Microbiota–gut–brain axis mechanisms in the complex network of bipolar disorders: potential clinical implications and translational opportunities

The intestinal barrier constitutes the interface between the gut lumen and blood torrent, being crucial for the preservation of homeostasis. The gut harbors its own immune system, which is called intestine and gut-associated lymphoid tissue (GALT), key for whole body immune function. In physiological conditions, GALT should allow a tolerance of commensal bacteria and dietary antigens and act as a primary line of defense against luminal antigens and harmful substances in the host [88].

Intestinal barrier has varying degrees of permeability throughout the gastrointestinal tract. Zonulin modulates intercellular tight junctions and increases intestinal permeability in jejunum and ileum [89]. The increment of serum zonulin levels may be related to higher susceptibility for depression induced by stimuli [90], and zonulin and claudin-5 have seen increased in patients with BD [91]. Evidence has even found that levels of claudin-5 are associated with an earlier onset of BD, while reduced levels of this protein is associated with an extended duration of BD [92]. Prior studies suggest that there is an association between stress from early adverse life events and the development of irritable bowel syndrome (IBS), a functional disorder associated with a higher intestinal permeability [93, 94]. Increases in intestinal permeability have also been associated with autoimmunity diseases, inflammatory bowel disease (IBD) or celiac disease [95, 96]. Similarly, emerging evidence indicates that patients with mental disorders seem to present alterations of the gut microbiota and increased intestinal permeability [97, 98]. Specifically, IBS [99], celiac disease [100] and IBD [101, 102] have been associated with an increment in the risk of developing BD. In fact, both incidence and prevalence of psychiatric disorders (including BD) are higher in IBD patients [103].

Gut microbiota can influence enterocyte junctions and therefore intestinal permeability [104]. When symbiotic relationship between gut microbiota and host is interrupted, dysbiosis leads to dysfunctions in mucosal barrier function, translocation of commensal microbes and chronic proinflammatory states [105, 106]. This disruption may have consequences CNS and immune response, potentially resulting in systemic disease [59, 107]. But, what is more; rising evidence supports that MGB axis establishes a bidirectional connection, so that central injury not only disrupts CNS, but also causes a gastrointestinal injury [108]. Furthermore, it has been well described that depression and other psychiatric disorders in which stress plays a key role, show alterations in gut microbiota, what consequently underpins translocation of bacterial products and triggers HPA axis activation [109]. Indeed, in BD bacterial translocation signs can be found. For instance, anti-Saccharomyces cerevisiae antibodies are higher in BD patients than in healthy controls, although these antibodies did not show to have an association with symptom severity or pharmacological treatment [110]. Candida albicans exposure has been associated with BD, especially in males and patients with somatic conditions [111].

An analyzable marker of bacterial translocation is the soluble cluster of differentiation (CD)-14; its levels are higher in BD patients compared with healthy individuals [112]. An association between soluble CD14 and anti-tissue transglutaminase IgG has also been described [112]. BD patients have increased levels of IgG antibodies to gliadin, especially during mania, compared to controls [113]. Further to this, the persistence of elevated antibodies to gliadin in patients with mania showed an association with rehospitalization rates in a 6-month follow-up [113]. Hence, bacterial translocation might be related to the clinical switch observed in these patients, although further studies are required in this field.

Moreover, microbial components can affect the intestinal barrier through diverse mechanisms. For instance, LPS is an endotoxin located in the outer membranes of numerous Gram-negative bacteria. This normally does not penetrate paracellular junctions because of its size, so that systems such as lipid rafts or clathrin-dependent mechanisms are necessary for LPS to penetrate into the cell [114]. Independently, when intestinal barrier is compromised, there is an increase in endotoxin in the blood torrent [114]. When LPS penetrates, the endotoxemia stimulates innate immune response, triggering systemic inflammation and aggravating neuroinflammation [115]. In this way, LPS levels can be used as a marker of bacterial translocation, presumably indicating that there is a weakened intestinal barrier, which is related to chronic systemic inflammation and insulin resistance [116, 117].

On the contrary, there are certain microbial products that modulate positively intestinal barrier function, besides, stimulating regulatory T CD4 cells (Tregs) and preserving intestinal epithelial lymphocytes [118]. These metabolites are short-chain fatty acids (SCFAs) among others and seem to be altered in BD as will be later discussed.

Cytokines and chemokines are crucial for intercellular communication and contribute to maintain intestinal homeostasis through inflammatory mechanisms, but when these are constantly elevated, epithelial barrier integrity results compromised [119]. Proinflammatory cytokines such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-1β or IL-18 induce the endocytosis of epithelial apical junctional proteins [120], promoting an increment in intestinal permeability [121]. IL-1β is a key player in inducing intestinal inflammation; it increases epithelial tight junctions permeability, disrupting this barrier thorough the canonical NF-κB pathway [122]. Also, IL-18 can damage intestinal barrier, as it has been involved in tight junction modulation, mucosal apoptosis [123] and in inhibiting goblet cell maturation [124].

