Gut feelings: the microbiota-gut-brain axis on steroids

Abstract

The intricate connection between central and enteric nervous systems is well established with emerging evidence linking gut microbiota function as a significant new contributor to gut-brain axis signaling. Several microbial signals contribute to altered gut-brain communications, with steroids representing an important biological class that impacts central and enteric nervous system function. Neuroactive steroids contribute pathologically to neurological disorders, including dementia and depression, by modulating the activity of neuroreceptors. However, limited information is available on the influence of neuroactive steroids on the enteric nervous system and gastrointestinal function. In this review, we outline how steroids can modulate enteric nervous system function by focusing on their influence on different receptors that are present in the intestine in health and disease. We also highlight the potential role of the gut microbiota in modulating neuroactive steroid signaling along the gut-brain axis.

INTRODUCTION

Evidence from various disciplines implicates bidirectional signals between the gut and central nervous systems (known as the gut-brain axis) in disease development. Considerable evidence over recent years also connects the gut microbiota to this signaling conduit, extending the commonly used terminology to the “microbiota-gut-brain axis” (1). Different signaling molecules, including steroids are involved in these complex communications (2). Steroids are lipid-derived molecules that generally contain four fused rings of carbon atoms with a chemical structure that plays an important role in a wide range of biological functions, including reproduction, metabolism, and immune responses. Some steroids also regulate neural activity independently of their origin. To highlight their importance in neuroscience the term “neuroactive steroids” was introduced to describe steroids that rapidly modulate neural activity through binding to membrane-bound receptors (3), whereas the term “neurosteroid” specifically refers to neuroactive steroids that are synthesized locally in the brain (4). Although the importance of neuroactive steroids in the central nervous system (CNS) has been extensively explored, limited information has linked this class of molecules to the enteric nervous system (ENS), which is often referred to as the “little brain” or “brain-in-the-gut.” This review summarizes how different steroids act on the CNS, and outlines how steroid signaling is involved in the microbiome-gut-brain axis in relation to potential effects on the ENS.

NEURO-MODULATORY EFFECTS OF STEROIDS

Steroids and steroid-like molecules include cholesterol, sex hormones, bile acids, corticosteroids, and vitamin D, all of which play important roles in maintaining human health. As previous reviews have extensively described neuroactive sex hormones and corticosteroids (5–9), here we consider how different steroid classes (Fig. 1) modulate central and peripheral nervous systems.

Figure 1.

Summary of synthesis pathway of the major steroids classes. CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; DHEA, dehydroepiandrosterone; LCA, lithocholic acid.

Sex Steroids

Sex hormones including testosterone, estradiol, and progesterone are extensively studied steroids. Although they play a critical role in reproductive and endocrine functions, hormonal steroids and their precursors or metabolites also modulate neural activity. For example, testosterone regulates the hypothalamic-pituitary-adrenal (HPA) axis in men (10). Higher testosterone levels are also associated with elevated serotonergic tone in healthy males (11). Sex hormones and certain metabolite-derivatives exhibit genomic effects through classical hormonal receptors including estrogen receptors (ERs), androgen receptor (AR), and progesterone receptor (PR). These receptors are also involved in nervous system functions. For instance, ER activation promotes development and survival of dorsal root ganglion and serotonergic neurons in the dorsal raphe (12, 13). However, it is also well recognized that neuroactive steroids mediate rapid neuromodulatory signals through nongenomic pathways via interaction with ion channels and membrane receptors, including γ-aminobutyric acid type A (GABA_A) and N-methyl-d-aspartate (NMDA) neuroreceptors (9). Sex hormones also exhibit nongenomic effects through binding and activation of G protein-coupled receptors (GPCRs), including G protein-coupled estrogen receptor (GPER) (14) and G protein-coupled receptor class C group 6 member A (GPRC6A) that are activated by androgens (15). Sex hormones also indirectly modulate GPCRs, for example serotonin receptors, which are neuroreceptors that are widely distributed throughout central and enteric nervous systems. Estrogens modulate the expression of serotonin 2A (5-HT2A) receptors (16), which is involved in cognition and intestinal smooth muscle contraction, as well as cognitive and mood changes in postmenopausal women (17). The precise mechanisms by which estrogens regulate serotonin receptors remain unclear but are suggested to act through ligand binding to estrogen receptors or GPER (17).

Accumulating evidence suggests that progesterone- and testosterone-related compounds are particularly potent in altering neural excitability and synaptic function. Studies have analyzed a spectrum of these neuroactive steroids in patients and found altered associated levels with neurological disorders such as depression, autism, multiple sclerosis, and schizophrenia (18–22). The neural impact of steroids may also be regulated by altered enzymatic activity modulating their synthesis. Several reviews have described how sex hormone-related steroidogenesis is carried out in the nervous system (23–25). In brief, cholesterol is transported across the mitochondrial membrane, a process regulated by steroidogenic acute regulatory protein (StAR) and translocator protein (TSPO). Cytochrome P450 side-chain cleavage (P450scc) then catalyzes the conversion of cholesterol into pregnenolone, which is further metabolized into other hormones including progesterone and testosterone. Downstream enzymes including 5α-reductase and 3α-hydroxysteroid dehydrogenase then catalyze the conversion of the hormones into other types of neuroactive steroids. Allopregnanolone, a 5α-reduced progesterone metabolite synthesized by the brain, was recently approved by the US Food and Drug Administration (FDA) as Zulresso for treatment of postpartum depression (26). It is a strong positive allosteric GABA_A receptor modulator and is deficient in patients with depression (19, 27). In addition to its influence on mood fluctuations, it demonstrates analgesic properties in neuropathic pain models, possibly through T-type calcium channels and GABA_A receptor (28, 29). A recent study also reported its inhibitory activity on Toll-like receptor 4 (TLR4), via MyD88-dependent signals that suppress neuroinflammation (30, 31). Pregnenolone sulfate, in contrast to allopregnanolone, inhibits GABA_A receptor signaling by enhancing receptor desensitization (32). Pregnenolone sulfate also potentiates NMDA and activates the nociceptor transient receptor potential M3 (TRPM3) channel, which is involved in insulin secretion and noxious heat sensation (33–35). Dehydroepiandrosterone (DHEA) is an androgenic precursor of testosterone, and its sulfated form (DHEA-S) represents the most abundant steroid in the systemic circulation. Because these steroids are synthesized by the adrenal glands they represent important biomarkers of HPA axis function and the stress response. They are associated with antidepressive effects and their abundance is lower in the circulation of patients with depression (36, 37). They are also reported to be involved in various neurological functions including neurogenesis, catecholamine signaling, and neuronal survival (38). DHEA and DHEA-S antagonizes the GABA_A receptor (39, 40) and positively modulate sigma-1 (41, 42) and NMDA (43) receptors. One study reported that DHEA-S potentiates NMDA-induced pain through activation of the sigma-1 receptor (44), whereas another study suggested that DHEAS enhances synaptic plasticity through chronic activation of sigma-1 receptor (45). The inhibitory effect of GABA_A agonist muscimol on medial vestibular nucleus neurons is suppressed by DHEA-S. Furthermore, muscimol reduces DHEA-S-induced mechanical allodynia (46). This appears to be predominantly associated with sulfation as the impact of DHEA on GABA_A receptor signaling is less potent (47, 48). Regarding their effect on gastrointestinal function, DHEA-S treatment alleviates visceral allodynia and reduces colonic permeability in stressed male rats through GABA_A, nitric oxide (NO), opioid, central dopamine D2, and peripheral CRF2 signaling (49). Another androgenic neuroactive steroid (androstenediol) suppresses inflammation of microglia through Estrogen receptor β (ERβ) in the brain (50). It also reduces demyelination-induced axonopathy and promotes remyelination in rodents (51, 52), suggesting it may have protective properties against neurological disease, such as multiple sclerosis.

