Table 1.

Summarized results reviewed in this work.

Microbial Metabolite	Microorganisms Implicated	Microbiota-Gut-Brain Axis	Status In MDD	Translational Approaches	References
Short-chain fatty acids (SCFAs)	Eubacterium rectale, Roseburia faecis, Eubacterium hallii, and Faecalibacterium prausnitziiappears to be the major producers of butyrate in the gut. Veilonella spp., Lactobacillus spp., Bacteroides spp., and Propionibacterium spp. are some of the most representative bacteria involved in propionate production. Conversely, acetate production is commonly spread among numerous bacterial classes	SCFAs are shown to be a central mechanism of gut-brain communication. They can cross the BBB activating several mechanisms in the brain, modulating the levels of neurotrophic factors, neurotransmitters, neurogenesis, and reducing neuroinflammation and glial dysfunction. SCFAs interact with enteroendocrine cells and promote indirect signaling to the brain by inducing the production of several hormones and neurotransmitters like GABA and serotonin in the gut. There is a positive association between Allobaculum, acetate, and serotonin levels.	Acetate, propionate, butyrate: Downregulated Isovalerate: Upregulated Reduced levels of butyrate producers like Faecalibacterium and Coprococcus spp. are correlated with MDD severity. Fecal measures of SCFAs also found a significant association between acetate, propionate, and butyrate levels with both depressive and gastrointestinal symptoms in young adults, therefore supporting that SCFAs are importantly related to the development of MDD. A significant reduction of fecal SCFAs between depressed and non-depressed women was also proposed to be a potential contributor of suffering from MDD with a possible inverse association with depression severity. Depressed patients show a prominent epigenetic footprint in comparison to non-depressed subjects, including critical alterations in DNA methylation, histone modifications, and non-coding RNAs (i.e., microRNAs). SCFAs act as histone deacetylases (HDAC) inhibitors altering gene expression. Propionate production is associated with a decreased anticipatory response of the reward system, related to the monoamine dopamine. Altered dopaminergic neurotransmission is a major feature underpinning MDD, which is related to anhedonia.	SCFA-mediated inhibition of HDAC may lead to the hyperacetylation of histones H3/H4 and hence increase BDNF expression, showing antidepressant effects in mice. This epigenetic modulation is mostly responsible for the immunomodulatory action of SCFAs. In the CNS, SCFAs are major mediators of microglial maturation and function whereas, in the gut, SCFAs induce the differentiation of Treg cells. Overall, the epigenetic and immunomodulatory effects of acetate, and more prominently propionate and butyrate exert promising antidepressant effects, as they are mostly correlated with favorable microbial populations. Prior studies have proven the anti-depressants effect of butyrate by reversing behavioral alterations in mouse models like anhedonia, low energy, cognitive and social abilities. Similarly, the use of rifaximin was related to a decreased depressive-like behavior due to its favorable effects on Ruminococcaceae and Lachnospiraceae, which positively correlated with butyrate production. Conversely, another type of SCFA, isovaleric acid has been shown to be correlated with certain bacterial populations related to MDD and augmented cortisol levels. A proposed mechanism of this pro-depressive effect of isovaleric acid is through interfering with synaptic neurotransmitter release.	[68,69,70,76,77,78,79]
Lactate	Lactic acid bacteria, bifidobacteria, or proteobacteria.	Lactate can cross the BBB to match the energetic needs of the brain, influencing many neuronal functions such as excitability, plasticity, and memory consolidation.	The role of lactate in the etiopathogenesis of MDD is poorly understood. However, a plausible explanation is an accumulation of lactate in the brain due to an impaired mitochondrial function -a major feature of different psychiatric diseases-. In MDD, there is increased ventricular lactate. Patients with severe depression show a significant detection of lactate in the urine in comparison to moderate and non-depressed subjects.	Peripheral administration of lactate reverts the effects of stress and exerts antidepressant effects, supporting hippocampal neurogenesis related to changes in serotonin receptor trafficking. Physical exercise may be a powerful link between lactate and antidepressant effects influencing not only the muscle production of lactate but also the MGB axis.	[97,98,99,100,101,102,103,104,105,106,107]
