Bile acids (BAs) are a heterogeneous group of amphipathic steroidal acids that facilitate emulsification and absorption of dietary fats and other lipophilic compounds (Hofmann, 1999). BAs signal to nuclear and membrane BA receptors, which regulate immune responses, intestinal permeability, glucose and energy metabolism, and liver BA synthesis (McGlone and Bloom, 2019; Li and Chiang, 2014; Thomas et al., 2008; Shapiro et al., 2018; Fiorucci et al., 2018; Trauner et al., 2010; Pols et al., 2017). Greater understanding of BA signaling pathways may provide insights into molecular targets relevant to development of chronic metabolic diseases, including metabolic syndrome (MetS), Type-2 diabetes (T2D), and cardiovascular diseases (CVD).

Serum BA concentrations increase after a meal fluctuating between 2 - 8 μM (Suzuki et al., 2014) in healthy human subjects; however, serum levels of BAs and BA precursors may fluctuate differentially in healthy humans compared to patients with obesity, diabetes, or liver dysfunction (Azer and Hasanato, 2021a; Sonne et al., 2016; Steiner et al., 2011). Fasting serum levels of the BA precursor 7α-hydroxy-4-cholesten-3-one were reported to be higher in patients with T2D and MetS than in healthy controls, but median total BA concentrations were not significantly different (Steiner et al., 2011). In T2D patients, postprandial total BA levels were higher than healthy controls after consumption of a high-fat meal and this increase was due mainly to glycine and taurine conjugated BAs (Sonne et al., 2016). A systematic review of 28 clinical studies including subjects with liver diseases indicated that there are no specific BAs or BA ratios that can serve as a reliable biomarker for liver dysfunction, except in patients with intrahepatic cholestasis of pregnancy (Azer and Hasanato, 2021a). Moreover, evidence indicates that biological sex and age may also have a profound impact circulating/postprandial BA in healthy and obese individuals (Frommherz et al., 2016; Montagnana et al., 2020).

Hepatic cytochrome P450 (CYP) enzymes play an integral role in xenobiotic metabolism of drugs, toxins, and carcinogens, as well as in BA synthesis and steroid hormone metabolism (Russell and Setchell, 1992). In the liver, CYP family enzymes synthesize primary BAs (PBAs) from cholesterol via the classical or alternative pathways (Elliott and Hyde, 1971; Russell, 2003) in liver of mice and humans (Fig. 1). The classical or neutral BA pathway is responsible for 90% of PBA production, while 10% is synthesized via the alternative or acidic pathway, so called due to acidic intermediate products (Šarenac and Mikov, 2018). PBA synthesis requires 17 enzymes across intracellular compartments including the cytosol, endoplasmic reticulum, microsome, and peroxisome (Russell, 2003). The classical pathway is initiated by hydroxylation of cholesterol via cholesterol-7α-hydroxylase (CYP7A1), which is the rate-limiting enzyme for all PBA production, after which sterol 12α-hydroxylase (CYP8B1) produces 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one from 7 alpha-hydroxy-4-cholesten-3-one, an intermediate product that determines the levels of cholic acid (CA) and chenodeoxycholic acid (CDCA) produced (Chiang, 1998; Chiang, 2009). Sterol 27-hydroxylase (CYP27A1) is the first enzyme of the alternative pathway, but also plays a role in the classical pathway. In the classical pathway, CYP27A1 hydroxylates sterol intermediates produced by CYP8B1 (Monte et al., 2009). In the alternative pathway, CYP27A1 initiates BA synthesis via oxidation of cholesterol to 27-hydroxycholesterol (Russell and Setchell, 1992). 25- and 27-hydroxycholesterol is hydroxylated by oxysterol 7-alpha-hydroxylase (CYP7B1), which leads to the formation of CDCA in humans (Monte et al., 2009). The alternative pathway can account for more than 10% of the BA pool under conditions where CYP7A1 activity is deficient (Beigneux et al., 2002). Cholesterol conversion and BA synthesis may be initiated in other organs as well. Sterol 24-hydroxylase (CYP46A1), which is mainly expressed in the brain, converts cholesterol to 24-S-hydroxycholesterol (Chiang and Ferrell, 2020; Lund et al., 1999), which is then subsequently hydroxylated by hepatic sterol 7α-hydroxylase (CYP39A1) to form the PBA, CDCA (Chiang and Ferrell, 2020; Li-Hawkins et al., 2000; Lund et al., 1999). In humans, 0.2 - 0.6 mg of BA are synthesized daily to replace similar levels of BAs lost through fecal and urine excretion (Di Ciaula et al., 2017).