As some neurological disorders including irritable bowel syndrome (IBS) and autism demonstrate sex bias in incidence and severity (2, 53), sexually dimorphic effects of steroids (particularly sex hormones) have been suggested as a possible etiology. Neuroactive hormone abundance under normal physiological conditions is different in females and males. For instance, DHEA-S is more abundant in males (54, 55). Furthermore, fluctuations in the levels of neuroactive steroids under stress and/or pathological conditions also show sex-dependent patterns. Changes in neuroactive steroids following a forced swimming test in rats were more prominent in females (56). Pregnenolone and 3α-Androstanediol (3α-diol) measured in the sciatic nerve are decreased in diabetic males but not in female rats; whereas progesterone and isopregnanolone are reduced only in diabetic female rats (57). In addition to sex-bias, the activity of neuroactive steroids demonstrates significant regional specificity. For example, neuroactive steroids are abundant in the circulation but this does not always correlate with levels in cerebrospinal fluid (58). Diabetes-induced changes in neuroactive steroid levels are also markedly different in sciatic nerve versus the cerebral cortex (57). Therefore, although sex hormone-related steroids modulate the nervous system and activity of receptors, it is also important to consider potential confounding factors when studying their effects.

Corticosteroids

Corticosteroids are mainly synthesized by the adrenal cortex from progesterone. There are two main types of corticosteroids: glucocorticoids and mineralcorticoids. Glucocorticoids including cortisol and corticosterone play a primary role in the stress response, by activating the HPA axis and releasing cortisol. In the adrenal cortex, progesterone and 17-hydroxyprogesterone are converted into intermediate products 11-deoxycorticosterone and 11-deoxycortisol respectively, a process catalyzed by 21-hydroxylase (CYP21A2) (59). These intermediate compounds are then transformed into corticosterone and corticosterone by 11β-hydroxylase and represent potential enzymatic targets of corticosteroid activity. Cortisol activity is antagonized by DHEA/DHEA-S; thus its ratio against DHEA/DHEA-S is a measure of stress level and HPA dysfunction (60, 61). Furthermore, deoxycorticosterone is a precursor of corticosterone, whereas 3α,5α-tetrahydrodeoxycorticosterone (THDOC; a 3α-reduced metabolite of deoxycorticosterone) is more abundant in patients with depression (62). At the same time, hypercorticism is believed to damage brain structure and contribute to dementia (63–65). In female patients with IBS, the cortisol:DHEA ratio is higher compared with controls (66), which could be caused by altered adrenocorticotropic hormone (ACTH) responses to corticotropin-releasing hormone (CRH) (67). Through the action of aldosterone synthase, glucocorticoids are converted into mineralcorticoids, including aldosterone that regulates electrolyte and fluid homeostasis, for example through the renin-angiotensin-aldosterone system, which contributes to blood pressure regulation. Excess aldosterone is associated with obesity and visceral adiposity, possibly due to the aldosterone-releasing factors released by visceral fat (68). Regarding its effect on neurological health, aldosterone is positively associated with anxiety and depression (69, 70).

Corticosteroids exert their effects by genomic and nongenomic actions through cytosolic and membrane-associated glucocorticoid receptors (GR) and mineralcorticoid receptors (MR), which are expressed throughout the body including the brain (71–74). These receptors regulate neuronal survival and neurogenesis (75), as well as synaptic function, including memory, mood changes, and pain sensation (76–78). They are also co-localized in neurons and their regulated balance is critical in mediating an appropriate stress response (79, 80). Corticosteroids and their metabolites are important regulators of the HPA axis. Treatment with THDOC protects against behavioral and neuroendocrine consequences of early adverse life stress in rats (81). Although MR and GR are involved in regulating the HPA axis (80), GABA_A receptor signaling also targets the HPA axis through suppressing the activity of corticotrophin-releasing hormone (CRH) neurons under steady-state (nonstressful) conditions. This inhibitory effect involves the K⁺/Cl⁻ co-transporter KCC2 that maintains low extracellular Cl⁻ concentrations. As a positive allosteric GABA_A receptor modulator, THDOC therefore suppresses CRH neural signaling (82). Interestingly, these GABA_A-mediated effects are reversed under stress conditions, possibly mediated by upregulation of the Na⁺-K⁺-2Cl⁻ cotransporter NKCC1 in terminal endings of CRH neurons (83). THDOC also upregulates the HPA axis following stress through dephosphorylation of KCC2 residue-Ser940, resulting in a Cl⁻ gradient shift (82). Corticosteroid also activates GPCRs, for example adhesion G protein-coupled receptor G3 (GPR97) that regulates B cell function and antimicrobial activity by human granulocytes (84, 85), whereas aldosterone activates the angiotensin II (AngII) type-1 receptor (AT1R) regulating blood pressure (86). In general, glucocorticoids regulate the stress response together with GABA_A receptor differently under steady-state and stress conditions, whereas mineralcorticoids play a critical role in regulating blood pressure. The importance of balance between cortisol and DHEA-S level also indicate cross talk between steroids, indicating the importance of evaluating the role of a spectrum of steroids instead of a single compound.

