Antidepressive Mechanisms of Probiotics and Their Therapeutic Potential

Abstract

The accumulating knowledge of the host-microbiota interplay gives rise to the microbiota-gut-brain (MGB) axis. The MGB axis depicts the interkingdom communication between the gut microbiota and the brain. This communication process involves the endocrine, immune and neurotransmitters systems. Dysfunction of these systems, along with the presence of gut dysbiosis, have been detected among clinically depressed patients. This implicates the involvement of a maladaptive MGB axis in the pathophysiology of depression. Depression refers to symptoms that characterize major depressive disorder (MDD), a mood disorder with a disease burden that rivals that of heart diseases. The use of probiotics to treat depression has gained attention in recent years, as evidenced by increasing numbers of animal and human studies that have supported the antidepressive efficacy of probiotics. Physiological changes observed in these studies allow for the elucidation of probiotics antidepressive mechanisms, which ultimately aim to restore proper functioning of the MGB axis. However, the understanding of mechanisms does not yet complete the endeavor in applying probiotics to treat MDD. Other challenges remain which include the heterogeneous nature of both the gut microbiota composition and depressive symptoms in the clinical setting. Nevertheless, probiotics offer some advantages over standard pharmaceutical antidepressants, in terms of residual symptoms, side effects and stigma involved. This review outlines antidepressive mechanisms of probiotics based on the currently available literature and discusses therapeutic potentials of probiotics for depression.

Keywords: gut microbiota; inflammation; major depressive disorder; microbiota-gut-brain axis; probiotics.

FIGURE 1

The maladaptive microbiota–gut–brain (MGB) axis in the pathophysiology of depression. Chronic exposure to stressors (e.g., psychological, poor nutrition) triggers prolonged release of (1) norepinephrine that alters gut microbiota composition by shifting to one that is enriched with pathogenic bacteria, and (2) acetylcholine and glucocorticoids that increase intestinal barrier permeability. The increased intestinal permeability allows bacteria and their toxins to enter systemic circulation, triggering stress responses from the HPA axis and immune system that, when excessive; (3) leads to chronic inflammation and HPA axis overactivity; (4) aggravate intestinal permeability; (5) alter composition of gut microbiota; and (6) disrupt neurotransmitter systems. Altered gut microbiota also results in an inflamed gut and (7) a shift in the production of bioactive molecules that regulate host neurotransmitter systems and gut motor functions. As a proof of concept, these five factors (in the circle) that depict the maladaptive MGB axis are often detected in MDD patients. Lastly, the constant negative emotions displayed by depressed patients further trigger a stronger reaction or sensitivity to various stressors.

FIGURE 2

Signaling mechanisms underlying antidepressive effects of probiotics mediated through secretion of (A) Neurotransmitters: L. rhamnosus and L. casei secrete GABA that may signal central GABAergic system and HPA axis via the neural route. L. brevis secretes GABA that enhances sleep. L. helveticus secrete 5-HT that may signal the central 5-HT system via the neural route. L helveticus also secretes NE that may affect the central NE system. L. reuteri secretes histamine that decreases secretion of proinflammatory cytokines by IECs. This may reduce circulating inflammatory markers, such as LPS, IL-6 and corticosterone, and subsequently prevent the inflammation-induced decrease in hippocampal BDNF. (B) Butyrate: L. plantarum produces butyrate that strengthens intestinal barrier and diffuses through the circulation to regulate BDNF expression and reduce inflammation in the brain. The latter consequently regulates the HPA axis and its regulator, the DA system. C. butyricum produces butyrate that influences central 5-HT and BDNF systems and stimulates L cell to secrete GLP-1 into the bloodstream which increases expression of GLP-1 receptors. F. prausnitzii produces butyrate that strengthens the intestinal barrier. B. infantis and L. paracasei promote growth of butyrate-producing bacteria. Through butyrate, B. infantis upregulates Tph1 activity of EC which increases circulating 5-HT and strengthens intestinal barrier to lower IDO activity and increase circulating TRP, both of which affect the central 5-HT system and BDNF expression. Through butyrate, L. paracasei may influence the central 5-HT system and BDNF expression. (C) Bacterial secreted proteins: L. gasseri secretes gassericins that increase parasympathetic activity to facilitate sleep and improves gut microbiota composition. B. longum secretes serpins that alter neural activities in the brain via the neural route. L. paracasei secretes lactocepins that decrease proinflammatory chemokines in IECs. This lowers IDO activity which, in turn, affects the central 5-HT system and BDNF expression. (D) Other bioactive molecules: B. infantis secretes bioactive factors (likely polysaccharides) that decrease circulating IL-6 which affects the central NE system. L. reuteri secretes H₂O₂ that decreases IDO activity and circulating KYN, and dgk that inhibits the initiation of proinflammatory pathways. B. breve converts albiflorin into BZA which affects the Glu system via the humoral route. L. kefiranofaciens secretes exopolysaccharides that have immunomodulatory and antibacterial properties, which may potentially prevent HPA axis overactivity. 5-HT, 5-hydroxytryptamine or serotonin; BDNF, brain-derived neurotrophic factor; DA, dopamine; BZA, benzoic acids; dgk, diacylglycerol kinase; ECs, enterochromaffin cells; EPS, exopolysaccharide; GABA, gamma-Aminobutyric acid; GLP-1, glucagon-like peptide-1; Glu, glutamate or glutaminergic; H₂O₂, hydrogen peroxide; HPA, hypothalamic-pituitary-adrenal; IECs, intestinal epithelial cells; IDO, indoleamine 2,3-dioxygenase; IL-6, interleukin-6; KYN, kynurenine; NE, norepinephrine; LPS, lipopolysaccharides; Tph1, tryptophan hydroxylase 1; TRP, tryptophan.