Altered levels in some of these cytokines have been observed in patients with BD, although more studies are needed in order to establish this relationship with intestinal permeability. Meanwhile, studies with varying results can be found in literature. Concretely, in a study with rapid cycling BD patients, IL-6 and IL-18 have been suggested as markers of manic episodes, due to significant levels in manic/hypomanic stages; however, IL-1 β was almost undetectable in plasma samples [125]. In another study, TNF-α, IL-6 and IL-18 were measured in serum from BD patients in manic, depressive and mixed state. The results concluded that TNF-α and IL-6 serum levels were significantly higher in manic, depressive and mixed-state patients compared with controls, but IL-18 was significantly higher only in depressive states. Nevertheless, it was alleged that confounding factors cannot confirm precisely the roles of these cytokines in the psychopathology of BD [126].

In general terms, systematic reviews of limited evidence affirm that it seems that TNF superfamily and proinflammatory cytokines contribute to the neuroprogression of the disease [127]. Moreover, what is known so far is that the abnormal immune response influence all stages of the disease, and potentially explains the elevated rates of comorbid inflammatory diseases found in these patients [128]. In fact, alterations can also be found in euthymia, when patients show to have greater levels of IL-8 in cerebrospinal fluid and monocyte chemoattractant proteins [129]. In patients with BD, stress-related neuroendocrine responses seem to be diminished while there is an increase in immune activation, related to incapability in reducing NF-κB and MAPK signaling [130].

Furthermore, during manic and depressive states, an elevated inflammatory signaling can be found; phospholipase A2 activity increases -liberating more arachidonic acid-, as well as levels of C-reactive protein, compliment and proinflammatory cytokines, compared to healthy individuals [131]. These alterations are attenuated in euthymia and with pharmacological treatment [131]. In relation to this, IL-6 in cerebrospinal fluid is significantly higher in patients with suicide attempts than in healthy controls, especially in violent attempts [132]. IL-13 levels have also been seen higher in euthymia and in mania [133]. Other findings also indicate that IL-6 and CRP levels are significantly higher in unipolar mania than in BD [134]. All these studies denote that BD is a group of complex mood disorders in which not only MGB axis is the central element. Evidence in recent years is demonstrating that elevated levels of peripheral proinflammatory signals are observed during all phases of BD, and that patients with autoimmune diseases present an increased risk of BD diagnosis.

Both innate and adaptive immunity play a prominent role in pathophysiology. Concretely, T helper-1 cells (Th1), which are IL-2, IL-6 and TNF-α producers, are hyperactivated in patients with BD; and also, a hyperactivation of Th2 has been associated with BD although more studies are required to elucidate clear links [135]. Also, some studies have exposed differences with MDD regarding immune cell populations. For instance, circulating levels of several subtypes of CD4+ Th cells, are higher in BD than in MDD including Th1, Th2, Th17 and Tregs [136]. However, there are contradictory results in other studies, as Treg populations are observed to decrease, but Th1 expansion is maintained as well as CD8+ cytotoxic T cell expansion [137]. All in all, intestinal integrity disruption and local and systemic inflammation go together with gut dysbiosis. The ecosystem harbored inside the intestine results damaged and, consequently, this increases inflammation (by bacterial components as described) and neuroinflammation, by neuroactive compounds (even from microbial metabolism) and other neuromodulatory mechanisms, as explained below.

Neuroinflammation consists of an inflammatory process within the brain or spinal cord, mediated by cytokines, chemokines, free radicals and other active ligands. Cytokines involvement in neurodegeneration has been discussed although it is not widely explained. A link between the elevated cytokines levels in CNS and in peripheral blood has been observed in postmortem studies of BD patients [138].

Low-grade systemic inflammation driven by several mediators previously debated, such as LPS, bacterial translocation and the increased proinflammatory cytokines and Th1 response, are all contributing to an immunological response in the brain [139]. A blood–brain barrier (BBB) dysfunction associated with BD is observed, also linked to gut microbiota, substance abuse and insulin resistance, all altering neuronal plasticity [140, 141]. BBB functions as a selective barrier that regulates the transport of molecules between blood and CNS, keeping necessities of nutrients and neurotransmitters in the brain. The dysregulation at this level enhances the activation of glial cells. Neuroinflammatory mediators are produced by these glial cells (microglia and astrocytes), besides endothelial and peripheral immune cells, all located in CNS [142]. Microglial hyperactivation induces damage to oligodendrocytes, affecting negatively myelination and neural circuits [143].