BA glucuronidation occurs by UDP-glucuronosyltransferase (UGT) (Strassburg et al., 1999) and sulfonation via sulfo-aminotransferases (SULTs) (Alnouti, 2009; Chiang, 2009). About 70% of BA in urine are sulfonated (Alnouti, 2009). BA-CoA:amino acid N-acyltransferase (BAAT) can conjugate with both glycine and taurine (Kase and Björkhem, 1989). PBA conjugation with taurine or glycine occurs via a two-step process; first BA–Coenzyme A synthase (BACS) generates BA-CoA then BAAT conjugates BA-CoAs with taurine (predominant in rodents) or glycine (predominant in humans) (Kase and Björkhem, 1989; O'Byrne et al., 2003; Solaas et al., 2000). BA conjugation with taurine, glycine, or sulfate groups regulates their toxicity, decreases intestinal re-absorption, enhances solubility, promotes excretion, and alters affinity to BA receptors (Perreault et al., 2013; Schaap et al., 2014; Wan and Sheng, 2018).

BA composition differs between humans and murine species as summarized in Fig. 1 (Thakare et al., 2018). CA is the major PBA in rodents while CDCA is the predominant PBA in humans (Chiang, 1998; Chiang, 2009). Hyocholic acid (HCA) also known as gamma-muricholic acid (γMCA), is considered aminor PBA in humans, synthesized from CDCA by enzyme CYP3A4 (Chavez-Talavera et al., 2020), making up ~3% of the BA pool (Zheng et al., 2021). CDCA is also reported to be converted to HCA in mice (Lefebvre et al., 2009a); however, is more commonly considered a bacterially-derived BA in rodents (Deo and Bandiera, 2008).

Other PBAs of physiological importance in mice include α-muricholic acid (αMCA) and βMCA, which are derived from oxidation of CDCA and ursodeoxycholic acid (UDCA) by Cyp2c70 in mice (Botham and Boyd, 1983; Takahashi et al., 2016) and by Cyp2c22 in rats (Botham and Boyd, 1983; Takahashi et al., 2016)..UDCA is another BA which is considered primary in mice, but not humans (Wahlström et al., 2016). Interestingly, deletion of hepatic Cyp2c70 in mice promoted a hepatic BA profile similar to humans (de Boer et al., 2020). In mice, CDCA is converted to αMCA and βMCA, with high efficiency (de Boer et al., 2020; Honda et al., 2020), however, humans do not express Cyp2c70 and so these MCAs are are not considered to be synthesized in humans (Francis et al., 2013), though have been detected in human urine in some studies (García-Cañaveras et al., 2012; Goto and KHaTN. CCLIV., 1991). No unconjugated α- or β-MCA were detected in healthy human serum or liver and only minute levels of TαMCA (2.9 ± 2.7 nM) were detected in serum (García-Cañaveras et al., 2012). Overall, α- or β-MCAmade up < 0.2% of the total BA pool of NASH and non-NASH patients, with significantly less detected in serum NASH patients (Chen et al., 2019), but more in urine of cholestatic adults (7.2% of total BAs) (Shoda et al., 1988). Greater concentrations of conjugated and unconjugated α- or β-MCA are detected in neonates (~1 μM) (Zöhrer et al., 2018), suggesting an age-dependent effect on this BA species. Despite their detection in circulation and urine, origins of α- or β-MCA are obscure in humans, and it is not known whether they are primary or bacterially derived in nature.

