Rolul probioticelor asupra axei microbiotă-intestin-creier în depresie

Introduction

Depression, a chronic mental health condition that can negatively affect the quality of life and even lead to suicide, is an increasingly worrying issue of potential global concern^(1,2). World Health Organization (WHO) estimates that the number of people living with depression across the world is approximately 264 million⁽³⁾. Healthcare workers can offer pharmacological treatments; however, they are ineffective in 30% of patients with major depressive disorder (MDD)^(2,4). Thus, the development of an alternative/adjuvant therapy to treat depression is a considerable long-term solution. The present article reviews the role of probiotic supplementation on the microbiota-gut-brain-axis associated with depression.

Microbiota and its role in depression

There are bidirectional communications between the gut and the brain through several pathways, particularly involving the immunoregulatory, neuroendocrine and vagus nerve⁽⁵⁾. Gut bacteria belong to seven dominant phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, Verrucomicrobia and Cyanobacteria, which communicate to the brain through various pathways^(6-8). The mechanism of communication between the gut microbiota and brain is not clearly defined. Possible pathways that could be involved in depression and the two main hypotheses that attempt to explain the mechanism of action of probiotics is discussed in brief here.

Neurotransmitters such as gamma-aminobutyric acid (GABA), 5-HT, glycine and catecholamine are secreted from gut microbiota, indicating that the gut plays a crucial role in the neurotransmitters modulation^(1,2,9). The neurotransmitters hypothesis suggests that probiotic supplementation improve central nervous system symptoms associated with depression by increasing the production of free tryptophan, and in turn increasing serotonin availability, furthermore probiotics upregulate the 5-HT-BDNF system to mediate the antidepressive effect.

Disruption in the gut barrier, known as leaky gut, where the epithelium is compromised as a result of different factors, such as infection, exposure to antibiotics, lack of natural birth or breastfeeding, psycho- and physiological stress, coupled with genetics of the host, can produce long-term modulation of stress response. This “leaky gut” phenomenon causes gut derived endotoxins and lipopolysaccharide (LPS) to leak in to the blood streams, leading to the activation of the immune system (Toll-like receptors; TLRs) and to the production of proinflammatory cytokines (interleukin-6, interferon-g, C-reactive protein, tumor necrosis factor a). The hypothesis suggests that probiotics may exert their therapeutic effects on the central nervous system by improving the integrity of the gastrointestinal lining, reducing the ability of endotoxins to leak into the bloodstream.

Methodology

Articles were retrieved from PubMed (from 2003 to 2022 June), using the following search MeSH terms: “depression”, “gut microbiota”, “probiotic” and “gut-brain-axis”, and after many filtrations, abstracts were assessed and free full texts read.

Results

The term “probiotic” originates etymologically from the words “pro bios” meaning “for life”, and the beneficial effect of lactic acid fermentation products on human health has ancient roots⁽⁹⁾. The effect of probiotics on mental health and its effects on the hypothalamic-pituitary-adrenal (HPA) axis, including kynurenine, tryptophan, neuropeptide Y, cortisol and ACTH pathway among petrochemical workers, were evaluated by Jazayeri et al.⁽¹⁰⁾

The general health profile and depression score improved after the consumption of probiotic yogurt or a multispecies probiotic for six weeks, compared to conventional yogurt. There was no significant effect of probiotic yogurt consumption and multispecies probiotic capsule supplementation on the HPA axis. Dapoigny et al. performed an RCT on 50 patients with irritable bowel syndrome (IBS)⁽¹¹⁾. Clinically relevant changes in depression score were not observed after consuming LCR35 for two weeks, the gastrointestinal lining reducing the ability of endotoxins to leak into the bloodstream. Similarly, Lyra et al. conducted an RCT on 391 adult IBS volunteers and evaluated the effect of L. acidophilus NCFM⁽¹²⁾. After 12 weeks, the depression scale improved significantly only in the high-dose group. In another study reported by Bercik et al., the probiotic B. longum NCC3001 (BL) was found to reduce depression⁽¹²⁾. Rudzki et al. showed the effect of augmentation of SSRI with L. plantarum 299v on 79 patients with MDD for 8 weeks⁽¹³⁾, asserting the first evidence of the role of probiotic in improving cognitive function and decreasing KYN concentration in depressed patients. Roberts et al. demonstrated the effect of the Ecologic Barrier® probiotic on 71 depressed participants, measuring the depression symptoms and microbiota composition, and observing decreased KYN concentration in MDD patients⁽¹⁴⁾.

