measures of beta diversity emphasize different factors (such as uniformity, phylogeny).

Machine learning/clustering methods can also be used to analyze whether groups can be distinguished based on microbial communities (for example, hierarchical clustering, random forest model).

Figure 3. A. Conceptual representation of β diversity: used to measure the differences between groups of microbes. B. Selected bioinformatics analysis: Use principal coordinate analysis [PCoA] and other multi-dimensional calibration techniques to visualize group differences based on β diversity measurement, while machine learning methods test whether it is possible to use β diversity (ie microbiota characteristics) to change The subjects are divided into groups (such as clinical group and control group).

Gut microbiota in anxiety and depression

This review identified 13 studies that compared the composition of the gut microbiota of subjects with major depression (MDD) versus a control group, or analyzed microbial genes associated with major depression.

Among them, Mason et al. (2020) include major depression, comorbid major depression, generalized anxiety disorder (GAD)/anxiety disorder (NOS), simple generalized anxiety/anxiety disorder ( NOS) and control subjects compared, so will be discussed in several chapters.

Six other studies examined the microbiota of subjects with depression, but did not specify the type of depression.

Three studies compared the gut microbiota of subjects with generalized anxiety disorder with a control group. In addition to a full-group comparison, Jiang et al. (2018) also stratified subjects with generalized anxiety disorder into subjects who are currently taking psychotropic drugs and subjects who have never taken drugs. Perform group analysis.

Four studies used the self-reported symptom questionnaire as the sole measure of psychopathology to examine the association between microbiota composition and anxiety and depression, and one study assessed the association between microbes and depressive symptoms.

alpha diversity

In three studies comparing the gut microbiota of subjects with generalized anxiety disorder with a control group, the alpha diversity index including richness and uniformity was tested (Figure 4). The Shannon Index was reported in all three studies.

In the three studies, there was no difference in alpha diversity between subjects with anxiety disorders (generalized anxiety disorder or anxiety NOS) and the control group.

Figure 4. Summary of α diversity analysis results by indicator type (richness: observed OTUs/ASVs; richness and uniformity: Shannon index; phylogenetic diversity: Faith’s disease (PD), in A. Depression Obstacles or B. Anxiety disorder subjects were compared with the respective control group. Inconsistent results were found. A few studies reported higher alpha diversity, and more studies reported lower alpha Diversity, but most studies report no significant differences or do not report analysis/results of specific indicators.

In two studies comparing subjects with generalized anxiety disorder and a control group, the richness of the community was examined.

In both studies, the richness of GAD subjects was lower compared to the control group. Phylogenetic diversity is not analyzed in any GAD study.

Three studies have investigated the cross-sectional association between depressive symptoms, but none of them reported an alpha diversity index that considers richness and uniformity.

In four studies, no significant association was observed between richness/uniformity index and depressive symptoms.

No studies have investigated the association between community richness and depressive symptoms. A study investigated the phylogenetic diversity, but found no association with depressive symptoms.

Of the five studies that included measures of anxiety symptoms, four studies investigated the correlation of the alpha diversity index (including richness and uniformity).

All four studies reported no association between Shannon Index and anxiety symptoms.

Only one study investigated phylogenetic diversity and no association was observed. No studies have checked the richness.

β diversity

The β diversity analyzed using PCoA showed that the overall microbial composition of the generalized anxiety disorder subjects was different from the control group in the two studies.

A study found that there was no difference in beta diversity between subjects with anxiety, major depression, comorbid anxiety/major depression, or control groups.

In one study, anxiety and depression symptoms were associated with beta diversity distance, but in another study, beta diversity was associated with insomnia scores, not anxiety/depressive symptoms. Two studies found no association between beta diversity and symptoms.

The role of inflammation in the gut-brain axis

It has been reported that many groups with higher relative abundance in clinical anxiety and depression are associated with gastrointestinal inflammation.

Given the premise that certain strains are generally regarded as anti-inflammatory and used as probiotics, our study also observed a higher proportion of Bifidobacteria/Bifidobacteria in patients with depression, which is of particular concern.

A recent study reported that compared with mice colonized with bifidobacteria depleted microbiota, mice colonized with a microbiota rich in human bifidobacteria had higher pro-inflammatory Th17 intestinal cells.

Similarly, the higher abundance of bifidobacteria is associated with inflammatory bowel disease, indicating that certain strains may have inflammatory potential.

Inflammation is widely regarded as a factor in the pathogenesis of depression and anxiety.

These hypotheses stem from the observation of high levels of acute-phase proteins and pro-inflammatory cytokines in other medically healthy individuals suffering from anxiety or depression.

The changes in the gut microbiota and the resulting pro-inflammatory communication cascade effect (Figure 6) have been a possible cause of immune regulation disorders observed in mental health disorders.

Peripheral inflammation may be related to brain function, through signal transduction across the blood-brain barrier (BBB) ​​and penetration of immune cells into the brain.

Inflammatory signals also activate the vagus nerve afferent, which transmits information from the enteric nervous system to the brain, and induces the increase of norepinephrine and acetylcholine in the local central nervous system, thereby inhibiting inflammation.

In addition, the infiltration of lipopolysaccharides and bacterial metabolites may activate innate drug-resistant receptors, leading to inflammation of the central nervous system.

It is hypothesized that the long-term induction of this system will weaken the down-regulation of HPA axis hormones, leading to a continuous increase in circulating cortisol levels in anxiety and depression.

Figure 6. Inflammatory gastrointestinal state is associated with higher levels of pro-inflammatory bacterial species and relatively low abundance of short-chain fatty acid (SCFA) producing species, which generally help maintain the integrity of the intestinal barrier. The resulting damage to the intestinal barrier allows bacterial translocation and higher levels of immune mediators. Peripheral inflammation transmitted to the brain is related to the disruption of the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, leading to increased circulating levels of stress hormones (including cortisol). CRH = corticotropin releasing hormone; ACTH = corticotropin.

Conclusion and Outlook

This review summarizes the research status of the gut microbiota characteristics of anxiety/depression patients. Anxiety/depressive disorder is characterized by more species of pro-inflammatory bacteria. The abundance of pro-inflammatory bacterial species produced by short-chain fatty acids for anxiety/depression is relatively low. The diversity of α and β is found to be inconsistent. Future research should evaluate the function of the gut microbiota in diet, psychotropic drugs, and inspection species.

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