Tryptophan (Trp) metabolites	Some bacterial communities may synthesize Trp like Escherichia coli. 5 phyla are involved in Trp metabolism: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Fusobacteria, with a central role of Clostridium, Burkholderia, Streptomyces, Pseudomonas, and Bacillus genera	Trp is importantly implicated in the synthesis of serotonin and other critical metabolites, including those belonging to the kynurenine pathway; tryptamine; indole, and derivates. All these components exert signaling actions in the brain, involved in its proper functioning.	Serotonin synthesis from Trp is impaired An altered kynurenine pathway is reported in patients with MDD, with an upregulation of the enzyme indoleamine 2 3-dioxygenase (IDO) and neurotoxic components like 3-hydroxykynurenine and quinolinic acid along with a reduction of neuroprotective members like kynurenine and kynurenic acid Increased tryptamine levels and indole metabolism	Probiotic bacteria (Bifidobacterium longum subsp. infantis E41 and Bifidobacterium breve M2CF22M7) were associated with an increased 5-hydroxytryptophan, tph1, serotonin, and BDNF in the brain. Current clinical trials are evaluating the efficacy of different probiotic strains with prebiotics and antidepressants in the Trp metabolism, kynurenine pathway, and other pathophysiological mechanisms involved in MDD. Anthocyanins, a group of polyphenols used as nutraceutical appears to modulate host Trp metabolism increasing neuroprotective kynurenic acid Ensuring an adequate nutritional and dietary context is crucial to prevent gut dysbiosis and Trp metabolism, although the evidence has failed to find benefits from increasing dietary Trp or through supplementation	[30,112,113,114,115,116,117,119,120,121,125,126,127,128,129,261]
Amino acids	Many bacterial groups are involved in the synthesis and metabolism of several amino acids including glutamate, phenylalanine, tyrosine, threonine, isoleucine, alanine, serine, and oxidized proline	Glutamate is an important neurotransmitter as well as GABA, which is synthesized from glutamate by different microbial communities, especially lactic acid bacteria. Phenylalanine is involved in the synthesis of the catecholamines epinephrine, norepinephrine, and dopamine	Glutamate, GABA, and catecholamines functioning in the brain is impaired in patients with MDD Chronic unpredictable mild stress rats, as well as specific pathogen-free (SPF) and germ-free (GF), have unraveled that gut microbiota is critical for serum levels of plenty amino acid, as well as the concentration of different amino acids in the host brain regions Reduced levels of phenylalanine, aspartate, glutamate, and serine are found in patients with MDD and heart failure	SCFAs from vinegar (acetic acid) is associated with an improved amino acid metabolism (Increased levels of glycine, serine, and threonine) in healthy subjects Creatine supplementation (Nutraceutical) may be related to an improved amino acid metabolism Little and controversial evidence is available regarding the benefits from the administration of some amino acids like phenylalanine and tyrosine Targeting gut microbiota and gut dysbiosis through lifestyle interventions seems to be the most adequate strategy to influence amino acid levels and metabolism	[131,132,133,134,136,137,138,139,140,141,143,144,145,247,251]
