Medicinal Plants and Their Impact on the Gut Microbiome in Mental Health: A Systematic Review

Abstract

Background: Various neurocognitive and mental health-related conditions have been associated with the gut microbiome, implicating a microbiome-gut-brain axis (MGBA). The aim of this systematic review was to identify, categorize, and review clinical evidence supporting medicinal plants for the treatment of mental disorders and studies on their interactions with the gut microbiota.

Methods: This review included medicinal plants for which clinical studies on depression, sleeping disorders, anxiety, or cognitive dysfunction as well as scientific evidence of interaction with the gut microbiome were available. The studies were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Results: Eighty-five studies met the inclusion criteria and covered thirty mental health-related medicinal plants with data on interaction with the gut microbiome.

Conclusion: Only a few studies have been specifically designed to assess how herbal preparations affect MGBA-related targets or pathways. However, many studies provide hints of a possible interaction with the MGBA, such as an increased abundance of health-beneficial microorganisms, anti-inflammatory effects, or MGBA-related pathway effects by gut microbial metabolites. Data for Panax ginseng, Schisandra chinensis, and Salvia rosmarinus indicate that the interaction of their constituents with the gut microbiota could mediate mental health benefits. Studies specifically assessing the effects on MGBA-related pathways are still required for most medicinal plants.

Keywords: anxiety; cognitive impairment; depression; gastrointestinal; gut bacteria; gut microbiome; gut microbiota; insomnia; medicinal plant; mental health; microbiome–gut–brain axis; phyto-psychobiotics.

Figure 1

(a) Potential pathways involved in the communication between the gut microbiome and brain (microbiota–gut–brain axis, MGBA). (b) Alterations in gut microbiome (dysbiosis) and MGBA communication in neurodegenerative disorders. Gut microbiome–brain communication occurs mainly via three pathways: (1) neural (vagus and enteric nervous system, neurotransmitters, blue letters), (2) immune (cytokine balance and functional microglia, pink letters), and (3) humoral/metabolic (gut hormones, short-chain fatty acids (SCFAs), and neuropeptides, green letters). Neural communication is established via the vagus nerve and the hypothalamic–pituitary–adrenal (HPA) axis and systemic communication via the immune and humoral/metabolic pathways. In neurodegenerative disorders, the composition and activity of the normal gut microbiome are altered, leading to abnormal microbial metabolite profiles such as altered levels of neurotransmitters and SCFAs. The result is disruption of the neural, immune, and humoral/metabolic pathways and increased risk for disease progression [12,17,19]. The red arrows indicate alterations during dysbiosis ( activation/upregulation, inhibition/downregulation). EC: enterochromaffin cell; EEC: enteroendocrine cell; SCFA: short-chain fatty acid; HPA: hypothalamus–pituitary–adrenal; TNF-α: tumor necrosis factor-α; INF-γ: interferon gamma; IL-6: interleukin-6; IL-1: interleukin-1; GABA: gamma-amino butyric acid. ⊕: stimulates/promotes.

Figure 2

Flowchart of the selection strategy and method (PRISMA statement). * Search terms were as follows: ((medicinal plant *) AND ((antidepressant) OR (mental stress) OR (mood disorder *) OR (insomnia) OR (sleep) OR (anxiety) OR (cognitive impairment *) OR (circadian clock) OR (circadian rhythm) OR (dementia) OR (memory) OR (adaptogen *) OR (focus and attention) OR (fatigue)) NOT ((Alzheimer’s disease *) NOT (Parkinson’s disease *)). ^# Search terms were as follows: (plant name OR plant name OR ……) AND (clinical study) AND ((anxiety) OR (insomnia) OR (antidepressant) OR (cognitive impairment *) OR (fatigue) OR (memory)). ^§ Search terms were as follows: (plant name OR plant name OR ……) AND ((gut microbiome) OR (gut microbiota) OR (gut bacteria)). ^& Search terms were as follows: “plant name” AND (“gut microbiome” OR “gut microbiota” OR “gut bacteria” OR “intestinal flora”).

Figure 3

Potential gut–brain communication pathways modulated by triterpenes in mental disorders. Triterpenes (such as ginsenosides) can alter gut–brain microbiome communication in impaired brain function and promote a healthy mental state. These beneficial effects are related to rebalancing the gut microbiome and influencing neural (blue letters), immune (pink letters), and humoral/metabolic (green letters) pathways. Triterpene glycosides are metabolized by the gut microbiome into active components (e.g., ginsenosides into compound K). These active metabolites are more bioavailable than the native compounds. Ginsenosides and their metabolites promote neurotrophic factors and reduce pro-inflammatory mediators and stress levels [207,209,210,211]. The major gut–brain mechanisms by which ginsenosides have a beneficial effect are marked with red arrows ( activation/upregulation, inhibition/downregulation). TJPs: tight junction proteins; BDNF: brain-derived neurotrophic factor; PI3K: phosphoinositol 3 phosphate; AKT: protein kinase B; IL-1β: interleukin-1β; NF-κB: nuclear factor-κB; PYY: peptide YY; GLP1: glucagon-like peptide 1; ⊕: stimulates/promotes.

Figure 4

Potential microbiome–gut–brain communication pathways modulated by polyphenols in mental disorders. Gut microorganisms metabolize polyphenols to potentially active metabolites. Polyphenols and their metabolites support the rebalancing of the altered gut microbiome during dysbiosis, and the metabolites can cross the intestinal epithelium and reach the systemic circulation and brain. These molecules may modulate gut–brain communication via neural (blue letters), immune (pink letters), and humoral/metabolic (green letters) pathways. Polyphenols and their metabolites can modulate vagus nerve communication, the HPA axis, pro-inflammatory mediators, neurotrophic factors, and serotonin levels, positively influencing brain functions. Polyphenols have antioxidant effects and can reduce ROS levels in brain disorders [27,220,250], and they can also stimulate gut microbiome production of SCFAs [251]. Furthermore, polyphenols and their metabolites may have local brain effects such as improved cerebrovascular blood flow and a reduction in neuroinflammation [252]. The major gut–brain mechanisms by which polyphenols may exert beneficial effects are indicated with red arrows ( activation/upregulation, inhibition/downregulation). BBB: blood–brain barrier; IDO: indolamine 2,3 dioxygenase; TDO: tryptophan 2,3-dioxygenase; QA: quinolinic acid; PPARγ: peroxisome proliferator-activated receptor gamma; AMPK: 5′AMP-activated protein kinase; ROS: reactive oxygen species; TOR: target of rapamycin; ⊕: stimulates/promotes.

Figure 5

Potential microbiome–gut–brain communication pathways modulated by plant-derived polysaccharides in mental disorders. Gut microorganisms metabolize polysaccharides that resist digestion in the upper gastrointestinal tract into SCFAs. SCFAs modulate gut–brain communication via neural (blue letters), immune (pink letters), and humoral/metabolic (green letters) pathways. SCFAs may reduce cortisol levels, inflammatory mediators, and microglial activation, have a beneficial effect on serotonin synthesis, neurotrophic factors, and various gut neuropeptides, and restore tight junctions in the leaky intestinal epithelium by increasing the expression of tight junction proteins (TJPs). In addition, SCFAs exert local beneficial actions that improve gut health (e.g., maintaining mucus production, anti-inflammatory effects) [37,253,254,255,256]. The major gut–brain mechanisms by which SCFA/active polysaccharide metabolites offer benefit are marked with red arrows ( activation/upregulation, inhibition/downregulation). HDAC: histone deacetylases; GDNF: glial cell-derived neurotrophic factor; NGF: nerve growth factor. ⊕: stimulates/promotes.