Major Depressive Disorder and Gut Microbiota: Role of Physical Exercise

Abstract

Major depressive disorder (MDD) has a high prevalence and is a major contributor to the global burden of disease. This psychiatric disorder results from a complex interaction between environmental and genetic factors. In recent years, the role of the gut microbiota in brain health has received particular attention, and compelling evidence has shown that patients suffering from depression have gut dysbiosis. Several studies have reported that gut dysbiosis-induced inflammation may cause and/or contribute to the development of depression through dysregulation of the gut-brain axis. Indeed, as a consequence of gut dysbiosis, neuroinflammatory alterations caused by microglial activation together with impairments in neuroplasticity may contribute to the development of depressive symptoms. The modulation of the gut microbiota has been recognized as a potential therapeutic strategy for the management of MMD. In this regard, physical exercise has been shown to positively change microbiota composition and diversity, and this can underlie, at least in part, its antidepressant effects. Given this, the present review will explore the relationship between physical exercise, gut microbiota and depression, with an emphasis on the potential of physical exercise as a non-invasive strategy for modulating the gut microbiota and, through this, regulating the gut-brain axis and alleviating MDD-related symptoms.

Keywords: gut microbiota; major depressive disorder; physical exercise.

Figure 1

Possible inflammatory mechanisms thought to mediate neuroinflammation in MDD. Systemic inflammation, gut dysbiosis and an imbalance in the HPA axis can lead to an increase in circulating pro-inflammatory cytokines, which consequently may lead to the disruption of the blood–brain barrier. These pro-inflammatory cytokines can reach the CNS, where they can activate various mechanisms that culminate in neuroinflammation. Gut dysbiosis may be one of the factors contributing to the increase in circulating LPS. This endotoxin can reach the brain, where it may activate TLR-4 microglial receptors, promoting the transcription of pro-inflammatory mediators, as well as the activation of the NLRP3 inflammasome, which culminates in the production of IL-1 β and IL-18. A pro-inflammatory state in the CNS causes the KYN pathway to be directed towards the production of QUIN, an excitotoxic NMDAR agonist metabolite, instead of the production of KYNA, a neuroprotective NMDAR antagonist metabolite. Abbreviations: ACTH: adrenocorticotropic hormone; BBB: blood–brain barrier; CNS: central nervous system; CRH: corticotrophin-releasing hormone; HPA: hypothalamic–pituitary–adrenal; IL-18: interleukin 18; IL-1β: interleukin 1 beta; KYN: kynurenine; KYNA: kynurenic acid; LPS: lipopolysaccharide; MDD: major depressive disorder; NF-kB: nuclear factor kappa B; NLRP3: NOD-like receptor pyrin domain-containing-3; NMDAR: N-methyl-D-aspartate receptor; QUIN: quinolinic acid; TLR-4: toll-like receptor 4.

