Constantly feeling low mood and blue, losing of pleasure in life and appetite or having difficulties to have good sleep.

These are just some of the symptoms of one of the most prevalent mental conditions worldwide: depression. It affects hundreds of millions people globally, particularly women. Although depression seems to have a genetic component, lifestyle factors like diet have been suggested to play possible roles in the development of this condition and the degree of their symptoms. In fact, many different studies have suggested that different healthy diets may have important benefits for depression.

did i eat thatIn a recently published meta-analysis at the prestigious scientific journal Molecular Psychiatry, Lassale and coworkers aimed to summarize current epidemiological evidence in relation to healthy dietary patterns and depression. They included a total of 41 high quality observational studies conducted in healthy people from different countries, focusing on several types of well-known healthy dietary indices: Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet, the Healthy Eating Index (HEI) and Alternative HEI (AHEI), and the Dietary Inflammatory Index. These healthy dietary indices score favorably for the consumption of different “healthy” foods, such as fruits and vegetables, nuts, cereals, legumes and healthy fats; and they penalize the consumption of “unhealthy” foods, such as processed foods.

The main findings of the Lassale meta-analysis revealed that those persons following more closely the Mediterranean diet, and those following less the pro-inflammatory diet, showed lower risk of depression and depressive symptoms. Similar beneficial results were observed with a high adherence to the HEI and AHEI diets, yet the evidence was not as strong as with the Mediterranean diet. Indeed, the dietary patterns evaluated in this study contain foods and nutrients which may modulate important biological processes related with depression. For example, healthy diets may reduce oxidative stress and inflammation processes, improve insulin sensitivity and blood circulation in the brain.

These important findings give a strong basis to the role of healthy dietary patterns like the Mediterranean diet in preventing depression and depressive symptoms, and they contribute to build future dietary recommendations to prevent this mental condition.

However, as the authors comment, it is important to keep in mind that all the studies included are observational, meaning, it is not possible to establish causal effects between diet and depression.

To establish causality that can be used to directly translate the knowledge into clinical practice, science needs specific intervention studies. In these studies, a healthy diet is followed for a long time and depression incidence is evaluated.

An example of this is the study conducted in the frame of the PREDIMED study with a population of Mediterranean adults at high cardiovascular risk. In this study, participants consuming the Mediterranean diet supplemented with nuts showed 41% protection against depression, although these benefits were only observed in people with diabetes. In view of the PREDIMED-Plus trial, a multicenter study is being conducted in Spain for the primary prevention of cardiovascular disease using an intensive lifestyle intervention. It will be possible to confirm these results and have new knowledge in the field of depression. With PREDIMED-plus, the investigators will be able to evaluate whether an energy-restricted Mediterranean diet,  with promotion of  physical activity, may be effective for reducing the risk of depression in elders at high cardiovascular risk. In case of the Eat2BeNice study we plan to analyse in the future the effect of PREDIMED-PLUS interventions not only on depression but also on mood and especially on impulsivity and compulsivity, two important domains related to brain function.

Overall, following a healthy diet, like Mediterranean diet, not only has important benefits for different aspects of human health but also it is likely that the diet prevents depression,  depressive-related symptoms and possible other mental related conditions. For this reason, a healthy diet nourishes a healthy mind.

 

References

Lassale C, Batty GD, Baghdadli A, Jacka F, Sánchez-Villegas A, Kivimäki M, Akbaraly T. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Mol Psychiatry. 2018 Sep 26. doi: 10.1038/s41380-018-0237-8.

Sánchez-Villegas A, Martínez-González MA, Estruch R, Salas-Salvadó J, Corella  D, Covas MI, Arós F, Romaguera D, Gómez-Gracia E, Lapetra J, Pintó X, Martínez JA, Lamuela-Raventós RM, Ros E, Gea A, Wärnberg J, Serra-Majem L. Mediterranean dietary pattern and depression: the PREDIMED randomized trial. BMC Med. 2013 Sep  20;11:208. doi: 10.1186/1741-7015-11-208.