Bile Acids

Bile acids are important mediators of microbiome-gut-brain axis signaling. Bile acids are steroid-like compounds that are synthesized by the liver from cholesterol, mainly through the classic pathway regulated by rate-limiting enzyme CYP7A1. The major human primary bile acids are cholic acid (CA) and chenodeoxycholic acid (CDCA), and their ratio is controlled by the activity of CYP8B1. After conversion into primary bile acids, they are conjugated with taurine or glycine in the liver before being secreted into the small intestine where they promote digestion and absorption of nutrients. In the intestine, bile acids are deconjugated and converted into secondary bile acids by the gut microbiota (discussed NEUROACTIVE STEROIDS IN MICROBIOTA-GUT-BRAIN AXIS SIGNALING). In addition to the extensive bile acid pool in the small intestine, bile acids are also present in the brain, where they are either transported from the systemic circulation and/or synthesized locally. In particular, CDCA is highly abundant in brain compared with systemic circulating levels in rodents (87).

In addition to their critical role in digestion, bile acids are recognized as important signaling molecules. Over the past few years, their impact on neural function has received much attention as altered bile acid levels are reported in several neuropathological conditions. For instance, brain bile acid levels are altered in patients with Alzheimer’s disease compared with cognitively normal individuals (88). Similarly, bile acid-related disorders are also associated with changes in neural activity. Cholestasis is associated with suppression of HPA axis activity, possibly through the interactions between bile acids and the glucocorticoid receptor in the brain (89). Also, cerebrotendinous xanthomatosis (CTX), a genetic disorder associated with decreased bile acid synthesis contributes to neural dysfunction including dementia, a finding that is supported by CDCA supplementation alleviating dementia symptoms (90).

Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (TGR5) that serve multiple functions and are expressed in various tissues, including in central and peripheral neurons throughout the intestine. Importance of the nuclear receptor FXR in nervous system function is demonstrated by altered neurotransmitter levels, and impaired cognitive function and motor coordination after deletion of FXR (91). It is also reported that FXR mediates bile acid-induced visceral hypersensitivity, with the involvement of mucosal mast cells, nerve growth factor (NGF), and transient receptor potential (TRP) vanilloid family 1 channel (TRPV1) (92). Meanwhile, the G protein-coupled bile acid receptor TGR5 is expressed in brain and peripheral neurons, and functions as a neurosteroid receptor after activation by allopregnanolone (93). Animal studies also suggest that TGR5 mediates bile acid-induced stimulation of sensory nerves and contributes to symptoms, including itching and analgesia in cholestatic disease (94). Furthermore, TGR5 is expressed by enteric neurons and mediates region-specific bile acid regulation of gastrointestinal motility. In mouse stomach and small intestine, bile acids activating TGR5 suppress motility and promote efficient absorption (95). Conversely, TGR5 overexpression enhances colonic motility, whereas ablation of TGR5 delays colonic transit (96). Certain bile acid species also activate pregnane X receptor (PXR), vitamin D receptor (VDR), and glucocorticoid receptor (GR), which independently regulate nervous system activity (89, 97–99). In addition to these receptors that show promiscuous activation by bile acids, CDCA in particular is highly abundant in brain and is reported to be a potential antagonist of NMDA and GABA_A receptors (100). Furthermore, ursodeoxycholic acid (UDCA) that shows neuroprotective effects against dementia enhances alertness via suppression of GABA_A receptor signaling (101). These findings support that bile acids are important mediators in the gut-brain axis and in regulating gastrointestinal function.

Vitamin D₃

Vitamin D₃ is a fat-soluble vitamin as well as a steroid. It is consumed as part of the diet or is synthesized from cholesterol after exposure to sunlight. In its active form, it has to be hydroxylated to 25-hydroxyvitamin D₃ [25(OH)D₃] by 25-hydroxylase (CYP27A1) and is further hydroxylated to 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] by 1α-hydroxylase (1α-OHase, also known as CYP27B1). It plays an important role in calcium absorption, immunity, and metabolic health. In recent years, vitamin D₃ is also recognized as a neurosteroid (102). 1α-OHase, the enzyme that transforms vitamin D into its active form is expressed by the human brain (103). Endothelial cells and neurons are capable of converting Vitamin D₃ into 25(OH)D₃, which is further metabolized into 1,25(OH)₂D₃ by neurons and microglia (104). Evidence from epidemiological studies and animal experiments shows that vitamin D₃ deficiency is associated with pain sensitization and neurological dysfunction, including Alzheimer’s disease, depression, and multiple sclerosis (105–109). This could be explained by the importance of vitamin D₃ in various neurological functions, including neuroinflammation, neurogenesis, synaptic function, and neuronal survival in the CNS (110–112). Furthermore, vitamin D₃ maintains blood-brain barrier integrity in in vitro and in vivo models (113). It has also been reported that vitamin D₃ deficiency leads to elevated basal GABA levels in rodents (110, 114). However, confounding factors, particularly sunlight exposure and lifestyle confounders, should be taken into account when studying the effects of vitamin D₃ in humans (108).

Similar to other steroids, vitamin D₃ acts through genomic or nongenomic pathways. Genomic actions are mainly mediated through the nuclear vitamin D receptor (VDR), which is present in various organs including the brain (103). In humans, VDR polymorphisms are associated with susceptibility and worsening symptoms in Parkinson’s disease and dementia (115, 116). VDR knockout animals also demonstrate altered locomotor behavior (117). Nongenomic actions also involve the VDR, as well as the membrane receptor protein disulfide isomerase family member (PDIA3) (118, 119). Although VDR is mostly expressed by astrocytes, PDIA3 is highly expressed by various cell types in the brain and is therefore suggested to be the major nongenomic vitamin D receptor type in the CNS (104). VDR and PDIA3 may also interact to mediate nongenomic effects (120). In addition, vitamin D₃ modulates signaling via other receptors. For instance, vitamin D₃ downregulates the expression of epidermal growth factor receptor (EGFR), a transmembrane protein involved in pain processing (121). Vitamin D₃ also targets opioid receptor signaling, as vitamin D₃ supplementation modulates the expression of genes involved in the signaling pathway and reduces neuropathic pain (122). Vitamin D₃ deficiency is recently reported to increase the risk for opioid dependence, possibly due to deficiencies in VDR signaling (123), suggesting interactions between VDR with other receptors that regulate nervous system function. Furthermore, vitamin D₃ is recently reported as an agonist of the calcium-selective channel TRPV1 that mediates pain sensation (124). In general, vitamin D₃ plays an important role in controlling neuroinflammation and neuropathic pain, which likely is mediated through VDR and different membrane receptors.

