Gut bacteria and insomnia influence each other in small but significant ways, study shows

New genetic analysis reveals that insomnia and gut microbes shape each other, offering fresh clues to why poor sleep and gut imbalances so often go hand in hand.

Study: Investigating bidirectional causal relationships between gut microbiota and insomnia. Image Credit: Leonid Sorokin / Shutterstock

Many researchers have investigated the link between sleep attributes and the state of the gut microbiome. A recent paper in the journal General Psychiatry assesses associations between insomnia and gut dysbiosis.

Introduction

Insomnia affects up to a fifth of people worldwide, and at least half of those affected have chronic sleep disturbances. This can leave them irritable or tired when they are awake and expected to be functioning. Insomnia is often the prelude to other mental or physical illnesses that not only have a heavy social cost but herald premature death. For instance, depression risk doubles among people with insomnia compared to those with normal sleep.

The causes of insomnia remain elusive, though genetic, environmental, and behavioral factors are known to intertwine in causing abnormal wakefulness. Stress due to work, family circumstances, unmet financial needs, or other illnesses often impacts sleep adversely.

The gut-brain axis connects the gut microbiome and its metabolites to brain functioning. In healthy adults, the gut microbiome is dominated by a mix of Firmicutes and Bacteroidetes, comprising up to 90% of the total. Diet, age, and stress all affect the structure and composition of the gut microbiome, as does pregnancy. Sometimes, the resulting changes cause gut disease reflected in systemic conditions like obesity, metabolic syndrome, and autoimmune illness.

The gut microbiota is key to the establishment of the enteric nervous system that regulates visceral gut movements, including peristalsis. Gut microbes produce short-chain fatty acids (SCFA) like butyric acid and the neurotransmitter serotonin. These act on the enteric neurons and nerves.

SCFA receptors are abundant in the brain, forming part of the gut-brain pathways. They impact cognitive and emotional pathways. Babies with higher propionate levels in the gut tend to sleep uninterrupted for longer periods. Older people with insomnia tend to sleep more poorly if they have higher SCFA levels.

Not getting enough continuous sleep can also change the gut microbiome, and vice versa. Depletion of the gut microbiota is associated with brain wave changes in rapid eye movement (REM) sleep. The tenth cranial nerve, the vagus, mediates the gut-brain axis and is instrumental in the pathogenesis of mild cognitive impairment and depression.

In the current study, the scientists expected to find two-way relationships between insomnia and gut microbiota. To uncover this, they used Mendelian randomization (MR). This is a method of analysis that aims to minimize the effect of confounding and help reveal causation in a single direction.

About the study

The data came from genome-wide association studies (GWAS) on 386,533 individuals with insomnia, and gut microbiome data from two different databases (MiBioGen n=18,340 and the Dutch Microbiome Project n=8,208; all participants of European descent). Over 211 taxa in MiBioGen and 207 taxa in the Dutch dataset were screened. This yielded 4,089 instrumental variables for the MR analysis, and 5,118 for the reverse MR analysis.

Multiple analytic methods were used to detect and validate the associations in either direction, as well as to verify causality.

Study results

There were 22 bacterial clades (an ancestor with all groups of descendants) that were causally related to insomnia. Among these, 14 bacterial taxa may increase the risk of insomnia, while eight are protective. After false discovery rate (FDR) correction, only the Clostridium innocuum group remained significant in the microbiota → insomnia direction, and forward-direction effect sizes were small (odds ratios ~1.01 to 1.04 for risk taxa and 0.97 to 0.99 for protective taxa).

At the same time, a reverse MR analysis revealed that insomnia contributed to a decrease in the abundance of seven taxa by up to 80%, while 12 taxa were increased in abundance by up to 4.4-fold. Most reverse-direction associations did not remain significant after FDR correction, and Cochran’s Q indicated heterogeneity for Sutterella. The directionality of the association for Odoribacter was supported by a Steiger test.

These findings agree with many earlier studies, despite some inconsistencies. Some biological support for these results comes from the knowledge that Clostridium innocuum produces acetate (an SCFA) and breaks down tryptophan (a neurotransmitter precursor) while Coprococcus 1 produces propionate (an SCFA). Tryptophan gives rise to serotonin and melatonin, both of which are important in regulating emotional, cognitive, and other psychological processes.

The gut microbiota structure and composition vary with the presence of major depression or bipolar disorder, as well as neurodegenerative disorders like Parkinson’s disease. For instance, Coprococcus 1 and Lachnospiraceae are linked to depressive symptoms. Prevotella is a taxon associated with chronic local and systemic inflammatory conditions, including periodontitis and rheumatoid arthritis.

How does insomnia affect the gut microbiome?

Insomnia also affects the gut microbiome. For instance, it may upregulate virulence genes in response to stress molecules like interleukin-6 (IL-6), released by the enteric nervous system. More evidence comes from changes in IL-6 in mice transplanted with gut microbiome from sleep-deprived humans. Insomnia also shifts the levels of serotonin and dopamine, in turn altering the gut microbiota that produces these neurotransmitters.

The circadian rhythm of the gut microbes may also be important in these associations. Circadian disruption of the host is reflected in the gut and the brain as well, finally causing gut dysbiosis and leaky gut phenomena – the outcome being metabolic disease. Conversely, disruption of gut microbiota circadian clocks can trigger similar shifts in the body clocks, within the gut and in other tissues, while the SCFAs and other bacterial metabolites may reset the host’s rhythms.

Conclusions

“Our study highlighted the reciprocal relationships between gut microbiota and insomnia.” These provide preliminary evidence of causal relationships. However, the authors note that only a small number of associations survived multiple-testing correction, and residual confounding cannot be entirely excluded. This predicts such relationships, but the underlying mechanisms need to be elucidated.

The study is preliminary, limited to individuals of European ancestry, and effect sizes were small, making the results hypothesis-generating rather than definitive. It may help scientists better understand how to prevent and treat insomnia through approaches that modify the gut microbiome.