Secondary bile acids (BAs)	Clostridium, Enterococcus, Bifidobacterium, Lactobacillus, Bacteroides genera, as well as E. coli, C. testosteroni, and Ruminococcus spp. Archaea like Methanobrevibacter smithii and Methanosphera stadmanae	BAs exert important signaling actions in the brain through Farnesoid-X-Receptor (FXR) and the G-Protein-Coupled Bile Acid receptor-1 (GPBAR-1). BAs may act directly by crossing the blood–brain barrier or indirectly, activating FXR and GPBAR-1 receptors in the gut, leading to the production of fibroblast growth factor 19 (FGF19) and glucagon-like peptide 1 (GLP-1), signaling to the brain	In neuropsychiatric disorders, the most prominent signaling route of BA is through the FXR. In the hippocampus, an increased FXR expression seems to cause depression-like symptoms and reduced BDNF levels in rats The use of some antidepressants such as paroxetine alter gut microbiota and BA production in mice	The activation of GPBAR-1 by the secondary bile acid tauroursodeoxycholic acid (TUDCA) as well as the activation of other receptors in the brain of BA like vitamin D receptor (VDR) and pregnane X receptor (PXR) activated by lithocholic acid (LCA) appears to present antidepressant effects Higher consumption of animal products and fats is associated with increased BA production, which is in turn inversely correlated with dietary fiber intake. Ensuring an adequate fiber intake, polyphenols, and high-quality fats while limiting overconsumption of red and processed meats, low-quality fats intake, or ultra-processed foods will benefit BA metabolism and actions in the brain	[30,149,150,152,153,157,158,159,160,277]
Vitamins	B1 producers are Bacteroides fragilis and Prevotella copri (phylum Bacteroidetes); Clostridium difficile, some Lactobacillus spp., and Ruminococcus lactaris (Firmicutes); Bifidobacterium spp. (Actinobacteria); and Fusobacterium varium. Bacteroides fragilis and Prevotella copri (Bacteroidetes); Clostridium difficile, Lactobacillus plantarum, L. fermentum, and Ruminococcus lactaris (Firmicutes) can synthesize B2 vitamin. Bacteroides fragilis and Prevotella copri (Bacteroidetes); Ruminococcus lactaris, Clostridium difficile (Firmicutes); Bifidobacterium infantis (Actinobacteria); Helicobacter pylori (Proteobacteria); and Fusobacterium varium (Fusobacteria) can produce B3 vitamin. B3 can be synthesized from Trp as well. Bacteroides fragilis and Prevotella copri (Bacteroidetes); some Ruminococcus spp. (R. lactaris and R. torques) (Firmicutes); Salmonella enterica and Helicobacter pylori (Proteobacteria) synthesize B5. B6 producers are Bacteroides fragilis and Prevotella copri (Bacteroidetes), Bifidobacterium longum and, Collinsella aerofaciens (Actinobacteria), and Helicobacter pylori (Proteobacteria). B7 producers are Bacteroides fragilis and Prevotella copri (Bacteroidetes); Fusobacterium varium (Fusobacteria) and Campylobacter coli (Proteobacteria) Folate or B9 is produced by Bacteroides fragilis and Prevotella copri (Bacteroidetes); Clostridium difficile, Lactobacillus plantarum, L. reuteri, L. delbrueckii ssp. bulgaricus, and Streptococcus thermophilus (Firmicutes), some species in Bifidobacterium spp. (Actinobacteria); Fusobacterium varium (Fusobacteria) and Salmonella enterica (Proteobacteria). Finally, B12 is produced by Bacteroides fragilis and Prevotella copri (Bacteroidetes); Clostridium difficile, Faecalibacterium prausnitzii and Ruminococcus lactaris (Firmicutes); Bifidobacterium animalis, B.infantis, and B.longum (Actinobacteria); Fusobacterium varium (Fusobacteria). Lactobacillus plantarum and L. coryniformis from fermented food also produce B12.	Gut dysbiosis impairs the synthesis of these vitamins which are crucial for the proper functioning of the brain.	Patients with MDD show deficiencies of vitamins, especially D and those from B complex. Low levels of vitamin B1 (thiamine), B2 (riboflavin) B3 (niacin), B6 (pyridoxine) B7/8 (biotin), B9 (folate), and B12 (cyanocobalamin) are pivotal B vitamins associated with MDD.	Besides vitamin D supplementation improves gut microbiota in MDD, several studies are confirming the benefits from using certain B vitamins in combination with probiotics, frequently represented by different species and strains of Bifidobacterium and Lactobacillus. In some studies, in comparison to the groups that only received vitamin B7 plus placebo or probiotics plus placebo, patients supplemented with both probiotics and vitamin showed an increased synthesis of vitamin B6 and B7 and improved clinical outcomes. Gut microbiota is crucial for determining the body levels of B vitamins, but an adequate dietary context is needed to obtain the benefits from those bacteria involved in vitamin synthesis, with noteworthy positive outcomes for the brain.	[164,165,166,167,168,169,301]