These disturbances would explain the findings in neuroimaging studies about white matter abnormalities in BD [144]. The inflammatory environment created by the release of cytokines by microglia in stressful situations seems to have a repercussion in behavioral phenotype in stress models, which is linked to neuropsychiatric disorders [145]. What is known so far is that cytokines-mediated neuroinflammation leads to dysregulations in the HPA axis, where the central regulator is cortisol releasing factor (CRF). Its hyperactivation produces an excess of cortisol, inducing depression-like behavior. This mechanism has been deeply studied in other psychiatric disorders like MDD [146]. As previously commented, this is consistent with the fact that so many patients with inflammatory-based diseases develop anxiety, MDD or BD [135]. Recent studies have found in BD a certain correlation between HPA axis dysfunction and the increased risk of relapses and cognitive impairments [47]. There is a growing body of evidence that suggest that dysfunctional microglia, oxidative damage, and mitochondrial dysfunction can play compelling roles in BD etiopathogenesis. Thus, an overactive neuroinflammatory response of astrocytes and microglia can contribute to BD development by alterations in immune response that leads to an increase in not only BBB integrity but also in intestinal permeability [147]. In fact, zonulin and claudin-5 have been proposed as biomarkers to detect BBB disruption [140] now that a diminished BBB integrity has been observed in patients with intestinal inflammation [148].

Although glucose is the principal energy fuel of the brain in normal conditions, lactate can be an alternative source during hypoglycemia and because of mitochondrial shifts in redox state or ischemia. Compared to healthy controls, higher levels of lactate from glycolysis in BD have been reported, which can relate to metabolic dysfunctions and a decrease in oxidative phosphorylation [149].

Abnormalities in mitochondria signaling lead to the production of free radicals like reactive oxygen species (ROS), which causes DNA damage, affecting neural plasticity and behavior [150]. ROS are produced in the brain mostly by microglia [32], and these products appear to be raised in patients with BD, which leads to oxidative and nitrosative damage. Indeed, dopamine, which is higher during mania, increases ROS, and it seems that, during mania and depression, there is a compensatory increase in antioxidant marker levels [151]. Furthermore, oxidative stress is associated with lower brain-derived neurotrophic factor (BDNF) levels [152]. This factor is crucial for the development, differentiation, plasticity, and survival of neurons, and it is decreased during mania and depression, but recovers at normal level in euthymic patients [32].

Particularly, numerous BD patients manifest HPA axis hyperactivity in whole circadian rhythm, especially during mania [47]. Childhood trauma has been demonstrated to have a crucial role in HPA axis alterations in BD patients [159]. These patients showed to have increased levels of cortisol as well as lower glucocorticoid receptor's function and alterations in glucocorticoid signaling. The hyperactivity of HPA axis is not the etiological factor that triggers BD, but undoubtable, it contributes to modify clinical presentations of BD and influence the genetic and environmental basic interaction in BD etiopathogenesis [47]. However, in patients with BD, neuropsychological performance is closely related to cortisol [160], and higher levels of this hormone have been related to poorer performance in some cognitive tasks [161, 162], especially working memory [163]. Moreover, abnormalities in this axis and in cortisol levels can be related to higher cardiovascular risk [164, 165], which may explain the increase in the mortality rate and in the cardiovascular risk factors prevalence observed in affective disorders, including BD [166].

Gut microbiota has bidirectional communication with HPA axis: certain microbial metabolites can attenuate it whereas translocated microbial antigens and exerted cytokines or prostaglandins productions activate it [95]. Moreover, dysbiosis status is associated with a constant increase in corticosterone synthesis in ileum, and, consequently, to glucocorticoid and insulin resistance, hyperglycemia and dyslipidemia [167]. This hypercortisolism is also associated with reduction in the immune response [97]. Then, HPA axis has an important impact on gut microbiota composition and neuroenteroendocrine functions, increasing gastrointestinal permeability, and contributing to the chronic low-grade inflammation [168]. Gut microbiota is not only a key player in regulating intestinal permeability, inflammation and neuroinflammation, but also in modulating behavior acting as an endocrine organ and modulating neural pathways through MGB axis as commented below.

As previously described, neurotransmitter dysregulation is a major pathophysiological signature of BD. Especially, GABA, glutamate, serotonin, dopamine, norepinephrine and acetylcholine appears to be importantly dysregulated in these patients [31, 170]. Gut microbiota is a central modulator of several neurotransmitters, being able to synthesize them and their precursors as well as promoting their degradation or metabolization to other products [171]. There are some species of bacteria grown in culture that can produce serotonin, although it seems that the most prominent role of gut microbiota in serotonin synthesis is achieved through the stimulation of enteroendocrine cells (EECs), especially by spore-forming bacteria [172]. The interplay between gut microbiota and EECs mostly occurs through different microbial metabolites, with a central role of SCFAs and tryptophan, as it will be later discussed.

