A new meta-analysis study reports regulating intestinal microbiota is more than 50% effective at helping to reduce anxiety

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People who experience anxiety symptoms might be helped by taking steps to regulate the microorganisms in their gut using probiotic and non-probiotic food and supplements, suggests a review of studies published today in the journal General Psychiatry.

Anxiety symptoms are common in people with mental diseases and a variety of physical disorders, especially in disorders that are related to stress.

Previous studies have shown that as many as a third of people will be affected by anxiety symptoms during their lifetime.

Increasingly, research has indicated that gut microbiota – the trillions of microorganisms in the gut which perform important functions in the immune system and metabolism by providing essential inflammatory mediators, nutrients and vitamins – can help regulate brain function through something called the “gut-brain axis.”

Recent research also suggests that mental disorders could be treated by regulating the intestinal microbiota, but there is no specific evidence to support this.

Therefore a team of researchers from the Shanghai Mental Health Center at Shanghai Jiao Tong University School of Medicine set out to investigate if there was evidence to support improvement of anxiety symptoms by regulating intestinal microbiota.

They reviewed 21 studies that had looked at 1,503 people collectively.

Of the 21 studies, 14 had chosen probiotics as interventions to regulate intestinal microbiota (IRIFs), and seven chose non-probiotic ways, such as adjusting daily diets.

Probiotics are living organisms found naturally in some foods that are also known as “good” or “friendly” bacteria because they fight against harmful bacteria and prevent them from settling in the gut.


The past decade has seen a paradigm shift in our understanding of the brain-gut axis.

The exponential growth of evidence detailing the bidirectional interactions between the gut microbiome and the brain supports a comprehensive model that integrates the central nervous, gastrointestinal, and immune systems with this newly discovered organ.

Data from preclinical and clinical studies have shown remarkable potential for novel treatment targets not only in functional gastrointestinal disorders but in a wide range of psychiatric and neurologic disorders, including Parkinson’s disease, autism spectrum disorders, anxiety, and depression, among many others.

Results from preclinical studies published during the past decade strongly support the concept of bidirectional brain-gut-microbiome (BGM) interactions.

Alterations in these interactions have been implicated not only in the pathogenesis and pathophysiology of classic brain-gut disorders such as irritable bowel syndrome (IBS) and other functional gastrointestinal disorders,12 but a growing list of psychiatric and neurologic pathologies including affective disorders,34 autism spectrum disorders (ASD),35 Parkinson’s disease,6 multiple sclerosis,7 and chronic pain.8

Although most of the literature associates gut microbiota composition with human health, development, and disease, evidence for causality remains sparse.

The BGM axis’ interface with fundamental and disease-susceptible processes make it a novel therapeutic target, but this network remains insufficiently understood for intervention.

In this review, we address current evidence supporting bottom-up and top-down signaling within the BGM axis and the emerging evidence supporting its contribution to human disease.

Clinical Evidence

Experimental approaches to study the role of gut microbes to brain signaling have been restricted mostly to small clinical studies showing the association of gut microbial community structure with brain parameters and subjective outcomes of interventions with probiotics and prebiotics.

Although no high-quality, controlled studies in human beings have reported the effects of interventions such as antibiotics or fecal microbial transplants on the brain or behavior, studies of probiotic interventions are increasing rapidly in number and gradually in scale and quality.

A double-blind, placebo-controlled, pilot study of the probiotic Bifidobacterium longum NCC3001 in 44 adults with IBS and diarrhea was shown to reduce responses in the amygdala and frontolimbic regions to negative emotional stimuli as measured by functional magnetic resonance imaging.58 

Although depression scores were lower with the intervention, anxiety and IBS symptoms were not affected.

In healthy female control subjects, consumption of a fermented milk product with probiotics over 4 weeks was associated with significant changes in the functional connectivity between brain regions during an emotion recognition task, notably without concomitant detectable changes in gut microbial composition.59 

Probiotic consumption also has been reported to reduce self-reported feelings of sadness and aggressive thoughts.60 

A probiotic cocktail used to achieve reduction of anxiety- and depression-related behaviors in mice48 also was administered to healthy human beings to a similar effect.61

The translation of promising findings obtained in rodent studies has been limited.

In a clinical trial with Lactobacillus rhamnosus (JB-1), the effects of which were seminally shown on mice by Bravo et al,16 performed no better than placebo on stress-related measures, hypothalamic pituitary adrenal axis response, inflammation, or cognitive performance in an 8-week trial with healthy males.62 

Moreover, the pilot trial of Bifidobacterium longum NCC3001 described earlier did not recapitulate the effects observed in mice by the same research group22 and has been criticized for its fragility.63 

This translational disconnect, or inconsistency, highlights the likelihood of host-specific microbiota interactions and underscores the importance of cautious extrapolation of preclinical findings.

