The Gut Microbiome and Depression

A summary of “The neuroactive potential of the human gut microbiota in quality of life and depression”

An abundance of research is being conducted on the relationship between human health and the gut microbiome. While the complex field is still in its emergence, scientists are already coming to amazing conclusions — it is truly becoming a hot topic.

More and more microbiome-based startups and companies are emerging, including Viome, offering personalized meal plans of foods based on gut microbiome composition.

Researchers are just beginning to explore the wonders of the gut microbiome.

Arguably the most fascinating finding is that microbes in the gut communicate with the brain, thus having the potential to affect mental health and behavior. This communication pathway, dubbed the “microbiome-gut-brain axis,” has been of great research in recent decades, and researchers are now beginning to find casual effects of gut microbes on the brain and behavior, as well as the metabolic pathways that these little microbes play a role in.

However, most of these studies have been conducted in animal models, often mice. For example, a study found that when germ-free mice are colonized with the microbiota from a patient with major depressive disorder (MDD) through the process of fecal microbiota transplantation (FMT), they begin to exhibit depressive-like symptoms!

While studies like this are certainly fascinating, it is unknown how well results like this will translate to humans.

In this article, I briefly summarize key takeaways from the first ever population-level study on the link between gut bacteria and mental health in humans. The study, published in Nature Microbiology, comes from Jeroen Raes and his team at VIB-KU Leuven in Belgium.

Don’t worry about reading any of this — I’ll explain.

More specifically, the study assesses how gut microbiota features correlate with one’s quality of life (QoL) and depression. They surveyed a large microbiome population cohort (Flemish Gut Flora Project, n=1,054), validating their results with independent cohorts.

There are two main components of this study:

  1. Analyzing how different bacteria in the gut microbiota are correlated with QoL and depression
  2. Analyzing the neuroactive potential (potential to produce molecules that communicate with the nervous system in one way or another) of bacteria in the gut microbiota

Here is a brief breakdown of the key points/innovations explained in this summary:

  • Specific gut bacteria are associated with higher QoL scores, as well as depression
  • Bacteroides enterotype 2 (a “type” of gut microbiota) was found to be more prevalent among patients with depression
  • The researchers created an analytical framework in silico to assess the neuroactive potential of the gut microbiota
  • Correlations exist between microbiota neuroactive potential and QoL, as well as depression

Note: If you’re not familiar with the gut microbiota, I strongly recommend reading my previous article here.

Analyzing how different bacteria in the gut microbiota are correlated with QoL and depression

In total, they found ten genus (a specific taxonomic category) abundances significantly correlated with QoL.

They found a positive association between QoL and Faecalibacterium and Coprococcus. What is interesting about this result is that Faecalibacterium and Coprococcus both produce butyrate. Butyrate is a short-chain fatty acid (SCFA) that strengthens the immune system, specifically the epithelial defence barrier, and reduces intestinal inflammation.

A previous study has found that the administration of SCFAs to mice undergoing psychosocial stress alleviates alterations in anhedonia (the inability to feel pleasure) and heightened stress‐responsiveness, as well as stress‐induced increases in intestinal permeability. It would therefore make sense intuitively that more butyrate-producing bacteria would increase QoL to some extent. In the past as well, both of these bacteria have been reported to be decreased in depression.

They additionally analyzed the gut microbiota composition of those with depression in the cohort. They found four taxa (taxonomic groups, in this context describing bacteria) significantly decreased in participants with depression/undergoing antidepressant treatment. However, they found antidepressant-use to be an important confounder of these specific genus-level findings. After getting rid of the effects of antidepressant-use on the gut microbiota, only Coprococcus and Dialister remained significant. These two are also associated with higher QoL, interestingly enough. These results were validated in an independent cohort as well.

For reference when looking at this figure: MCS, mental component summary; MH, emotional well-being; SF, social functioning; VT, vitality; RE, role limitations caused by emotional health problems; GH, general health perception; PF, physical functioning; RP, role limitations caused by physical health; BP, body pain; PCS, physical component summary.

The figure above summarizes the results and other variables the researchers took into account.

Fig. a shows the variables (covariates) that explain gut microbiota variation. For example, it can be seen that QoL accounts for just more than 0.5% of gut microbiota compositional variation. Fig b. is not entirely necessary to completely understand the study’s findings, however, it shows the cumulative (overall) effect sizes of covariates on gut microbiota community variation.

Fig. c shows the associations between gut bacteria, and QoL and depression, after getting rid of the effects of covariates. A positive correlation is shown with a blue dot, whereas a negative correlation is represented by a red dot. If a dot has a check mark, it means this associated was validated in an independent cohort, called the Dutch LifeLines DEEP (LLD) cohort.

Furthermore, the study analyzed the association between enterotypes, and QoL and depression. An enterotype is a “type” of gut microbiota — it’s a classification of living organisms based on the organism’s bacteriological ecosystem in the gut microbiota. Humans can have one of three enterotypes according to their gut microbiota: Prevotella, Bacteroides or Ruminococcus. Bacteroides can be further broken down into Bacteroides enterotype 1 and Bacteroides enterotype 2.

The researchers actually found that depression and lower QoL are associated with the Bacteroides enterotype 2. It has also been shown to have increased prevalence among those with Crohn’s disease, further supporting its dysbiotic (potentially harmful) nature.