Once conjugated, PBA enter the gastrointestinal tract (GIT) where they may be metabolized to secondary BAs (SBAs) by bacteria encoding deconjugating, dehydroxylating, epimerizing, and reducing enzymes (Wahlström et al., 2016) (Fig. 2). Prerequisite to SBA formation is deconjugation of PBA taurine or glycine moieties (e.g., TCA →CA) by microbial bile salt hydrolases (BSH) (Sayin et al., 2013). Gut microbial 7α-dehydroxylases (7αDHs), 7βDHs, reductases, hydroxysteroid dehydrogenases (HSDH), and epimerases (Ridlon et al., 2006) subsequently modify unconjugated PBAs to produce diverse SBA species.

Next-generation sequencing analysis revealed that strains from Clostridium, Lactobacillus, Bacteroides, Bifidobacterium, and Enterococcus genera possess multiple bsh genes within and across taxa, encoding BSH enzymes with different specific activities (Fiorucci and Distrutti, 2015; Ridlon et al., 2006; Song et al., 2019; Winston and Theriot, 2020). Post-deconjugation, other bacterial modifications of unconjugated PBA include dehydroxylation, epimerization and reduction reactions catalyzed by select gut bacteria, including Bacteroides, Peptostreptococcus, Ruminococcus, Eggerthella, Clostridium, Escherichia, and Eubacterium genera (Ridlon et al., 2006; Ridlon et al., 2016).

The activity of SBA-producing enzymes may vary between gut microbes; BSH from Lactobacillus strains exhibited superior deconjugation activity compared to BSH found in Bacteroides strains, which had variability in deconjugation activity (Song et al., 2019). Clostridium XIVa, Clostridium XI, and Eubacterium taxa produce SBA, such as deoxycholic acid (DCA) and lithocholic acid (LCA), using 7α/βDHs encoded by BA inducible (bai) operon genes (Doerner et al., 1997; Takamine and Imamura, 1995; Wang et al., 2020) (Fig. 2). Some gut bacteria, such as Clostridium hiranonis TO-931, encode BSH and 7α/βDH and therefore perform both reactions needed to modify conjugated PBA into DCA and LCA (Ridlon et al., 2016). BSH genes were also identified in archaeal species, such as Methanobrevibacter smithii ATCC 35061 and Methanosphaera stadtmanae DSM 3091 (Heinken et al., 2019; Samuel et al., 2007). Human intestinal archaea may also possess 3α/12α-HSHD activity in addition to BSH, which suggests archaea may influence SBA pools and BA signaling (Doden et al., 2018).

In the intestinal lumen of humans and rodents, the most concentrated SBAs include ωMCA, hyodeoxycholic acid (HDCA), murideoxycholic acid (MDCA), LCA, DCA, HCA, as well as their taurine or glycine conjugates (Eyssen et al., 1999; Ridlon et al., 2014). While rodent gut bacteria can convert βMCA to ωMCA, the origin of ωMCA in humans is unclear (GDP et al., 1983; MP et al., 1985). UDCA is a PBA in rodents and bears, but a SBA in humans (Wahlström et al., 2016). Structures of unconjugated and conjugated PBA and SBA species common to humans and mice and are shown on Fig. 3. Iso-, allo-, 3-oxo-, 7-oxo-, and isoallo- forms of CA, CDCA, LCA, and DCA, are rare SBA species synthesized by bacteria from Parabacteroides, Bacteroides, Alistipes, Clostridium, Odoribacter, Hungatella, and Lachnospiraceae taxa (Heinken et al., 2019), and may be associated with longevity (Sato et al., 2021). Due to microbial metabolism of PBAs, human and murine fecal samples contain high concentrations of SBA (Kakiyama et al., 2014) (Fig. 2). Close to 100% of BAs in colon content are derived from microbial modulation (Devlin and Fischbach, 2015; Ridlon et al., 2006).