Glutamate and GABA can be obtained from dietary sources or produced by the gut microbiota. Several bacteria are able of producing glutamate including Coryneform and lactic acid bacteria (LAB). Interestingly, glutamate also exert important modulatory effects on EECs, sending sensory signals to the vagus nerve [173] GABA is biosynthesized from glutamate due to the action of the enzyme glutamate decarboxylase, which is found in eukaryotic cells and in a broad spectrum of bacterial species [174]. However, LAB and more specifically certain Lactobacilli strains are the most important GABA producers in the gut [175]. In this sense, one study explored the possible role of Lactobacillus and Bifidobacterium in patients with BD. Interestingly, they show that notwithstanding the counts of Bifidobacterium or Lactobacillus were not significantly varied in patients with BD, it seems to exist a negative correlation between Lactobacillus and Bifidobacterium counts with sleep and cortisol levels respectively, being both important mechanisms in BD pathophysiology [77].

A broader number of bacteria have been reported to be able to produce other monoamines like dopamine and norepinephrine whereas only Lactobacillus plantarumseems to take part in the synthesis of acetylcholine [176, 177]. Despite the role of gut microbiota in the modulation of dopamine and norepinephrine remains to be fully understood, germ-free (GF) animal models have shown that there is a noteworthy alteration of these neurotransmitters in the gut as well as in the brain, which could have important consequences in the behavior [178].

Last but not least, nearly 117 types of bacteria have been identified as major histamine producers [179]. Apart from its well-known immunomodulatory role, histamine can act as a neurotransmitter in the brain, acting as a critical modulator of other neurotransmitters, and influencing arousal, motivation, and energy balance [180]. Neurons located in the posterior hypothalamus projects to all the major regions of the CNS, also participating in the regulation of sleep-wakefulness [181]. Likewise, the central histamine system in the brain is mediated via G-protein-coupled H1-H4 receptors and also appears to be involved in additional functions like arousal, control of pituitary hormone secretion, suppression of eating and cognitive functions [182]. Currently, there are some hypotheses supporting that patients with BD may have an altered histaminergic system, with upregulated histamine levels in manic phases and downregulated in depression, being their fluctuations closely related to other pathophysiological mechanisms [183]. An upregulated histamine production in the brain seems to drive to sleep-wake alterations in vivo, being associated with behavioral and metabolic disorders similar to those caused by voluntary sleep restriction in humans [184]. Conversely, animal models have also established that low levels of histamine-induced depression-like behavior, decreased locomotor activity in the home cage, and impaired aversive memory, leading to a decrease in wakefulness as well [185]. Hence, it is likely that the different alterations reported in the gut microbiota of patients with BD can be partially involved in the differential production of histamine and in turn this may be related to the described effects. Similarly, histamine production from gut microbiota appears to provide anti-inflammatory effects by suppressing TNF-α [186]. Thus, compelling evidence suggest the relevance of gut microbiota as pivotal player of brain function, influencing in the levels of several neurotransmitters and neuromodulators [187].

SCFAs are end-products of saccharolytic fermentation of indigestible carbohydrates from our diet [188]. Also, proteins and peptides can be metabolized in the cecum and colon [189], as protein fermentation lead to branched SCFAs production [188]. The concentration of SCFAs is higher in cecum and proximal colon, and their levels decrease toward the distal colon [189]. The most important SCFAs are butyrate, propionate, and acetate, accounting approximately for 80% of the total, although the production of others like formate and valerate should also be highlighted [188 –190]. Acetate and propionate are mainly produced by members of Bacteroidetes whereas butyrate is mainly synthesized by Firmicutes. Furthermore, butyrate can also be synthesized by the gut microbiota from acetate and lactate, although the last is not considered a SCFAs [191]. Notwithstanding mostly SCFAs uptake, signaling and functions occurring in the gut, associative studies show that SCFAs have an important role in human metabolism, the immune system and the entire organism, being able to cross the BBB [192, 193]. Critically, SCFAs are master epigenetic regulators, acting as inhibitors of the enzyme histone deacetylase (HDAC), which is involved in the histone modification [194, 195]. Thus, SCFAs are pleiotropic components produced by the gut microbiota involved in multiple processes of health and disease.

