The Effects of Probiotics on Symptoms of Depression: Protocol for a Double-Blind Randomized Placebo-Controlled Trial

Abstract

<b><i>Background:</i></b> A growing body of evidence has linked mental health outcomes to the gut microbiome. This has led to the investigation of the GI tract as a target for novel treatments and interventions for depression, including probiotic supplementation. Our recent pilot study provided the first evidence of probiotics improving symptoms of depression in treatment-naive depressed patients. To further support and expand upon this evidence, data from the pilot study were used to plan a 16-week, double-blind, randomized, placebo-controlled trial to assess the effects of probiotics on depression. Here, we report the protocol for this trial. <b><i>Methods:</i></b> Participants diagnosed with depression will orally consume a probiotic supplement containing <i>Lactobacillus helveticus</i> and <i>Bifidobacterium longum</i> or placebo once daily. Participants will undergo assessments measuring clinical outcomes using a battery of validated clinical scales and questionnaires. Sleep architecture and quality will be measured using polysomnography. Neuroimaging data will be collected using magnetic resonance imaging to examine functional and structural neurophysiological changes. Molecular data will be collected from blood, stool, and urine samples to examine cytokine levels and explore potential genes and proteins that may predict outcomes in depression. <b><i>Results:</i></b> We expect results to replicate and expand on our pilot data demonstrating that probiotics may be effective in alleviating symptoms of depression, and to find biomarkers that will predict these outcomes. <b><i>Conclusions:</i></b> The findings from this study will add to the growing body of research in this emerging field, which eventually may provide evidence for probiotics having a role in alleviating symptoms of depression.

Probiotic Supplement Preparation Relieves Test Anxiety by Regulating Intestinal Microbiota in College Students

“…Growing evidence has explored the potential influence of microbiota on the brain-gut axis in health and disease, including nutrition, immunity, host physiology, and brain development [3,4]. It has also been suggested that the intestinal microbiota is involved in the modulation of behaviour in stress-related disorders [3,5,6].…”

The Effect of Lactobacillus acidophilus YT1 (MENOLACTO) on Improving Menopausal Symptoms: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial

“…Moreover, a mixture of Lactobacillus strains improves lumbar spine-bone loss in postmenopausal women [60]. However, there are no studies directly addressing whether probiotics relieve menopausal symptoms, although clinical trials have been conducted in relation to symptoms of insomnia, depression, fatigue, and headache [61][62][63][64].…”

Probiotics, Prebiotics, Synbiotics, and Paraprobiotics as a Therapeutic Alternative for Intestinal Mucositis

“…Studies have shown that benefits for human health are attributed to consumption of probiotics, mainly for GIT diseases ( Fedorak et al, 2015 ; Acurcio et al, 2017 ), though also for other diseases, including osteoporosis ( Collins et al, 2018 ), cancer ( Zaharuddin et al, 2019 ), obesity and type 2 diabetes ( Saez-Lara et al, 2015 ; Wang et al, 2017 ; Hsieh et al, 2018 ), depression ( Wallace et al, 2020 ), and atopic dermatitis ( Rather et al, 2016 ). In this context, the main mechanisms of action described for these microorganisms in the host include: (i) colonization and regulation of a dysbiotic intestinal microbiota ( Shi et al, 2017 ); (ii) protection of the epithelial barrier by maintaining tight junction integrity ( Blackwood et al, 2017 ); (iii) induction of mucin production ( Aliakbarpour et al, 2012 ) and B-cell-secreting IgA, which are important defense mechanisms necessary to maintain epithelial integrity and to protect the intestine from the external environment; (iv) increasing adherence to the intestinal mucosa and inhibiting of concomitant pathogen adherence based on competition for available nutrients and sites of mucosal adhesion ( Collado et al, 2010 ; Monteagudo-Mera et al, 2019 ); (v) competitive exclusion of pathogenic microorganisms, such as Staphylococcus aureus and Salmonella typhimurium ( Halder et al, 2017 ; Plaza-Díaz et al, 2017 ); (vi) production of antimicrobial substances such as acetic and lactic acids, and bacteriocins, which have strong inhibitory effects against Gram-negative bacteria and have been considered as the main antimicrobial compounds produced by probiotics against pathogens ( Alakomi et al, 2000 ; De Keersmaecker et al, 2006 ; Makras et al, 2006 ; Bermudez-Brito et al, 2012 ; Mokoena, 2017 ; Gaspar et al, 2018 ; Castilho et al, 2019 ); (vii) production and secretion of metabolites of SCFAs with anti-inflammatory properties, such as acetate, propionate, and butyrate, which exert beneficial effects on intestinal and immune cells, being important compounds for cell proliferation, cell differentiation, and gene expression, and they are signaling molecules of immunological pathways; butyrate is the primary energy source of colonocytes, and it has an epithelial barrier function; SCFAs can also induce expression of the anti-inflammatory cytokine IL-10, inhibiting inflammatory responses ( Parada Venegas et al, 2019 ); (viii) inhibition of the activation of the NF-κB signaling pathway ( Kaci et al, 2011 ; Gao et al, 2015 ); (ix) interaction with the gut–brain axis via the production of metabolites such as γ-aminobutyric acid (GABA) ( Kim N. et al, 2018 ); and (x) modulation of the host’s innate and/or adaptive immune system responses through interaction with epithelial cells, ...…”