In summary, a plethora of evidence supports the neuromodulatory effect of steroids, capable of regulating various receptors associated with neural signaling pathways. In particular, several steroids modulate GABA_A and NMDA receptors, implicating a potential involvement of steroids in clinical disorders involving synaptic dysfunction. Although many membrane receptors are influenced by steroids, some studies also suggest cross-activation between receptors upon steroid activation that deserves further investigation. It is also demonstrated that steroids regulate gastrointestinal function, which has led to intense interest in understanding how steroids signal along the gut-brain axis.

NEUROACTIVE STEROIDS IN MICROBIOTA-GUT-BRAIN AXIS SIGNALING

The gut is innervated by the ENS, which is the largest division of the peripheral nervous system and the third division of the autonomic nervous system. It plays an important role in regulating gastrointestinal function, including gastric secretion, gut motility, and intestinal epithelial cell activity. ENS dysfunction is associated with a number of clinical disorders, including autism spectrum disorder and IBS (125, 126). The ENS usually communicates with the CNS, but is also capable of local function independently of the brain. Many of the structural and neurochemical components of the ENS resemble that of the CNS. For instance, neurons (and enteroendocrine) cells secrete serotonin or gastrointestinal hormones that activate signals transmitted through the vagal nerve to the brain (127). Also, neurons of the ENS are surrounded by enteric glia that are structurally similar to CNS glia and support neural networks (128). Furthermore, membrane channels or receptors including NMDA and TGR5 that are modulated by steroids are expressed in the gut (129). These features suggest that molecules including steroids that act on the CNS could also influence the enteric nervous counterpart.

The cross talk between the gut and CNS is well recognized, and in the last decade the gut microbiota has been included as a significant contributor to this signaling network (130). The term “psychobiome” was introduced to describe gut bacteria that influence how we think, feel, and act (131). Growing clinical evidence indicates that shifts in gut microbiome composition are associated with changes in central and enteric nervous system function and behavior. For example, specific gut microbiome features are associated with quality of life and depression in the Flemish Gut Flora Project (132). Also, probiotic use is reported to alleviate anxiety and depression (133, 134). The significance of the microbiome-gut-brain axis is also demonstrated by dysregulated hippocampus neurogenesis, serotonergic signaling, and microglial responses to antibiotics or by inducing a germ-free state in animal models (135–137). Regarding the ENS, germ-free rodents show abnormal myenteric plexus structure and altered intrinsic primary afferent neuron excitability (138, 139). In addition, the gut microbiota can mediate dietary effects on the nervous system, for instance the antiseizure properties of ketogenic diets (140).

Mechanisms by which gut microbiota modulate the nervous system remain incompletely understood, but considerable evidence suggests that microbial metabolites are involved. Gut microbiota release and/or regulate the synthesis of neurotransmitters and neuromodulators that act locally on enteric neurons or transmit signals to the brain via for example the vagus nerve (141). At the same time, they convert steroids and/or other compounds into microbial metabolites that may exhibit different biological effects on the nervous system compared with their parent forms. Finasteride is a drug for benign prostate hyperplasia and androgenetic alopecia, as well as an irreversible inhibitor of 5α-reductase, an enzyme involved in the synthesis of some neuroactive steroids. Patients with postfinasteride often have altered neuroactive steroid profiles and demonstrate depressive symptoms (142, 143). Functional magnetic resonance imaging has confirmed abnormal function in brain areas related to sexual arousal and depression in these patients (144). Recently, an altered gut microbiota composition was reported in patients with postfinasteride (145). Although microbiota community shifts associated with steroid levels were not investigated, these results implicate a potential connection between the gut microbiota and neuroactive steroids. This section summarizes how different types of steroids interact with the gut microbiota and subsequently how this interaction may regulate gut-brain axis signaling (Table 1 and Fig. 2).

Table 1.

Examples of how different steroids interact with gut microbiota

Steroids	Modulation of Steroids by Gut Microbiota	Effect of Steroids on Gut Microbiota
Sex hormones	Deconjugation by enzymes including sulfatase and glucuronidases Biotransformation of unconjugated hormones	Enhances intestinal alkaline phosphatase (IAP) activity Facilitates intraluminal transport of sIgA which neutralizes pathogenic bacteria Regulates plasma immunoglobulin levels and B cell function
Corticosteroids	Regulate intestinal corticosteroid production in response to stress Biotransform into 21-dehydroxylated products or androgens Influence GR activity	Mediate the effects of stress through modulation of the microbiome Modulate the oral microbiome in a metatranscriptomic study Modulate infant intestinal microbiota composition with altered maternal cortisol level
Bile acids	Deconjugates by bile salt hydrolase (BSH) Conversion of primary into secondary bile acids by 7-dehydroxylation, 12α-dehydrogenation and desulfation	Exhibit antimicrobial and cytotoxic properties by inducing membrane damage or through FXR Regulate gut microbiota composition through FXR
Vitamin D3	Increase 25-hydroxyvitamin D and biosynthesis of 7-dehydrocholesterol by probiotics and prebiotics, respectively Upregulates VDR expression by probiotics Hydroxylate and activate vitamin D3 by cytochrome enzymes	Increase gut microbial diversity and Akkermansia abundance Elevate tight junction protein expression and improves intestinal barrier function Enhance the production of antimicrobial peptides

FXR, farnesoid X receptor; VDR, vitamin D receptor.

Figure 2.

Schematic diagram of how steroids are involved in microbiota-gut-brain axis signaling. CNS, central nervous system.

Sex Hormones

Gut microbiota composition is different in males and females, for instance, Akkermansia is reportedly more abundant in females than in males (146). As gut microbiota composition appears to be sex-biased, systemic sex hormone levels are also associated with altered gut microbiota profiles (147, 148). Furthermore, alteration of serotonin metabolism and microglial responses in the absence of gut microbiota are sex-biased, demonstrating the importance of sex and consideration of estrus cycle when studying the microbiota-gut-brain axis (135, 137).