In this great context, butyrate is the most widely studied SCFA. Patients with BD show reductions in butyrate-producing bacteria which, being a central feature of MGB axis disruption [68]. In this sense, lower levels of Coprococcus, Faecalibacterium and Roseburia have been reported, while there seems to be an increase in bacteria populations that consume lactate, such as Megasphaera [86]. A recent systematic review has shown that despite the need for further studies, changes in butyrate-producer bacteria like Faecalibacterium may characterize BD in both a trait and state-dependent fashion [196]. In the gut, colonocytes consume butyrate locally, and this SCFA is crucial for maintaining the intestinal barrier [197]. SCFAs also stimulate enteroendocrine cells (EECs), promoting serotonin production in the colon [198]. This augmented production of serotonin leads to enhanced levels of serotonin in systemic circulation and in the brain, also stimulating vagal pathways and similar events occur with GABA, glucagon-like peptide 1 (GLP1) and peptide YY (PYY) [190].

Besides, immune cells have a high expression of SCFAs receptors, and it seems that SCFAs can regulate the function of colonic Treg cells [189, 199]. Despite butyrate and propionate seem to have the greatest immunomodulatory properties, all SCFAs can regulate the immune response [200]. Mostly, SCFAs exert anti-inflammatory properties. They induce the production of IL-10, closely related to intestinal homeostasis [201], and the production of IL-22 by innate lymphoid cells (ILC) requires the presence of gut microbiota IL-22 is not only crucial in intestinal homeostasis and mucosal barrier function, but also in host defense against infections [202]. Interestingly, most of the pharmacological treatment used in BD showed to increase IL-22, so the efficacy of these drugs may also be in relation with changes in this immune altered response [203]. Thus, reduced levels of butyrate and other SCFAs in patients with BD can have important consequences in the intestinal inflammation and permeability.

Moreover, SCFAs also have direct effects on the brain. For instance, SCFAs are associated with improved neuronal and cognitive function, BBB integrity and decreased neuroinflammation in the brain, representing a critical mechanism of interplay between gut microbiota and glial cells [190, 204]. Hence, despite more investigation is needed, it is conceivable that SCFAs can play a key role in the neural alterations observed in psychiatric disorders. The role of SCFAs in BD symptomatology has not been studied yet. However, a recent work analyzed SCFAs in fecal samples from 125 patients with psychiatric disorders (including 23 with BD). Interestingly, they found that self-reported depressive symptoms were positively associated with fecal acetate concentrations and negatively associated with butyrate and propionate levels [205]. Furthermore, there are in vivo studies showing that SCFAs can alleviate repeated psychosocial stress alterations, exerting antidepressant and anxiolytic effects [206]. Moreover, the therapeutic use of butyrate has been demonstrated to revert manic-like behavior in rats and regulates the antioxidant enzyme activities, protecting the brain against oxidative damage [207] therefore supporting the important role that SCFAs may play in the brain alterations in patients with BD.

Overall, there are plenty of potential effects of SCFAs in patients with BD, although more studies are required to unleash the microbial populations involved in this dysregulation. Furthermore, studying local and systemic levels of SCFAs would be of great aid to understand the pathophysiological basis of MGB axis disruption in BD, especially focusing on its different phases and types.

Tryptophan is an essential amino acid with multiple metabolic fates and crucial in cell danger response, being again gut microbiota a modulator of its metabolic pathways [208]. Indeed, differences in tryptophan metabolizing bacterial pathways can be found in patients with neurological diseases [209] and psychiatric disorders including BD [210].

Gut microbiota can play a pivotal role in the metabolism of tryptophan. Five bacterial phyla including Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Fusobacteria can participate in tryptophan metabolism, being those belonging to the Clostridium, Burkholderia, Streptomyces, Pseudomonas or Bacillus genera the most important modulators [209]. First, via hydroxylated pathway tryptophan is the precursor for serotonin or melatonin [176]. Thus, a large amount of serotonin is produced by enterochromaffin cells of the gastrointestinal tract [58, 208] and it is also present in enteric nerves [208]. Although tryptophan can cross the BBB, serotonin produced in the gut cannot [211]. However, serotonin can affect both vagus nerve and BBB permeability [69], and it modulates intestinal inflammation [212] and numerous physiological processes, including gastrointestinal secretion and peristalsis, vasoconstriction, behavior, and other neurological functions [177]. Besides, it can indirectly affect central serotoninergic pathways by modulating tryptophan and tryptamine availability. Thus, gut microbiota can play a central role in the serotoninergic dysfunction observed in patients with psychiatric disorders, although further studies are required.

The role of tryptamine in the brain is not well understood, although it is hypothesized that they may cross the BBB and exert important neurotransmitter or neuromodulatory actions [213]. Besides, increased tryptamine production can be associated with decreased circulating tryptophan and serotonin synthesis in the brain and could represent one mechanism by which tryptamine influence behavior [214]. Furthermore, tryptophan can be metabolized by gut microbiota to form indole and their derivates including indole-3-aldehyde, indole-3-acetic-acid and indole-3-propionic acid [176]. The role of tryptamine, indole and their derivate has been suggested in different psychiatric disorders, although little is known about their possible implication in BD [215].