Microbes metabolize BAs and BAs in turn shape the gut microbial community. Due to their amphipathic nature, BAs act as detergents with strong antimicrobial properties (Stacey and Webb, 1947) that influence composition and diversity of the gut microbiota (Tian et al., 2020; Winston and Theriot, 2020). Unconjugated BAs exhibit more potent antibacterial activity than conjugated BAs and gram-positive gut bacteria are more sensitive to detergent properties of BAs than gram-negative bacteria (Tian et al., 2020). It was recently shown that pathogenic bacterial species, Klebsiella pneumoniae and Enterococcus faecalis are resilient to high BA levels in vitro (An et al., 2022), suggesting elevated BA levels may not protect against all pathogens. Interestingly, BAs rapidly alter host gut microbial metabolism including amino acid, nucleotide, and carbohydrate metabolic pathways (Tian et al., 2020). Concomitant alterations in gut microbial communities and BA profiles are associated with metabolic and intestinal diseases (Wahlström et al., 2016). Intestinal BAs may benefit metabolic health by inhibiting pro-inflammatory gut bacteria/pathogens and subsequent intestinal inflammation.

BA transport is a highly regulated process crucial to maintenance of BA homeostasis (Fig. 4). BAs are secreted into the bile duct canaliculus via ATP-dependent bile salt export pump (BSEP) and multi-drug resistance protein 2 (MRP2), and stored in the gallbladder prior to being secreted post-prandially into the duodenum via mechanisms driven by cholecystokinin (Chiang, 2009; Choi et al., 2006). Substrates for BSEP includes monovalent BAs like taurine- and glycine-conjugated BAs while less abundant divalent BAs like sulfate- or glucuronide-conjugated BA are transferred by MRP2 (Hidetaka Akita et al., 2001). Sulfated BAs inhibits BSEP transport via allosteric binding (Hidetaka Akita et al., 2001).

The majority of BAs (~95%) secreted into the intestine are reabsorbed into enterohepatic circulation via BA-specific transporters, namely apical Na+-dependent bile salt transporter (ASBT) on the apical side of enterocytes (Balakrishnan and Polli, 2006). Most BA recirculation occurs in the ileum, where ASBT is highly expressed (Thomas et al., 2008; Ticho et al., 2019). Ileal ASBT facilitates uptake of predominantly conjugated BA while deconjugated BA are reabsorbed via passive diffusion throughout the intestinal tract (Balakrishnan and Polli, 2006). Located in cytoplasm of enterocytes, ileal bile-acid-binding protein (IBABP), also known as fatty acid binding protein-6 (FABP6), promotes BA flux to protect enterocytes from BA accumulation (Grober et al., 1999).

Within enterocytes, BAs can interact with intracellular nuclear or membrane-bound G-protein-coupled BA receptors prior to entering circulation or being excreted (Ticho et al., 2019). Nuclear transcription factor farnesoid X-receptor (FXR) is a BA receptor classically known for its role in regulating hepatic BA synthesis and efflux (Makishima et al., 1999; Parks et al., 1999; Wang et al., 1999). Intestinal FXR activation by BAs initiates transcription of fibroblast growth factor-15 (Fgf15) in mice or FGF19 in humans, which enters circulation and binds to the fibroblast growth factor receptor 4 (FGFR4)/βKlotho receptor in the liver to trigger a cascade of reactions to inhibit BA synthesis (Sayin et al., 2013; Shapiro et al., 2018).

On the basolateral side of enterocytes, enterohepatic BA transport is mainly mediated by MRP3 and MRP4 (Borst et al., 2007), as well as organic anion transporting polypeptide 2 (OATP2), and heteromeric organic solute transporter-alpha (OSTα) and -beta (OSTβ) (Beaudoin et al., 2020; Rao et al., 2008). Conjugated and unconjugated BAs are absorbed during BA uptake in the terminal ileum; however, conjugated PBAs (e.g., TCA) are preferentially re-absorbed (Roberts et al., 2002). BA can also be re-excreted into the intestine via MRP2, which is expressed on the apical side of enterocytes (Bodó et al., 2003). Unabsorbed BAs enter the colon and some unconjugated BA (e.g., CA, CDCA) passively diffuse across colonocytes (Thomas et al., 2008). Lower concentrations of unconjugated BA are reabsorbed into the portal vein compared to conjugated BA species, most unconjugated BA are excreted in feces while conjugated BA recirculate back to the liver (Chiang, 2009; Thomas et al., 2008; Ticho et al., 2019).