Gut microbiota and sex steroids interact in reciprocal ways. On the one hand, the gut microbiota regulate the levels of sex steroids, with animal studies showing that shifts in gut microbiota composition result in abundant changes of neuroactive sex steroids. For instance, prebiotic supplementation reduces the elevation of neuroactive pregnanolone-type compounds induced by stress (149). In a study of type 1 diabetes, transfer of gut microbiota from male to female mice induced an elevation in testosterone levels and conferred protection from autoimmune disease (150). These effects are also reported to be dependent on AR activity. The gut microbiota express enzymes such as sulfatase and glucuronidases that deconjugate steroids for intestinal reabsorption. Therefore, conjugated steroid levels are higher in germ-free compared with conventional mice (151). The deconjugation process may also influence the potency of sex steroids on the nervous system. It is reported that DHEA induces neural AR expression and activity whereas DHEA-S fails to do so (152). At the same time, unconjugated sex steroids can be further converted into other metabolic products by specific bacteria. For instance, Steroidobacter denitrificans biotransforms testosterone through the 9,10-seco-pathway (153). Microbial metabolism of estrogens may also modify their estrogenic potential through producing different estrogenic metabolites (147, 154).

On the other hand, sex hormones regulate gut microbiome structure and function, which in part could explain differences in gut microbiome profiles between the sexes. Ovariectomy changes gut microbiota composition in rodents as demonstrated by an increase in the relative abundance of Firmicutes and Proteobacteria, with decreases in Bactoidetes (155, 156). Neuroactive DHEA treatment modulates gut microbiota composition and alleviates intestinal inflammation in experimental dextran sulfate sodium (DSS)-induced colitis (157). In a study of metabolic syndrome, 17β-estradiol reduces Proteobacteria and increases Akkermansia in male mice, and protected the mice against metabolic syndrome (155). Furthermore, fecal DHEA-S levels are elevated and gut microbiota composition is altered in polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism (157, 158). The mechanisms by which steroids regulate gut microbiota likely involve regulation of host intestinal function, such as motility and immune responses. Estrogens are reported to upregulate intestinal alkaline phosphatase activity that dephosphorylates LPS and antimicrobial peptides, which prevents Escherichia coli overgrowth (155). In an in vitro study, estrogens also facilitated the transport of secretory immunoglobulin A (IgA), which binds to and neutralizes pathogenic bacteria (159). Furthermore, an increase in estrogen to androgen ratio in male mice is associated with elevated plasma immunoglobulin levels and altered B cell function (160). In general, microbiota metabolize sex hormone-related steroids and modulate their activity, while steroids also play important roles in shaping the gut microbiome and host immunity. Sex-dependent effects of steroids are also reported in disease models. It is therefore important to investigate how their cross talk differs between sexes and contributes to disease pathogenesis. There is also inadequate direct evidence on how desulfation of steroids by the gut microbiota modulates their potency. Given that the inhibition of GABA_A receptor by DHEA-S is associated with its sulfation, it is possible that the microbial desulfation will reduce the inhibitory effect.

Corticosteroids

Glucocorticoids are the primary hormones driving the stress response, whereas stress is also a major factor that alters gut microbiota composition. The gut microbiome is associated with HPA axis activity, which is often measured based on glucocorticoid levels (161). For example, in infants, gut microbiota diversity is associated with stress-induced saliva cortisol responses (162).

Emerging evidence supports a role for gut microbiota regulation of glucocorticoid synthesis and metabolism. Germ-free male mice shows higher plasma corticosterone levels after restraint stress compared with SPF mice, and this increase was alleviated by Bifidobacterium infantis (161). Another potential psychobiotic, Bifidobacterium longum 1714, reduces reported stress and attenuates increases in stress-induced salivary cortisol in healthy volunteers (163). Furthermore, intestinal corticosterone production in response to stress is reduced in germ-free mice (164). Anaerobic bacteria including Eggerthella lenta metabolize glucocorticoids into 21-dehydroxylated products, 11β-OH-progesterone or 11β-OH-(allo)-5α-preganolones, which are associated with hypertension (165, 166). Clostridium scindens has also been reported to transform glucocorticoids into androgens (167). Gut microbiota also influence depression and anxiety through downstream actions on the glucocorticoid receptor in germ-free animals (168). Glucocorticoids are suggested to mediate the effects of stress through modulation of the microbiome. For instance, cortisol treatment modulated the oral microbiome in a metatranscriptomic study (169). Furthermore, maternal prenatal and postpartum stress that are measured by saliva cortisol levels are associated with infant intestinal microbiota composition (170, 171).

In addition to glucocorticoids, mineralcorticoids are also influenced by gut microbiota activity. In an early study, antibiotics reduced urinary 21-dehydroxylated aldosterone products in healthy volunteers and in patients with liver cirrhosis, suggesting a role for the gut microbiota in aldosterone metabolism (172). As the renin-angiotensin-aldosterone system is closely associated with hypertension, this could possibly reflect how the gut microbiota may regulate blood pressure. Taken together, the interaction between corticosteroids and gut microbiota is likely to mediate their effect on stress response and blood pressure regulation. While stress and glucocorticoids induce various changes to host phenotype, including inflammation and oxidative stress, gut microbiota are also closely influenced by these factors. At the same time, gut microbiota play important roles in regulating host immune responses and steroid metabolism. These form a multifactorial link between gut microbiota, steroids, and stress.

Bile Acids

Primary bile acids are synthesized by the liver and are secreted as conjugated molecules into the small intestine as bile. Over 95% of bile acids are reabsorbed, primarily as conjugated species in the distal ileum, and recirculate back to the liver as part of the enterohepatic circulation. The remaining bile acids reach the large intestine and are excreted in feces while interacting with the microbiota in the colonic lumen.

Together with the enterohepatic circulation, the gut microbiota play an important role in regulating bile acid compositional profiles. Germ-free mice have a larger bile acid pool, and less fecal bile acids are excreted compared with conventional mice (173). Gene expression profiles involved in bile acid metabolism are also different in the absence of gut microbiota, including elevated mRNA accumulation of hepatic bile acid synthesis genes (173). Significant alterations in bile acid species in the brain of Alzheimer’s disease patients suggest an association with the microbiota-gut-brain axis (88). Indeed, the gut microbiota metabolize bile acids and increase the diversity of the bile acid pool. Numerous strains of gut bacteria possess bile salt hydrolase (BSH) activity (174–176) and deconjugate bile acids, which is a requirement for microbial conversion into secondary bile acids in the colon. In the small intestine, this action prevents the reabsorption, as conjugated bile acids are transported more effectively through active transport (177). Unconjugated bile acids enter the colon where they are metabolized into secondary bile acids by a much more limited repertoire of bacteria that are capable of 7-dehydroxylation including some Clostridium or Eubacterium species (178). Generally, cholic acid (CA) is transformed into deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) is transformed into lithocholic acid (LCA). Certain strains including Clostridium scindens and Eggerthella lenta have been a focus because of their potential to produce secondary bile acids (179, 180), and alterations in bile acid profiles and circulating secondary bile acid levels influence central and peripheral nervous systems, including the ENS. Changes in bile acid profiles are potentially important as bile acid receptor signaling is preferentially activated by specific bile acid ligands with distinct signaling potency. For instance, CDCA is more potent in activating FXR compared with DCA and LCA (181), whereas the murine-specific tauro-β-muricholic acid is recognized as an FXR antagonist (173). Also, unconjugated bile acids, particularly LCA and DCA promote colonic transit, with more potent effects on male compared with female mice (96, 182). Mechanistically, the effect could be mediated through TGR5 activation and/or the serotonergic system. Furthermore, DCA excites colonic afferent nerves, implicating its potential role in visceral hypersensitivity (183). Apart from 7-dehydroxylation, other microbial modifications including 12α-dehydrogenation and desulfation occur producing different bile acid species with unknown signaling potential (184).