Figure 2

Signaling pathways through which physical exercise and skeletal muscle metabolites impact the brain. Irisin and cathepsin B are capable of increasing BDNF synthesis in the CNS. BDNF interacts with the TrkB receptor and triggers the activation of different downstream pathways, including the PLCγ/IP3/Ca²⁺/CaMKII/CREB, PLCγ/DAG/PKC/ERK/CREB and PLCγ/PI3K/Akt/mTOR pathways, leading to pro-neurogenic effects. Physical exercise can also increase other growth factors, including IGF-1 and VEGF, which further contribute to neurogenesis. Lactate can reach the brain through MCT and increase SIRT1 activity, which in turn induces the FNDC5/irisin pathway, further increasing BDNF gene expression. In addition, lactate activates the GPR81/HCAR1 receptor, which stimulates the expression of synaptic-plasticity-related genes, such as Arc, c-Fos and Zif268, through a mechanism involving NMDA receptor activity and its downstream signaling cascade ERK1/2. The activation of GPR81 by lactate also inhibits the NLRP3 inflammasome complex by activating β-Arrestin 2. Finally, physical exercise has a hormetic effect leading to the activation of cellular protective systems, such as the transcription factor Nrf2, resulting in the expression of antioxidant proteins. Abbreviations: 4EBP: initiation factor 4E-binding protein; Akt: protein kinase B; Arc: cytoskeleton associated protein; ARE: antioxidant response elements; ATP: adenosine triphosphate; BDNF: brain-derived neurotrophic factor; Ca²⁺: calcium; CaMKII: calcium/calmodulin-dependent protein kinase II; cAMP: cyclic adenosine monophosphate; c-Fos: fos proto-oncogene, AP-1 transcription factor subunit; CREB: cAMP response element-binding protein; P-CREB: phosphor-CREB; DAG: diacylglycerol; ERK 1/2: extracellular-signal-regulated kinase 1/2; Fndc5: fibronectin type III domain-containing 5; GPR81/HCAR1: G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1; IGF-1: insulin-like growth factor-1; IGF-1R: insulin-like growth factor-1 receptor; IP3: inositol trisphosphate 3; Keap1: Kelch-like ECH-associated protein 1; LDH1: lactate dehydrogenase 1; MCT: monocarboxylate transporter; mTOR: mechanistic target of rapamycin; NAD⁺: nicotinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide reduced; Nrf2: nuclear factor erythroid-derived related factor-2; NLRP3: NOD-like receptor pyrin domain-containing-3; NMDAR: N-methyl D-aspartate receptor; p70S6K: 70-kDa ribosomal protein S6 kinase; PGC-1α: proliferator-activated receptoFndc5r gamma coactivator-1α; PI3K: phosphatidylinositol-3-kinase; PIP2: phosphatidylinositol 4,5-bisphosphate; PKA: protein kinase A; PKC: protein kinase C; PLC: phospholipase C; Shc: Src-homologous and collagen-like protein; Sirt-1: sirtuin 1; TrkB: tropomyosin receptor kinase-B; VEGF: vascular endothelial growth factor; Zif268: zinc-finger-containing transcription factor 268; ?: receptor not characterized.

Figure 3

Possible mechanisms underlying the role of physical exercise in the management of MDD. Physical exercise can modulate the gut microbiota by increasing the production of SCFAs, especially butyrate. SCFAs interact with GPRs, which are involved in the production and secretion of GLP-1 and PYY, the stimulation of anti-inflammatory pathways and the inhibition of NLRP3. In particular, butyrate activates GPR109A, which not only inhibits the NLRP3 inflammasome and pro-inflammatory pathways but also inhibits HDACs that regulate gene expression, contributing to the strength and function of the intestinal barrier and to gut homeostasis. The gut microbiota also produces lactate, which can be converted into different SCFAs by several bacterial species. In the muscle, SCFAs are involved in signaling pathways that culminate in protein synthesis, mitochondrial biogenesis, the production of anti-inflammatory cytokines and the regulation of Trp metabolism, increasing the expression of KAT, which increases KYNA production. KYNA is able to protect intestinal mucosa and exerts neuroprotective effects. Modulation of physical exercise in muscle and gut metabolism can affect the brain by inhibiting neuroinflammation, enhancing the production of growth factors and stimulating neurogenesis and synaptogenesis, thus contributing to the antidepressant effects of physical exercise. Abbreviations: AdipoR1: adiponectin receptor 1; Akt: protein kinase B; AMP: adenosine monophosphate; AMPK: adenosine monophosphate-dependent kinase; ATP: adenosine triphosphate; BDNF: brain-derived neurotrophic factor; Ca²⁺: calcium; eCBs: endocannabinoids; EVs: extracellular vesicles; FNDC5: fibronectin type III domain-containing 5; GDNF: glial cell line-derived neurotrophic factor; GLP-1: glucagon-like peptide 1; GPR43/41/81;109A: G-protein-coupled receptor 41/43/81;109A; HDAC: histone deacetylase; IDO: indoleamine 2,3-dioxygenase; IGF-1: insulin-like growth factor-1; KAT: kynurenine aminotransferase; KYN: kynurenine; KYNA: kynurenic acid; mTOR: mechanistic target of rapamycin; NF-kB: nuclear factor kappa B; NGF: nerve growth factor; NLRP3: NOD-like receptor pyrin domain-containing-3; p38MAPK: p38 mitogen-activated protein kinase; pAMPK: phosphorylated AMPK; PGC-1α: proliferator-activated receptoFndc5r gamma coactivator-1α; PI3K: phosphatidylinositol-3-kinase; PYY: peptide YY; SCFAs: short-chain fatty acids; TNF-α: tumor necrosis factor α; Trp: tryptophan; VEGF: vascular endothelial growth factor.