BAs from enterohepatic circulation can enter the liver via Na+-taurocholate co-transporting polypeptide (NTCP) or OATP1 and activate hepatic FXR signaling (Meier and Stieger, 2002). Hepatic FXR activation initiates transcription of small heterodimer partner (SHP), which inhibits expression of CYP7A1 in the liver (Brendel et al., 2002), although intestinal FXR signaling is the predominant pathway for suppressing BA synthesis. In the liver, BAs can enter systemic circulation via hepatic MRP3, MRP4, and by bi-directional transporter OSTα-OSTβ heterodimer (St-Pierre et al., 2001). In normal physiological conditions, less than 1% of the total BA pool reaches systemic circulation (Van der Werf et al., 1985). Liver injury causes increased efflux of BA into circulation, a feature associated with T2D, cardiomyopathies, cholestasis, and liver diseases (Sonne et al., 2016; Sun et al., 2016; Wang et al., 2016; Xie et al., 2020; Zhang et al., 2019). Preclinical and clinical data highlight the relevance of BA signaling and BA receptor modulation in mediating metabolic health (Ferrell and Chiang, 2019; Holter et al., 2020; Molinaro et al., 2018).

Uncovering the signaling properties of BAs has revolutionized understanding of BA biology (Schaap et al., 2014). FXR and Takeda G-protein coupled receptor 5 (TGR5) (Maruyama et al., 2002; Watanabe et al., 2006) are the best studied BA receptors. Constitutive androstane receptor (CAR), pregnane X-receptor (PXR), retinoid X-receptor (RXR), liver X-receptor-α and -β (LXRα/β) and vitamin D receptor (VDR) are non-canonical nuclear BA receptors (Wan and Sheng, 2018), while sphingosine-1-phosphate receptor-2 (S1PR2) (Studer et al., 2012), cholinergic receptor muscarinic 2 (M2R) and 3 (M3R) (Raufman et al., 2003; Sheikh Abdul Kadir et al., 2010) are non-canonical G protein-coupled BA receptors found on cell membranes (Table 1 and Fig. 5).

Discovered as a BA receptor 20 years ago (Makishima et al., 1999; Parks et al., 1999; Wang et al., 1999), FXR is expressed in many tissue and cell types and is involved in multiple metabolic processes (Shapiro et al., 2018). Interestingly, both suppression and activation of FXR have been reported to improve metabolic health in models of metabolic diseases. Suppression of intestinal FXR was shown to improve metabolic phenotypes via an intestinal FXR-ceramide signaling axis which lowered circulating ceramides to promote insulin sensitivity and/or glucose metabolism in murine models of genetic and diet-induced obesity (Jiang et al., 2015; Tveter et al., 2020; Xie et al., 2017). FXR activation may indirectly activate TGR5, which is expressed in metabolic tissues including heart, kidney, small intestine, brown and white adipose tissue (BAT, WAT). Tgr5 activation has been shown to increased energy expenditure and mitochondrial markers of non-shivering thermogenesis (Pathak et al., 2017; Pathak et al., 2018; Watanabe et al., 2006). Unlike the other GPCRs, TGR5 was reported to be activated by unconjugated BA (e.g., LCA, DCA, CDCA, CA, UDCA) (Maruyama et al., 2002). TGR5 may aid in processes related to innate immune regulation (Shi et al., 2021), regulation of glucose metabolism via GLP-1 secretion (Thomas et al., 2009), and enhanced energy expenditure (Velazquez-Villegas et al., 2018). Due to the metabolic potential of TGR5, it is frequently analyzed using models of metabolic illnesses. TGR5 also promotes GLP-1 secretion, which stimulates insulin production (Thomas et al., 2009).