Although the gut microbiota influences bile acid profiles, they also serve as important host factors in shaping the gut microbiome. A recent study reported bile acids as signals for gut microbiota maturation in newborn mice (185). Also, neonatal cholestasis is associated with gut dysbiosis in infants (186). In in vivo studies, bile acid treatment and bile duct ligation alter gut microbiota composition (187–189). Certain unconjugated bile acids including CDCA and DCA exhibit antimicrobial and cytotoxic properties and inhibit growth of commensal bacteria by inducing membrane damage (190). This could possibly explain the bacterial overgrowth and translocation when there is a blockage of bile flow (191, 192). Furthermore, bile acid receptors may mediate the effect of bile acids on gut microbiota. For instance, FXR-deficient mice have reduced Firmicutes:Bacteroidetes ratio and Proteobacteria, as well as higher abundance of Desulfovibrionaceae, Deferribacteraceae, and Helicobacteraceae (193). FXR is also associated with antibacterial activity and protects against bacterial overgrowth and mucosal injury (194). However, future studies that characterize microbiota changes in the absence of specific intestinal bile acid species are still required to evaluate their modulatory role on gut microbiota community structure and function. For example, CYP8B1-deficient mice lacking cholic acid and its secondary bile acid derivatives did not demonstrate marked shifts in microbiota composition or function (195). In this same bile-acid deficient model rederived under germ-free conditions, microbiota protection (both human and murine) against neurogenic inflammation of the colon was demonstrated to occur independently of bile acid signaling. Given the considerable amount of evidence demonstrating a close relationship between bile acids and gut microbiota, as well as studies reporting the effect of secondary bile acids on visceral sensitivity and gut motility, there is solid ground to continue exploring how their interactions contribute to central and enteric nervous system function and underlying disease mechanisms. However, there is a need to test such findings in animal models that rigorously address causation.

Vitamin D₃

Gut microbiota are associated with vitamin D₃ metabolism and VDR signaling. Probiotics studies have suggested that vitamin D₃ is involved in their protective effects on intestinal disease, such as colitis (196). Oral probiotic supplementation of patients with hypercholesterolemia showed increased systemic 25-hydroxyvitamin D levels, indicating an improvement in vitamin D status (197). It is also proposed that prebiotics could enhance biosynthesis of provitamin D3 7-dehydrocholesterol (198). Gut microbiota may also regulate vitamin D₃ signaling by modulating VDR expression and activity, with animal models demonstrating that probiotics elevate VDR expression (199). In addition, gut microbiota species such as Streptomyces griseolus and Amycolata autotrophica express cytochrome enzymes that hydroxylate and activate vitamin D₃ (200, 201).

Accumulating evidence suggests that vitamin D₃ modulates gut microbiota composition, although changes reported have been inconsistent (202). In a recent study of healthy women with vitamin D₃ deficiency, supplementation increased gut microbial diversity and abundance of Akkermansia and Bifidobacterium (203). One consistent finding with other studies is that higher vitamin D₃ baseline or vitamin D₃ supplementation is positively associated with Akkermansia abundance in healthy individuals, as well as in patients with multiple sclerosis (204, 205). A genome-wide association study (GWAS) identified a significant association between VDR genetic variants and human gut microbiota composition, while Vdr-knockout mice support this finding by showing a different gut microbiota composition compared with wild-type mice (206). As vitamin D₃ plays important roles in immune system function, it may regulate the gut microbiome through regulation of intestinal immunity. Mice with VDR deletion or vitamin D₃ deficiency are more prone to intestinal inflammation, pathogen infection, and bacterial overgrowth (207–209). In terms of adaptive immunity, vitamin D₃ supplementation elevates tight junction protein expression and improves intestinal barrier function in in vitro and in vivo studies (210, 211). For innate immunity, vitamin D₃ enhances the production of antimicrobial peptides, which exhibit antimicrobial activity and protects the host against pathogen colonization (212, 213). As gut microbiota modulates vitamin D₃ metabolism, these protective effects of vitamin D₃ signaling may also mediate some of the beneficial effects of probiotics. Also, while altered Akkermansia abundance is found in multiple diseases (214, 215), the clinical significance of the consistent positive association between vitamin D₃ and Akkermansia warrants further investigation.

Overall, steroids and gut microbiota closely interact in a bidirectional fashion that may influence signaling to either gut or brain. Evidence also suggests that steroids interact with the gut microbiota and these signals may serve as mediators of beneficial probiotic effects. Nevertheless, we still lack a detailed understanding of how these complex interrelationships regulate the gut-brain axis, as direct evidence is limited and requires further investigation.

ALTERED STEROID-GUT MICROBIOTA INTERACTIONS IN DISEASE STATES

Considerable evidence has independently shown that steroids and gut microbiota play critical roles in various diseases; however, how they interact under pathological conditions remains unclear. Alterations in secondary bile acid profiles that originate from gut microbiota activity are found in different types of disease, suggesting dysregulated steroid-microbiota interactions. Understanding these interactions in the context of disease development may assist in advancing future diagnostic tools and therapeutic interventions.