 

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Recently, the idea that gastrointestinal microbiota are able to affect host behaviour is gaining momentum and it is based on studies conducted with animal models but also in humans with neurological disorders. However, the mechanisms that underlay this complex interplay between gut, brain and microbiota are not completely understood. Here we discuss recent findings on how microbial products could potentially affect the gut-brain axis.

Intestinal microbiota grow through the fermentation of undigested carbohydrates that end up in the large intestine. It was shown that absence of microbes or disruption of the microbiota, led to increased populations of impaired microglia cells in mice. Microglia cells are the primary effector cells for immune signalling to the central nervous system. The presence of a complex microbiota community, was shown to be essential for proper microglia maturation and function [1].

The main products of microbial fermentation in the gut are; acetate, propionate and butyrate, collectively known as short chain fatty acids(SCFA’s). Their beneficial role in human physiology have been well described, and recently evidence suggests that these molecules are able to cross blood brain barrier [2]. Moreover, gut microbiota have been associated with the brain barrier integrity. Mice raised in absence of bacteria are reported to have reduced brain barrier integrity. Once colonized with either a butyrate or an acetate/propionate producing bacteria, significant improvements were reported in the barrier [3]. Notably the integrity of the blood-brain barrier from the germ free mice was able to be restored through the oral administration of butyrate.

Gut_Microbes and Mental HealthSCFA’s are among the molecules having the privilege to cross the blood brain barrier and access the brain directly, their role should be studied in detail.

Recent studies also demonstrate that gut microbes regulate levels of intestinal neurotransmitters. The enteric nervous system interacts with a plethora of neurotransmitters (more than 30 have been identified so far.) Actually, the bulk of serotonin production ~90%, a neurotransmitter associated with mood and appetite is located in the gut. Specialized cells known as enterochromaffin cells are the main serotonin producers in the gut. In the absence of intestinal microbiota gastrointestinal serotonin levels are depleted. However, they can be restored by the addition of a specific spore forming consortium of intestinal bacteria. Specific bacterial metabolites have been reported to mediate this effect [4].

Other intestinal microbiota have been reported also to regulate the levels of the GABA neurotransmitter. Reduced levels of GABA have been associated with anxiety, panic disorder and depression. Bacterial GABA producers have been known to exist for years but it was not until 2016 that a gut bacteria was identified as GABA consumer [5]. For example, decreased levels of bacterial GABA producers were identified in a human cohort of depressed individuals. Studies in mice reinforce these findings. Intervention with the lactic acid bacteria Lactobacillus rhamnosus (JB-1) in healthy mice reduced anxiety related symptoms (accompanied by a reduction in the mRNA expression of GABA receptors in the Central Nervous System.) Lactic acid producing bacteria have also been reported to produce GABA in several food products such as kimchi, fermented fish and cheese [6].

Collectively, our gut microbiota encodes for ~100 times more genes than the human genome. The potential for some of these microbial genes to produce compounds able to interact with the nervous system and regulate critical pathways implicated in the gut brain axis is realistic and worth being explored.

Authors Prokopis Konstanti, MSc and Clara Belzer, PhD are working in the Department of Molecular Ecology, Laboratory of Microbiology, Wageningen University, Netherlands.

Footnotes

  1. Erny, D., et al., Host microbiota constantly control maturation and function of microglia in the CNS. Nature neuroscience, 2015. 18(7): p. 965-977.
  2. Joseph, J., et al., Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Frontiers in Neuroscience, 2017. 11(155).
  3. Braniste, V., et al., The gut microbiota influences blood-brain barrier permeability in mice. Science translational medicine, 2014. 6(263): p. 263ra158-263ra158.
  4. Yano, J.M., et al., Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 2015. 161(2): p. 264-276.
  5. P. Strandwitz, K.K., D. Dietrich, D. McDonald, T. Ramadhar, E. J. Stewart, R. Knight, J. Clardy, K. Lewis; , Gaba Modulating Bacteria of the Human Gut Microbiome. 2016.
  6. Dhakal, R., V.K. Bajpai, and K.-H. Baek, Production of gaba (γ – Aminobutyric acid) by microorganisms: a review. Brazilian Journal of Microbiology, 2012. 43(4): p. 1230-1241.

 

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