Estévez et al. reported that, after receiving the probiotic ERGYPHILUS Plus®, the Beck Depression Inventory (BDI) was reduced among 40 patients diagnosed with fibromyalgia⁽¹⁵⁾. The consumption of the probiotic freeze-dried L. reuteri DSM 17938 exhibited a modest effect in the probiotic arm and the stress levels decreased at weeks 8 and 12, as documented by Schoultz et al.⁽¹⁶⁾ In another study, Wang et al. demonstrated the effect of L. paracasei strain Shirota (LcS) on constipation in depressed patients⁽¹⁷⁾. The study included 82 patients who consumed fermented dairy beverages and a placebo every day for nine weeks. BDI and Hamilton Depression Rating Scale (HAM-D) scores were all significantly decreased, and the degree of depression was significantly improved in both the placebo and the LcS groups. Yoon et al. included 156 healthy adults with subclinical symptoms of depression. After receiving the probiotic NVP-1704 for four and eight weeks, serum IL-6 and the depressive symptoms significantly reduced, as evidenced by BDI‑II score, as well as an increase in Bifidobacteriaceae and Lactobacillacea was noted, along with a decrease in Enterobacteriaceae in the gut microbiota⁽¹⁸⁾.

Mörkl et al. reported an effect of the probiotic ­OMNi‑BiOTiC Stress Repair® on 82 depressed patients for 28 days⁽¹⁹⁾. After 28 days, it significantly decreased the IL-17 expression and altered b-diversity of R. gauvreauii and Coprococcus. Bengesser et al. also investigated the effects of OMNi-BiOTiC Stress Repair® on gene expression of inflammatory genes on 61 participants with MDD⁽²⁰⁾ and, after four weeks, IL-6 gene expression levels were decreased in probiotic group. Yang et al. reported that the daily administration of L. plantarum PS128 capsule on 40 depressed participants resulted in a decrease in depressive symptoms⁽²¹⁾. Asemi et al. conducted a trial on 60 women with polycystic ovary syndrome (PCOS) to check their mental health parameters⁽²²⁾.

A significant improvement on Beck’s depression inventory, general health profile scores and depression scores was observed compared to placebo. Asemi et al. conducted another study where they showed that the coadministration of vitamin D and probiotics for 12 weeks to women with PCOS had beneficial effects on mental health parameters⁽²³⁾.

De Weerth et al. reported an RCT that included 40 pregnant women with low-risk pregnancies and elevated thedepressive symptoms⁽²⁴⁾. They consumed Ecologic Barrier®, a probiotic multispecies mixture, and a placebo once every day from 26-30 weeks of gestation until delivery. After eight weeks of intervention, there was no significant difference between the probiotic and the placebo groups for depression scores. Serlachius et al. also reported that probiotics did not improve mental health outcomes in up to 36 weeks of pregnancy in their multiethnic cohort of 230 pregnant women with obesity⁽²⁵⁾. In contrast, Barthow et al. conducted a trial (Probiotics in Pregnancy Study) where 400 pregnant women received probiotic supplementation by L. rhamnosus HN001 from 14 to 16 weeks of gestation until delivery and continuing until 6 months postpartum⁽²⁶⁾. The maternal depression rate was decreased in the postpartum stage. Mitchell et al. reported that the patients (423 women with 14-16 weeks of gestation) who received HN001 had significantly lower depression and anxiety scores in the postpartum period compared to the placebo group⁽²⁷⁾.