Alzheimer’s Disease

Alzheimer’s disease is a major neurodegenerative disease characterized by the progressive damage and/or dysfunction of neurons, with symptoms including cognitive impairment and mood changes. As steroids are important regulators of neuronal survival and differentiation, altered neurosteroid levels are often found in patients with dementia. For example, DHEA-S and allopregnanolone are reduced in patients with Alzheimer’s disease (216, 217). At the same time, allopregnanolone supplementation reverses neurogenic and cognitive deficits in a translational mouse model (218). Furthermore, steroidogenesis regulators including StAR are altered in Alzheimer’s tissue (219). Mechanisms underlying neuronal death in Alzheimer’s disease include dysregulation of neuroinflammation, protein aggregation, oxidative stress, and DNA damage. Evidence has shown that various neurosteroids modulate these mechanisms. Regarding protein aggregation, pregnenolone sulfate and DHEA-S are negatively associated with β-amyloid peptide detection and phosphorylated tau proteins in brain, respectively (220). Furthermore, androstenediol, progesterone, and allopregnanolone promote myelin regeneration, suggesting that myelin represents a target for protection against neurodegenerative disease (52, 221). Meanwhile, the human gut microbiome structure shifts during aging and could contribute to neurodegenerative disease (222). β-Amyloid is also reported to induce gut dysbiosis (223). Various studies have reported gut dysbiosis in patients and animal models with neurodegenerative diseases (224–227) and these studies form the foundation for probiotic therapy (228). Studies also found positive associations between cognition and secondary bile acids in Alzheimer’s brain tissues and serum, indicating potential involvement of steroid-microbiota interactions in cognition (88, 229). This is possibly because secondary bile acid DCA induces oxidative stress and DNA damage, which are risk factors for neurodegeneration (230, 231). Furthermore, Lactobacillus helveticus NS8 treatment alleviated cognitive symptoms and restored brain serotonin levels in a chronic stress model while lowering plasma corticosterone and ACTH (232), suggesting stress-associated steroids are involved in the beneficial effects of probiotics against dementia.

Although the mechanisms underlying the effects of steroids and gut microbiota are not fully known, various membrane receptors are likely to be involved. As described in previous sections, both gut microbiota and steroids modulates synthesis and receptor activity of neurotrophic factors that are also important factors in Alzheimer’s disease. The balance between inhibitory GABA and excitatory glutamate transmission is important for proper neuronal function. GABA_A receptor dysfunction is reported to be associated with Alzheimer’s disease (233). Although an earlier study suggested GABAergic neurons are resistant to β-amyloid toxicity (234), later studies reported that β-amyloid impairs GABA inhibitory interneuron function (235, 236). At the same time, GABA treatment and activation of GABA_A receptor during early life protects against β-amyloid-induced cognitive impairment in mice (237), which may explain reduced GABA levels in patients with Alzheimer’s disease (238). As neurosteroids are modulators of the GABA_A receptor, allopregnanolone and DHEA protect neurons from apoptosis while upregulating α1 and β2 mRNAs of GABA_A receptor (239). The promotion of myelin formation by allopregnanolone is abolished by the selective GABA_A receptor antagonist bicuculline, suggesting the neuroprotective effect is GABA_A-dependent (221). DHEA-S also demonstrates neuroprotective effects that are abolished by bicuculline, despite DHEAS commonly being regarded as a GABA_A antagonist (240). In addition to the GABA_A receptor, NMDA receptors play important roles in cognitive function and neuronal survival. Although glutamate is important for neuronal survival and synaptic transmission, excitotoxicity resulting from excessive glutamate and glutamatergic activity leads to neuronal dysfunction and death. Synaptic dysfunction caused by Ca²⁺ influx into neurons through the NMDA receptor has also been suggested as a mechanism underlying β-amyloid toxicity in Alzheimer’s disease (241). In this regard, steroids including allopregnanolone, DHEA(S) and vitamin D protect against NMDA-induced toxicity (242–244). Furthermore, pregnenolone sulfate that positively modulates the NMDA receptor enhances memory and reduces competitive NMDA receptor antagonist-induced retention deficits (245–247). These findings implicate neurosteroids as modulators of pathological components of Alzheimer’s disease through GABA_A and NMDA receptors. At the same time, the gut microbiota regulates neurotransmitter synthesis and neuroreceptor activity in Alzheimer’s disease. Using the Mendelian randomization approach, a study reported that GABA and Blautia, a potential GABA producing genus, are protective against Alzheimer’s disease (248). NMDA receptor expression is also influenced by the presence of gut microbiota (249). Taken together, the interaction between steroids and gut microbiota could be involved in Alzheimer’s disease through regulating GABA_A and NMDA receptor activity.

In addition to neurotrophic factors and neuroreceptors, altered bile acid profiles in Alzheimer’s disease suggest that bile acid receptors could be involved. FXR activation is reported to enhance β-amyloid-induced neural apoptosis, whereas the TGR5 agonist has an opposite effect (250, 251). As the subtypes and conjugation extent of bile acids affect their potency as ligands activating receptors, microbiota-regulation of bile acid profiles is likely to modulate the balance of the receptors. Furthermore, cortisol increases the risk of Alzheimer’s disease, indicating the potential involvement of stress response and GR (64). Also, the GR antagonist mifepristone is protective against cognitive deficit and reduces both β-amyloid and tau protein in brain (252, 253). As cortisol level changes in response to gut microbiota alterations, it could mediate the impact of dysbiosis on Alzheimer’s disease through activating GR. Nevertheless, the evidence linking Alzheimer’s disease and steroid-microbiota interactions is still tentative and largely correlative, there is still a lack of consensus on the underlying mechanisms and this merits further investigation.

Irritable Bowel Syndrome

Although patients with IBS often experience gastrointestinal discomfort, IBS is considered a disorder caused by ENS dysfunction and gut-brain axis dysregulation. At the same time, the gut microbiota is closely associated with ENS function and IBS symptoms. For instance, fecal transplant from patients with IBS to germ-free animals induced increases in visceral sensitivity (254). The female predominance of IBS suggests that sex hormones are involved in its pathogenesis (2). Indeed, steroids are associated with IBS symptoms including visceral hypersensitivity, gastrointestinal dysmotility, and depression. For instance, estrogens increase visceral sensitivity in animals, which may explain the higher sensitivity to pain in females (255). This could be due to estrogen potentiating TRPV1 channel activity (256), which contributes to pain sensation and is upregulated in IBS (125). Furthermore, sex steroids regulate the serotonergic system (2), which could also explain why sex dependence is evident in alterations of the serotonergic system in IBS, which is another signal associated with pain (257). Despite the lack of consistency in IBS-associated microbiome signatures, the gut microbiota could mediate the effect of steroids in IBS pathogenesis. For example, Akkermansia muciniphila is positively associated with estradiol and vitamin D, as well as increased colonic serotonin concentration (258) in patients with IBS-C (259). At the same time, the microbial metabolite butyrate is a TRPV1 channel agonist and modulates neuropathic pain (260), indicating that gut microbiota activity may modulate visceral sensitivity through producing metabolites that modulate ion channels.