It can be seen in Fig. a that “B2,” or Bacteroides enterotype 2, is associated with lower quality of life measures. Fig. b compares the distribution of enterotypes in depressed vs. control subjects. Bacteroides enterotype 2 was the only one with a different distribution.

Analyzing the neuroactive potential of bacteria in the gut microbiota

In addition to the results described above, the researchers analyzed the neuroactive potential of bacteria in the gut microbiota. The team developed a way to profile and interpret metagenomic data in the context of microbiota–gut–brain communication. Metagenomic data is simply the genetic material from a whole community of many organisms, in this case microbes in the gut.

Their framework describes the microbial pathways that metabolize molecules that have the potential to interact with the human nervous system (neuroactive compounds). They annotated and put together 56 gut–brain modules (GBMs). A GBM is basically a group of genes associated with the production or degradation of a single neuroactive compound.

To validate the GBMs, they conducted GBM detection on the genomes of microorganisms isolated from the human gastrointestinal tract included in the Integrated Microbial Genomes (whose neuroactive potentials were already known). They found that the GBMs they curated were able to predict the neuroactive potential of the genomes accurately, with a median detection sensitivity of 70%. They even identified additional genera encoding thus far experimentally unassessed neuroactive metabolism, perhaps leading to future in vitro studies!

Their framework allowed them to create the first ever catalogue of gut microbiota neuroactive potential.

For reference: Ach, acetylcholine; deg, degradation; GHB, γ-hydroxybutyric acid; Glu, glutamate; Isoval, isovaleric acid; KYN, kynurenine; NO, nitric oxide; PUFAs; polyunsaturated fatty acids; QUIN, quinolinic acid; SAM, s-adenosyl methionine; synt, synthesis; Trp, tryptophan; Vit K, vitamin K

The left graph in Fig. a shows the frequency of each GBM (again, each associated with a single neuroactive compound) in human-gut associated microbial genomes. On the right, you can see the microbial strains encoding for two or more rare GBMs.

In Fig c., only GBMs with an effect size > 0.1 and present in < 90% of genomes are shown (n= 10). For your reference: F, Fusobacteria; S, Synergistetes; V/L, Verrucomicrobia/Lentisphaerae; E, Euryarchaeota; T, Tenericutes. The concentric circles have the order and colour of the legend.

Fig b. compares GBM distribution of species that strictly reside in the gut vs. free-living species. On the other hand, Fig c. to the right shows the phylogenetic distribution of host-associated GBMs in gut reference genomes, in other words, which bacteria encode for which GBM corresponding with a neuroactive compound.

To determine whether neuroactive compound metabolism is associated with QoL and depression, the researchers applied the GBM framework to the metagenomic data of 80 patients diagnosed as depressed and 70 healthy controls.

The researchers found three GBMs covarying with various mental QoL scores. However, only the synthesis of 3,4-dihydroxyphenylacetic acid, or DOPAC — a metabolite of dopamine which had a positive correlation to QoL and depression — was replicated in the independent LLD data set.

What’s interesting is that DOPAC has been found to have anti-proliferative effects on colon cancer cells. Reduced DOPAC levels in cerebrospinal fluid have been proposed as a biomarker for Parkinson’s disease.

DOPAC synthesis potential was most strongly associated with the relative abundance of Coprococcus, which if you remember, was found to be associated with higher QoL scores! Only the second step of the DOPAC synthesis GBM, the conversion of 3,4-dihydroxyphenylacetaldehyde to DOPAC, was encoded in the analyzed genomes, specifically Coprococcus comes and Coprococcus catus. This suggests that other mechanisms besides butyrate production could be responsible for the beneficial association of Coprococcus with QoL.

Additionally, two GBMs in the glutamate pathway, glutamate degradation I and GABA synthesis III, were found to be respectively decreased and increased in participants with depression. While statistically not significant, both observations are intriguing.

Interestingly, decreased glutamate degradation potential in participants with a diagnosis of depression was validated in the independent TR-MDD data set. GABA is the main inhibitory neurotransmitter in the brain and alterations in GABA signalling have been linked to anxiety and depression.

Increased GABA levels in the blood of patients with MDD have been reported, as well as a role of microbially produced GABA in gut–brain communication. In turn, glutamate acts as an excitatory neurotransmitter in the brain, and comparatively higher levels have been reported in peripheral blood of participants with MDD. Thus, these results are very intriguing and may motivate future in vitro studies.

What makes these results even more convincing is that fact that it is a population-level study that actually studies humans, with validation from large independent data sets.

Overall, the findings of this study are extremely fascinating and will likely motivate several future studies, including translational research in the future to create microbiome-based therapeutics for psychiatric, neurological and many other disorders linked to the gut microbiota.

Again, here is a brief breakdown of the key points/innovations explained in the summary above:

  • Specific gut bacteria are associated with higher QoL scores, as well as depression
  • Bacteroides enterotype 2 (a “type” of gut microbiota) was found to be more prevalent among patients with depression
  • The researchers created an analytical framework in silico to assess the neuroactive potential of the gut microbiota
  • Correlations exist between microbiota neuroactive potential and QoL, as well as depression

👋 Hi! I’m Mikey, a 16 y/o researcher passionate about understanding biological complexity and solving big problems. I’ve been diving deep into fields like machine learning, genomics and of course, the human microbiome! Do send me a message if you’re interested in nerding out:)

machine learning and neurotechnology developer and researcher.

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