Romijn et al. demonstrated that probiotic formulation is effective in treating low mood, or in moderating the levels of inflammatory and other biomarkers among 79 participants⁽²⁸⁾. Chen et al. found that depressive severity in 11 patients with MDD significantly ameliorated, but the markers of inflammation, gut permeability and gut microbiota composition did not significantly change after eight weeks of PS128 L. plantarum intervention⁽²⁹⁾. Messaoudi et al. reported that the consumption of probiotic formulation containing L. helveticus R0052 and B. longum R0175 in combination mitigated psychological distress in three tests without displaying any adverse event⁽³⁰⁾. Schöpf et al. evaluated the multistrain probiotic administration (Omni-Biotic Stress Repair®) in 45 healthy participants⁽³¹⁾. The probiotic modulated the functional connectivity of the brain related to depression. Schmidt et al. reported a study where depressed patients consumed a daily dose of probiotic supplement (Vivomixx®)⁽³²⁾. Depressive symptoms (HAM-D scores) decreased relative to the placebo group. Ghaderi et al. conducted an RCT on 35 patients with mental and metabolic disorders⁽³³⁾. After receiving the probiotic supplement LactoCare® for 12 weeks, the symptoms of depression were significantly reduced. The daily administration of two capsules of PS128 (L. plantarum) for 30 days may lead to a decrease in depressive symptoms, as documented by Tsai et al.⁽²¹⁾

Discussion

The probiotic treatment on depressive symptoms, the effects of the alteration of the gut microbiota and the probable mechanisms of action are discussed in this article. In many randomized clinical trial studies, the selection of the target population is a crucial factor⁽³⁴⁾. Some studies selected patients with irritable bowel syndrome (IBS), a chronic biopsychosocial disorder, one study recruited participants with constipation and depression symptoms^(12,13,19), while MDD was the major criteria in other studies^(14,20,21), and some studies selected only healthy populations⁽²³⁾. L. acidophilus NCFM and B. longum NCC3001 reduced the depression and the IBS symptoms, whereas LCR35 was not effective in the reduction of the depression score^(12,13,19). Rudzki et al. reported for the first time that the administration of L. Plantarum 299v leads to the decrease of kynurenine concentration with subsequent improvement of cognitive functions in depressed patients⁽¹³⁾.

The imbalance or dysbiosis in gut microbiome decrease in commensal Bifidobacterium and Lactobacillus strains and an increase in pathogenic gut microbes leading to a “leaky gut” can stimulate the secretion of proinflammatory cytokines, including IL-1, IL-6 and IL-18 proteins which are frequently linked to MDD. Probiotic NVP-1704 and OMNi-BiOTiC Stress Repair® reduced the serum proinflammatory cytokine levels and also helped to balanced gut microbiota composition, thereby improving the depressive symptoms⁽¹⁹⁾. The effects of probiotics on pregnant participants were evaluated in many studies^(26-29). Probiotic capsules (L. rhamnosus GG and B. lactis BB12) did not improve the depression score of pregnant women with obesity. This finding may be due to self-reported capsule consumption of patients (prone to bias) and restricted sample size (result obtained of 164 women out of 230)⁽²⁷⁾.

Contrary, probiotic L. rhamnosus HN001 in pregnancy and breastfeeding can reduce the rates of maternal depression. Gut microbiota plays a crucial role in regulating behavior and brain processes – i.e., central GABA (gamma amino butyric acid) receptor expression⁽²¹⁾. Four-week multistrain probiotic administration in whole-brain functional and structural connectivity associated with midbrain, insula and sensorimotor cortex brain regions. Among numerous plausible molecular mechanisms associated with gut-brain interactions, the vagus nerve pathway might be related to brain functional connectivity. The study of Bagga et al. demonstrated the close relationship between the effects of the probiotic intervention on behavioral (depression) and neuroimaging readouts. There is still little clinical research looking at probiotic supplementation in depressed people. Large-scale investigations are highly needed, but they are also challenging to conduct⁽³¹⁾.

Smaller studies with superior designs may also offer a unique perspective on the connections between gut microbiota and depression, but they need to be more consistent. Except for a few studies, most reported clinical trial data have demonstrated a correlation between the gut microbiota and depression, but they did not evaluate the possible mechanism underlying this disease. This analysis could increase research into the fundamental mechanisms of depression and help understand how to prevent, diagnose and treat it.

Conclusions

This review article evaluated the beneficial role of probiotic supplementation on the gut-brain axis in human underlying depression through clinical and preclinical studies. However, only a few research articles evaluated all the standard depression parameters and hallmark genes specific for depression related to the gut-brain axis. Further studies are needed to fully evaluate the therapeutic potential of probiotics. These studies should provide a basis for advanced therapeutic approaches, along with current therapeutic modalities, as well as the identification of novel biomarkers for early diagnosis and intervention of depression.