As IBS often manifests clinical symptoms at prepubertal age when gonadal hormone production is still low, other steroids including adrenal hormones could be preferentially involved in the sex bias of functional gastrointestinal (GI) disorders in children. A study reported that DHEA-S and DHEA-S/DHEA is lower in patients with irritable bowel syndrome (IBS) (predominantly males) (261), whereas another study reported higher DHEA levels in IBS females under stress compared with controls (66). These studies also reported an altered cortisol:DHEA(S) ratio in IBS, implicating HPA-axis dysfunction. How these steroids influence IBS symptoms is still unclear but could possibly involve modulation of neuroreceptors. As described in previous sections, DHEA-S antagonizes the GABAA receptor and potentiates sigma-1 and NMDA receptors. At the same time, these signaling pathways are reported as altered in IBS. Activation of the colonic NMDA receptor contributes to visceral hypersensitivity (262). In contrast, GABAergic compounds, including pregabalin and gabapentin alleviate pain in patients with IBS (263, 264), while reduced GABAergic signals are found in patients with IBS-D (265). Bifidobacterium dentium produces GABA and desensitizes sensory neuron activity in a rat model of visceral hypersensitivity (266), demonstrating the role of gut microbiota in regulating GABAergic signals. However, before attributing neurotransmitter signaling by specific members of the microbiota community there is a need to establish that neurotransmission is maintained in vivo under physiological conditions, and that the impacted signaling pathway is validated using chemical and/or genetic intervention in the host. Taken together, these findings implicate that steroid-microbiota interaction may alter neurotransmitter synthesis and neuroreceptor activity, and subsequently modulate IBS symptoms. It should also be noted that changes in DHEA(S) appears to be sex-dependent in IBS, and therefore warrants study results to be stratified by sex when evaluating underlying mechanisms.

In addition to sex-related steroids, altered bile acid and related microbiome features are reported in some patients with IBS where they associate with gut dysmotility. Patients with IBS-C have lower fecal bile acids and DCA, whereas patients with IBS-D have excess fecal bile acids and a Clostridia-rich microbiome (267, 268). Secondary bile acids including DCA activate TGR5 that promotes colonic motility. At the same time, Coriobacteriaceae including its genus Eggerthella that regulates steroid and bile acid metabolism (269) are also increased in IBS (270, 271). Taken together, steroids and gut microbiota overlap in modulating many potential mechanisms underlying IBS pathology, including neuroreceptor activity, serotonergic tone, TRP channels, and bile acid signaling. Given that all of these factors are important in regulating gastrointestinal function, further investigations of how their cross talk modulates ENS function may provide further insight into IBS pathogenesis.

PHYTOSTEROL IMPACT ON THE MICROBIOTA-GUT-BRAIN AXIS

In addition to endogenous steroids, humans are exposed to plant steroids contained in the diet. These include phytosterols, steroid saponins, brassinosteroids, etc., which can influence microbiota-gut-brain axis signaling. Phytosterols including sitosterol, campesterol, stigmasterol, and cycloartenol are structurally similar to cholesterol. Dietary phytosterols are negatively associated with serum cholesterol levels (272). As cholesterol is important for the nervous system, the cholesterol-lowering property of phytosterols is possibly associated with neurological function. It is reported in animal studies that phytosterols can pass through the blood-brain barrier and accumulate in the brain, although no associated phenotypic alterations has been identified (273, 274). Some studies propose phytosterol intake is protective against cognitive and mood disorders. A study reported that stigmasterol inhibits the formation of amyloid-β and may protect against Alzheimer’s disease (275). Another study found that protective cognitive properties of stigmasterol are mediated by estrogen or NMDA receptors (276). Meanwhile, β-sitosterol exhibits antidepressant and anxiolytic effects (277, 278), possibly mediated through serotonergic, GABAergic, and dopaminergic mechanisms. Furthermore, phytosterols modulate the activity of endogenous steroid receptors. For instance, stigmasterol is reported to antagonize the bile acid receptor FXR (279). However, contrasting evidence show phytosterols do not impact neurocognitive function or mood changes, thus further confirmation is needed (280). In terms of gastrointestinal function, phytosterol alleviates symptoms of DSS-induced colitis in rodents, accompanied by changes to intestinal bile acid profiles and bile acid-deconjugating bacteria (281).

A reciprocal relationship between microbiota and phytosterols is also reported, connecting phytosterols to the microbiota-gut-brain axis. Gut microbiota biotransform phytosterols into phytostanone and phytostenone, and subsequently into phytostanols (282). At the same time, phytosterols modulate gut microbiota composition. In vitro fermentation of phytosterol increased Eubacterium hallii and reduced Erysipelotrichaceae abundance, which is associated with metabolic disorders (283). Consistent with this finding, plant sterol esters reduced the abundance of Erysipelotrichaceae in hamsters (269). A study with high-fat diet fed rats also reported changes in gut microbiome by phytosterol esters, with partial restoration of a healthy microbiota (284). Based on the current evidence, phytosterols are potential candidates for use as therapeutic interventions in disorders of the gut-brain axis. Future studies are needed to investigate how they could be applied to reverse alterations in steroids-microbiota interactions.

CONCLUSIONS

Steroids are well recognized for their role in regulating the gut-brain axis through modulating membrane receptors activities. Considerable evidence also demonstrates that the gut microbiota influences this network. Furthermore, both steroids and the microbiota-gut-brain axis are implicated in multiple disease etiologies. Multiple studies indicate steroids-microbiota interaction could influence disease development through modulating GABAA and NMDA receptors. However, there is limited direct evidence of detailed mechanisms underlying their disease associations. There is also inadequate information on the effect of neurosteroids on the ENS. Further effort is required to unravel this complex interplay involving multiple factors and signals. This review highlights how various steroids are involved in the microbiota-gut-brain axis via different potential mechanisms, and provides a fundamental basis to explore the many interconnected facets that comprise this network.

GRANTS

This work was supported by National Institutes of Health (NIH) Grants from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) P30-DK56338 and R01DK130517, NIAID U01-AI24290 and P01-AI152999, and National Institute of Nursing Research (NINR) R01-NR013497.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

S.S. and T.C.S. conceived and designed research; S.S. prepared figures; S.S. and T.C.S. drafted manuscript; S.S. and T.C.S. edited and revised manuscript; S.S. and T.C.S. approved final version of manuscript.