Activation of intestinal FXR inhibited LPS-induced intestinal inflammation in rodent models of colitis as well as human and murine macrophages (Vavassori et al., 2009). Hepatic FXR activation reduced lipogenesis and gluconeogenesis in db/db mice leading to less hyperlipidemia and hyperglycemia (Gadaleta et al., 2011; Zhang et al., 2006). Activation of FXR and SHP may protect against deregulated inflammatory pathways characteristic of metabolic diseases (Hotamisligil, 2006). FXR transactivates SHP (Goodwin et al., 2000) which inhibits assembly of NOD-like receptor pyrin domain containing 3 (NLRP3) (Yang et al., 2015). NLRP3 is predominately expressed in macrophages and promotes transcription of inflammatory cytokines (Lu and Wu, 2015). Blocking NLRP3 inflammasome activation was shown to protect against HFD-induced obesity in rodents (Biao et al., 2022; Pan et al., 2021); polymorphisms of NLRP3 was associated with T2D in Chinese Han populations (Rheinheimer et al., 2017). Alterations in hepatic FXR and SHP signaling were shown to regulate expression of lipogenic genes, such as Srebf1, to reduce HFD-induced hypertriglyceridemia (Watanabe et al., 2004). The activation or suppression of FXR in metabolic tissues was shown to promote metabolic resilience via different mechanisms; however, these studies did not investigate how other BA receptors are affected.

Nuclear BA receptor RXR heterodimerizes with FXR or LXR to alter expression of PBA biosynthesis and cholesterol transport genes (Repa et al., 2000). RXR may also heterodimerize with PXR, VDR, peroxisome proliferator-activated receptor-gamma (PPARγ), or CAR to regulate lipid and glucose metabolism, BA synthesis, and protect against toxic BA species (e.g., LCA) in the intestine and liver (Cave et al., 2016; Makishima et al., 2002; Moore et al., 2002; Staudinger et al., 2001). Activation of PXR by LCA was shown to induce expression of CYP3A and promote detoxification pathways (Xie et al., 2001). PXR may also regulate expression of hepatic Oatp2 and Cyp7a1, which suggests PXR may influence hepatic BA transport and synthesis mechanisms as well (Staudinger et al., 2001). LXR is a transcription factor involved in regulating metabolism of cholesterol to oxysterols in the liver (Baranowski, 2008). FXR may also mitigate inflammatory responses and lipogenesis via PPARγ signaling (Renga et al., 2011; Savkur et al., 2005).

M2R and M3R were reported to interact with conjugated PBAs and SBAs including TCA, TLCA, TDCA, and GDCA (Cheng et al., 2002; Raufman et al., 2002). M2R and M3R predominate in epithelial and smooth muscle tissues (Eglen, 1996). A study using neonatal rat cardiomyocytes showed BA-induced arrhythmia was driven via M2R, which may help regulate cardiac contractions (Sheikh Abdul Kadir et al., 2010). M2R and M3R may also play a role in regulating blood glucose and insulin levels (Gautam et al., 2006; Wess et al., 2007). Known BA ligands for S1PR2 includes TCA TDCA, TUDCA, GCA, and GDCA (Studer et al., 2012). Hepatic activation of S1PR2 by conjugated BAs promoted extracellular regulated kinase (ERK)1/2 and protein kinase B (PKB, also called AKT) signaling pathways, which may increase susceptibility to hepatocyte damage or exacerbate cholangiocarcinoma (Liu et al., 2014; Studer et al., 2012). TCA-induced activation of S1PR2 upregulated expression of sphingosine kinase 2 (Sphk2) and genes involved in hepatic nutrient metabolism within primary mouse hepatocytes in a S1PR2- and Sphk2-dependent manner (Nagahashi et al., 2015). Collectively, these findings highlight the potential of S1PR2 to interfere in hepatic metabolism and cellular processes.