Choline-derived metabolites	Firmicutes phyla (Clostridium cluster XIVa and Eubacterium strains), Actinobacteria, and Proteobacteria	Choline may be transformed into plenty of metabolites like trimethylamine (TMA), betaine, phosphocholine, and acetylcholine (neurotransmitter). The gut microbiota status and the TMA production and its metabolic product derived, trimethylamine N-oxide (TMAO) are crucial biomarkers of choline metabolism and predictors of the beneficial or detrimental effects in the brain	An increased TMA and TMAO levels related to gut dysbiosis are directly correlated depressive symptoms severity in females and males Elevated levels of choline-consuming bacteria are related to an aberrant global DNA methylation pattern in mice and abnormal behavior in mice	Similar to BA, some animal products and fatty foods may contain high levels of choline and then, it may raise TMA/TMAO levels. However, if maintaining a eubiotic environment with an adequate dietary fiber intake, polyphenols, vitamins, high-quality fats while limiting overconsumption of red and processed meats, low-quality fats, excessive salt, additives, or ultra-processed foods TMA levels will not have any detrimental effect. Conversely, the variety of components included in a proper dietary pattern like those included in the Mediterranean diet will benefit the host health and aid to ameliorate depressive symptoms.	[30,170,171,176,177,179,180,181,182,183]
Estrobolome	This term refers to a set of bacteria that are able of metabolizing and modulate the estrogen levels in the body. The gut microbiota is a major determinant of the circulating levels of estrogens through different mechanisms. In men and postmenopausal women, gut microbiota diversity and functions influence the levels of non-ovarian estrogens via enterohepatic circulation, where Clostridia taxa and genera from the Ruminococcaceae family could be key microbial populations involved in this regulation.	Gut microbiota may influence estrogen metabolism and signal in the brain. There are some neuroprotective effects of estrogens mediating some neuroplastic actions in the hippocampus and regulating serotonin receptors levels.	Gut dysbiosis may significantly impair the action of gut microbiota in the estrogen metabolism, driving to the reduction of circulating estrogens, which is associated with a plethora of adverse outcomes ranging from obesity, metabolic syndrome, malignancies, endometrial hyperplasia, endometriosis, polycystic ovary syndrome, fertility, cardiovascular disease, and cognitive dysfunction. The evidence supporting the role of altered sexual hormones in the pathogenesis of MDD in women could be found in the existence of three different types of depression related to the menstrual cycle: Premenstrual dysphoric disorder (PMDD), postpartum depression, and perimenopausal depression. The use of estradiol, but not progesterone appears to be effective for PMDD, postpartum, and moderate/severe perimenopausal depression.	Despite neuroprotective effects, the use of estradiol as the first line-treatment is not supported by current scientific evidence Instead, targeting the estrobolome in the prevention and treatment of these specific disorders could be an effective interesting approach, as women may benefit from the actions of these bacteria. Some studies have reported that lower levels of testosterone but estrogen were associated with more severe depressive symptoms in a group of women with MDD. Other reports allege that gut microbiota transplantation of male to female mice led to an augmentation of testosterone levels so future studies may consider the benefits from using testosterone-producer microorganisms to raise testosterone levels. As gut microbial diversity is directly related to the levels of non-ovaric estrogen levels and the intake of certain dietary components like polyphenols may aid in the modulation of beneficial microbial communities and ER activation, nutritional and lifestyle interventions may be a potential strategy for boosting the estrobolome.	[184,188,189,190,191,192,193,194,195]