On the other hand, tryptophan can be metabolized via the indoleamine 2,3-dioxygenase (IDO) [58, 176] or through the enzyme tryptophan-2,3-dioxygenase (TDO) to form N-formylkynurenine (Kyn) [216]. This is known as the Kyn pathway, and accounts for ~95% of dietary tryptophan degradation [217]. The indoles and their derivates can also be transformed into Kyn [58, 218]. Many components of the Kyn pathway are neuroactive, and influence neuroplasticity and/or exert neurotoxic effects; and this pathway is modulated by, and in turn modulates many other systems that are commonly disrupted in psychiatric disorders, including immune, endocrine, metabolic, and hormonal systems [219]. In a simple manner, Kyn can be metabolized either to kynurenic acid (KYNA), with neuroprotective properties, or to the neurotoxic components quinolinic acid (QA) and 3-hydroxykynurenine (3-HK) [208]. KYNA acts as an NMDA receptor antagonist or through the inhibition of the α7 nicotinic acetylcholine (α7nACh) receptors whereas QA acts as an agonist toward the NMDA receptors, thus promoting excitotoxic neuronal damage [220]. Regarding 3-HK, this molecule seems to exert a dual role in the CNS. On the one hand, it appears to induce oxidative damage and cell death, and high levels of 3-HK are associated with several psychiatric disorders. In contrast, some experimental studies have provided evidence of antioxidant and scavenging properties inherent to this component [221]. Howsoever, the synthesis of 3-HK from Kyn by the flavoprotein kynurenine-3-monoxygenase (KMO) is another critical point in the Kyn pathway, determining the balance between the neurotoxic component 3-HK and the neuroprotective KYNA [216]. Besides, it seems that Kyn and its downstream products exert pivotal immunomodulatory actions in the brain [222]. Thus, alterations in the Kyn pathway, with an augmentation of neurotoxic components like QA at the expense of neuroprotective derivates like KYNA, seem to have a central role in neuroinflammation in many neuropsychiatric disorders [223]. Likewise, systemic inflammation and glucocorticoids can also cross the BBB and influence the formation of QA in the brain by the microglia and infiltrated macrophages, enhancing the neuroinflammatory cascade [224]. Moreover, Kyn pathway may critically influence glutamate neurotransmission [225]. Thus, the gut microbiota can be a major modulator of Kyn pathway in different mental disorders, impairing tryptophan metabolism and influencing the brain and systemic inflammation [226]. Indeed, Kyn pathway seems to be abnormally activated in BD patients [227, 228]. Significant changes in different molecules of the Kyn pathway in BD patients have been described. For instance, meta-analysis on the peripheral blood levels of these components demonstrates that individuals with BD present lower peripheral blood levels of tryptophan, Kyn, KYNA, xanthurenic acid (a component derived from 3-HK), KYNA/Kyn and KYNA/QA ratio [229]. Besides, it seems that individuals with manic episode showed the greatest reductions in tryptophan levels whereas KYNA levels were more notably reduced among individuals in the depressive phase [229]. Other meta-analyses, however, despite showing that patients with BD present lower peripheral levels of tryptophan, Kyn or KYNA, did not find any significant differences between manic and depressed phases [230]. Intriguingly, it seems that this shift in the tryptophan metabolism from serotonin to the kyn pathway is associated with BD, MDD and SZ, but only in mood disorders (BD and MDD) there was a preferential metabolism of Kyn to the potentially neurotoxic QA [231], demonstrating the biological differences in this pathway between various psychiatric disorders. Interestingly, Kyn/tryptophan relation, which appears to represent IDO activity, is also elevated in BD patients [232]. Importantly, the increased IDO activity is a crucial mechanism related to the inflammation-induced depressive-like behavior by endotoxemia [233], thus showing the relevance that gut dysbiosis and bacterial translocation may have on BD patients. Van den Ameele et al. [234] observed that there was a strong relation between TNF-α and Kyn, Kyn/tryptophan, 3-HK and QA in the manic subgroup whereas in the depressed subgroup the KYNA/3-HK decreased and there was a strong association between interferon-y and Kyn pathway activation. Besides, both depressive and manic subgroups were characterized by presenting low levels of KYNA in comparison to healthy controls, which seems to support the relevance of the Kyn pathway in the context of neuroinflammation in BD and how it may be differentially modulated. Beyond, it seems that there is an inverse relationship between Oscillibacter (a genera increased in patients with BD) and the levels of tryptophan and KYNA, thereby supporting the relevance of gut microbiota in the altered Kyn pathway and neuroinflammation [235]. These findings could have important therapeutical implication for BD patients; as some antidepressant like ketamine can influence the Kyn pathway [227].