Furthermore, as shown by several studies, probiotic supplementation in human beings does not appear to change the gut’s microbiota composition but induces its effect on behavior via transient modification of the collective microbiome transcriptional state, as shown in GF mice and confirmed in monozygotic twins.64 

This finding demands measurement of probiotic intervention on gut microbial profiles with technologies integrating metatranscriptomics and metabolomics and fundamental reconsideration of the functional equivalence of transient vs resident microorganisms.

Better characterization of microbial community dynamics and metabolism coupled with improved models of their community ecology will help refine the mechanisms responsible for these effects and identify putative targets for therapeutic intervention.Go to:

Signaling Mechanisms From the Gut Microbiota to the Brain

Current evidence indicates that bottom-up modulation of the CNS by the microbiome occurs primarily through neuroimmune and neuroendocrine mechanisms, often involving the vagus nerve.16656667 

This communication is mediated by several microbially derived molecules that include short-chain fatty acids (SCFAs), secondary bile acids (2BAs), and tryptophan metabolites.656869 

These molecules propagate signals primarily through interaction with enteroendocrine cells (EECs), enterochromaffin cells (ECCs), and the mucosal immune system, but some cross the intestinal barrier, enter systemic circulation, and may cross the blood-brain barrier.687071 

It remains poorly understood if these molecules reach brain sites directly or only induce central responses via long-distance neural signaling by vagal and/or spinal afferents.1672 

In addition to generating these metabolites that activate endogenous CNS signaling mechanisms, the microbiota can independently produce or contribute to the production of a number of neuroactive molecules including but not limited to γ-aminobutyric acid,7374 5-HT,7576 norepinephrine,7677 and dopamine,757677 although it is unknown if they reach relevant receptors or achieve sufficient levels to elicit a host response.


The researchers found that probiotic supplements in seven studies within their analysis contained only one kind of probiotic, two studies used a product that contained two kinds of probiotics, and the supplements used in the other five studies included at least three kinds.

Overall, 11 of the 21 studies showed a positive effect on anxiety symptoms by regulating intestinal microbiota, meaning that more than half (52%) of the studies showed this approach to be effective, although some studies that had used this approach did not find it worked.

Of the 14 studies that had used probiotics as the intervention, more than a third (36%) found them to be effective in reducing anxiety symptoms, while six of the remaining seven studies that had used non-probiotics as interventions found those to be effective — a 86% rate of effectiveness.

Some studies had used both the IRIF (interventions to regulate intestinal microbiota) approach and treatment as usual.

In the five studies that used treatment as usual and IRIF as interventions, only studies that had conducted non-probiotic ways got positive results, that showed a reduction in anxiety symptoms.

Non-probiotic interventions were also more effective in the studies that used IRIF alone.

In those studies only using IRIF, 80% were effective when using non-probiotic interventions, while only 45% were found to be effective when using probiotic ways.

This is an illustration of gut microbes

Gut microbes illustration. The image is adapted from the BMJ news release.

The authors say one reason that non-probiotic interventions were significantly more effective than probiotic interventions was possible due to the fact that changing diet (a diverse energy source) could have more of an impact on gut bacteria growth than introducing specific types of bacteria in a probiotic supplement.

Also, because some studies had involved introducing different types of probiotics, these could have fought against each other to work effectively, and many of the intervention times used might have been too short to significantly increase the abundance of the imported bacteria.

Most of the studies did not report serious adverse events, and only four studies reported mild adverse effects such as dry mouth and diarrhoea.

This is an observational study, and as such, cannot establish a cause. Indeed, the authors acknowledge some limitations, such as differences in study design, subjects, interventions and measurements, making the data unsuitable for further analysis.

Nevertheless, they say the overall quality of the 21 studies included was high.

The researchers conclude: “We find that more than half of the studies included showed it was positive to treat anxiety symptoms by regulation of intestinal microbiota.

“There are two kinds of interventions (probiotic and non-probiotic interventions) to regulate intestinal microbiota, and it should be highlighted that the non-probiotic interventions were more effective than the probiotic interventions. More studies are needed to clarify this conclusion since we still cannot run meta-analysis so far.”

They also suggest that, in addition to the use of psychiatric drugs for treatment, “we can also consider regulating intestinal flora to alleviate anxiety symptoms.”

Source:
BMJ
Media Contacts: 
Press Office – BMJ
Image Source:
The image is adapted from the BMJ news release.

Original Research: Open access
“Effects of regulating intestinal microbiota on anxiety symptoms: A systematic review”. Beibei Yang, Jinbao Wei, Peijun Ju, Jinghong Chen.
General Psychiatry. doi:10. 1136/gpsych-2019-100056

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