As aforementioned, not only certain drugs used in BD exerted antimicrobial activity, but also antimicrobials could have noteworthy effects on mental functioning, because of their direct effect on gut microbiota. For instance, it has been suggested that tetracycline antibiotics might represent an attractive therapeutic alternative for different psychiatric disorders [315]. Minocycline is a tetracycline antibiotic that showed to increase neuronal survival, as well as being able to reduce proinflammatory cytokines production and modulating glutamate and monoaminergic pathways, which explains its anti-inflammatory and neuroprotective activity [316]. Aspirin and minocycline combination showed to be effective in BD depression, and minocycline was especially effective at higher baseline levels of IL-6, suggesting that both options could be evaluated as an adjunctive therapy [317]. Likewise, the use of minocycline can be particularly effective for the therapy of bipolar depression in patients with high glutathione (GSH) levels [318]. Similar roles have been given to another tetracycline, doxycycline, which appears to be a promising adjunctive therapy with lithium for treating BD, according to preclinical models [319]. Other studies and systematic reviews, however, did not find any benefits from using minocycline as adjunctive therapy in patients with BD [320, 321], and contrary to some proposals, doxycycline exposure in the adolescence did not report any causal relationship between this tetracycline and BD development [322]. Regarding the effects of minocycline treatment on gut microbiota, it seems that this therapy decreases the Firmicutes/Bacteroidetes ratio [323]. Likewise, changes in other genera have been reported under minocycline treatment, such as decreases in Allobaculum, Bifidobacterium, Turicibacter and Clostridium or increases in Akkermansia muciniphilla, Lachnospiraceae and Ruminococcaceae incertae sedis [324]. Regarding the effects of doxycycline on gut microbiota, previous studies have noticed an effect of this antibiotic on a short-term reduction of LAB like Bifidobacterium or Lactobacillus [325, 326]. On the other hand, there are some antibiotics that may be associated with the development of mania, what experts have designed as "antibiomania" [327]. According to a systematic review of 47 cases of antibiomania, 12 different antibacterial agents were implicated, with antitubercular agents, macrolides and quinolones being the most common causative groups [328]. Despite the pathophysiological basis of antibiomania remains to be fully unraveled, the suspected drug should be immediately discontinued and manic symptoms according to the clinical guidelines. Hence, despite some preliminary evidence is available supporting the use of antimicrobials in the clinical management of BD, further studies are warranted to evaluate the effects of antimicrobials in the gut microbiota and its association with clinical outcomes in these patients.

Fecal microbiota transplantation (FMT) is another promising translational approach targeting gut microbiota. In a simple manner, FMT consists of transferring stool from a healthy donor into the colon of a patient with an established pathology with the aim to restore the normal microbiota and cure or at least ameliorate the disease [329]. Currently, FMT can be considered to treat recurrent Clostridium difficile infection, although there are multiple lines of research opened in intestinal and extraintestinal pathologies [330]. In the literature, there is a case report of a woman diagnosed with BD who went through FMT from her healthy husband at least nine times. Afterward, she had neither manic nor depressive symptoms in the following sixth months, also showing an important weight loss of nearly 33 kg [331]. However, despite these promising results, further studies are needed to evaluate FMT in patients with psychiatric disorders, as this field entails several challenges regarding donors and recipients [55]. Currently, there is a clinical trial (NCT03279224) conducted to assess the feasibility, efficacy, safety, and tolerability of FMT on patients with BD depression. The results of this trial are not available yet (on November 4, 2022), but in this workshop participants are randomized to receive either screened and processed donor stool (allogenic FMT) or their own stool (autologous FMT) via colonoscopy and monitored for 24 weeks post intervention. Then, depressive and manic symptoms, treatment acceptability, gastrointestinal and other side effects are assessed at baseline (prior to randomization) and weekly, whereas stool samples to evaluate microbiome composition are obtained at baseline and 3 and 6 months [332].

Immune-based therapeutic strategies have been suggested for some patients with BD and MDD, although due to the biological and clinical heterogeneity of these complex disorders, this type of therapy could be considered as a part of personalized approach, beneficiating approximately one in three patients, according to previous studies [333]. Thus, some immunomodulatory drugs such as COX inhibitors exert not only anti-inflammatory outcomes but also antidepressant effects [334]. In this sense celecoxib showed to be a safe and a highly effective therapeutical option in resistant bipolar depression, reducing anxiety and accelerating treatment response [335], in a similar way to aspirin [336]. It should be highlighted that, although short-term administration of celecoxib does not seem to alter the bacterial abundance, relative changes in some bacterial populations have been described although changes in butyrate production are not observed after its administration [337]. TNF-α inhibitors have also shown antidepressant properties [338], so they have also been proposed as a potential treatment in BD with contradictory and unsatisfactory results [339]. For instance, in a study with BD patients, the administration of the TNF-α inhibitor infliximab did not report either clinical improvement after its use or significant differences in gut microbiota composition [340]. Despite not exerting a direct anti-inflammatory but an antioxidant effect, N-acetylcysteine (NAC) has also proven potential benefits for patients with BD, especially as a coadjutant for ameliorating depressive symptoms [333, 341]. Likewise, according to previous studies, the use of NAC alleviates gut dysbiosis and glucose disturbances in mice fed with high-fat diet [342], denoting the potential benefits that this drug may have on gut microbiota and BD.

Active lifestyle approaches with regular physical activity and sleep hygiene as well as psychosocial interventions are prominent coadjutants to pharmacotherapy [343]. Regarding physical activity levels, patients with BD appear to be less active and more sedentary than the general population [344]. Exercise also displays pleiotropic effects in the organism, including favorable effects on gut microbiota, including the augmentation of the number of beneficial bacteria, microbial diversity while improving the functioning of the whole MGB axis [345]. Because of that, compelling evidence is supporting the role of exercise in patients with BD, improving health measures including depressive symptoms, functioning and quality of life [346]. However, there is still a lack of studies that do not permit to establish a cause-effect relationship between mood and physical exercise and further research is needed to determine the recommended intensity, duration and frequency of exercise programs [347]. An interesting approach could be to study changes in gut microbiota composition before and after following an adapted physical activity training program and possible implications in patients with BD, aiding to understand the effects derived from this intervention.

On the other hand, irregular circadian patterns can promote mania and depression episodes, and potential interventions to ameliorate this disruption have been explored [46]. Aberrant light cycles can modify gut microbiota composition, altering especially relative abundance of Lactobacillus and Bacteroidetes [348]. In this way, novel approaches have been proposed, such as light and social rhythm therapies, which aim to regulate everyday activities, to enhance social relationships and, consequently, reduce the effect of circadian patterns disturbances [46]. These approaches showed to modify gut microbiota in a beneficial way [349] and it seems to be helpful in BD [350], but the capacity of ameliorate mood symptoms and preventing episodes is yet uncertain [351]. Similarly, midday bright light has been proposed, which has already shown efficacy in increasing remission rates in BD [352]. In relation to this fact, not only circadian but also seasonal variations appear to have a major effect on BD patients. Indeed, it seems that there is a peak in hypomanic/manic symptoms in the spring and early summer months versus a peak in depressive symptoms in the late fall and early winter; and these observations may correspond to seasonal changes in solar insolation, alterations in melatonin production and seasonal influence on the hypothalamic–pituitary–thyroid (HPT) axis, especially at locations of increasing distance from the equator [353]. Gut microbiota is equally affected by seasonal variations. For instance, increased levels of Actinobacteria and Firmicutes to Bacteroidetes ratio can be observed in summer [354], partially explained by dietary fluctuations across seasons [355]. Thus, it would be interesting to research if there is a specific relationship between seasonal variations in gut microbiota with the onset and/or switch of different episodes in patients with BD, with a special focus on dietary variations in these patients.

Some studies have reported associations between the menstrual cycle and BD, particularly in a subgroup of women with enhanced hormonal sensitivity, who seem to experience menstrual cycle effects on depressive, hypomanic, and manic episodes. These phase-episode effects appear to be heterogeneous and may have implications for treatment [356]. Although some studies have failed to find these associations [357, 358], a recent narrative review on this topic [359] supports that, despite there are little works in the field (only 22), certain women with BD may have their mood shifts affected by menstrual cycle events, with different patterns according to the type of BD. The co-occurrence of BD with menstrual cycle-related disorders such as premenstrual dysphoric disorder (PMDD) appears to have a noteworthy impact on these patients, leading to greater chronobiological disruptions across the follicular and luteal phases of the menstrual cycle [360]. In this sense, prior works have related menstrual cycles variations with gut microbiota, and nowadays it is widely accepted that there are certain microorganisms directly implicated in the metabolism and effects mediated by estrogens and sex hormones, conforming what is designed as the estrobolome [361]. There are no studies evaluating the role of the estrobolome in women with BD yet, and how variations in these microorganisms can be important in this group. However, deepening on this field could be specially beneficial for these patients, aiding to develop specific interventions to ameliorate the effects of menstrual cycle in mental disorders [362].