BA signaling plays a pivotal role in mediating energy homeostasis (Cave et al., 2016); therefore, BA-receptor pathways gained attention as promising targets for therapeutics (Li and Chiang, 2014; Schaap et al., 2014). Consumption of food stimulates BA secretion and influences gut microbial composition and in-turn BA profiles; therefore, the impact of dietary compounds on BA receptor activity may occur via modulation of gut microbiome (Just et al., 2018). Dietary compounds targeting BA receptors or downstream signaling pathways may lead to development of novel therapeutics for metabolic, liver, and cardiovascular diseases (Chiang, 2017; Lefebvre et al., 2009b; Thomas et al., 2008).

To ensure cholesterol homeostasis, cholesterol conversion to BAs is tightly coordinated during the day/night to align with feeding-fasting times, and light-dark cycles. Cyp7a1 expression oscillates during the day in rodents and humans and increases in response to feeding, supporting a food- and circadian-dependent influence on BA synthesis (Duane et al., 1983; Gielen et al., 1975). Circadian clockwork is coordinated by the suprachiasmatic nuclei (SCN) of the hypothalamus and peripheral organs via a feedback loop between a complex of heterodimerized transcriptional activators, i.e., circadian locomotor output cycles Kaput (CLOCK) complexed to brain and muscle-ARNT-Like 1 (BMAL1), and period proteins complexed to cryptochromes (Yang and Zhang, 2020a). Increased levels of CLOCK:BMAL1 during waking hours activate transcription of orphan nuclear receptor, reverse erythroblastosis virus-α/β (REV-ERBα/β), a regulator of lipid metabolizing genes (Preitner et al., 2002). REV-ERB genes recruit histone deacetylase 3 to different regulatory genes and change their expression by deacetylation (Feng, 2013). Expression of BA regulating genes were shown to correlate with increased REV-ERBα/β during waking hours (Duez et al., 2008; Le Martelot et al., 2009), suggesting REV-ERBα/β may regulate BA homeostasis genes. REV-ERBα deficient mice had reduced hepatic Cyp7a1 and increased Shp mRNA levels (Duez et al., 2008; Le Martelot et al., 2009). Knock-down studies have postulated that REV-ERBα accumulation may modulate BA synthesis by inhibiting insulin-induced gene 2 (Insig-2) gene expression and preventing its inhibition of SREBP (Le Martelot et al., 2009). SREBP promotes synthesis of cholesterol precursors, like oxysterols, which can function as ligands to LXR and promote Cyp7a1 transcription (Le Martelot et al., 2009). Relative mRNA levels of Fxr, BA synthesis regulatory genes (Fgf15 and Shp), and BA transporters (Asbt, Ostα, Mrp2) in livers and ileal tissue were differentially altered by circadian rhythms (Zhang et al., 2011). The circadian serum and liver BAs profiles in C57BL/6 mice indicated enhanced dehydroxylation during fasted state, and increased host re-conjugation of hepatic BAs post-feeding (Zhang et al., 2011), which suggested that gut bacterial BA metabolism also responded to circadian rhythm (Zhang et al., 2011).

In humans, shift work-induced disruption of circadian rhythms has been linked to MetS and CVD (Frommherz et al., 2016). HFD daytime restricted feeding regimen in mice was employed to mimic shiftwork eating and was shown to abolish the circadian fluctuation of hepatic CYP7A1 and CYP8B1 genes, as well as period proteins and cryptochrome genes in the SCN, and of CLOCK and CRY genes in the ileum (Chiang, 2017). In a model of metabolic disease, HFD-feeding was shown to disrupt the circadian regulation of the gut microbiome (Azer and Hasanato, 2021a; Sonne et al., 2016), which could further influence circadian rhythms of BA profile (Zhang et al., 2011). Supplementing mice with high-fat milk for four weeks in the evenings promoted fatty liver and hypercholesteremia in association with reduced hepatic Clock and Bmal1, and increased Cry2 mRNA levels (Wang et al., 2013), implicating that genes involved in regulating circadian rhythm may influence mechanisms underlying hepatobiliary diseases. These alterations occurred with reductions to hepatic Cyp7a1, which was hypothesized to contribute to increased liver cholesterol (Wang et al., 2013). Thus, both obesogenic diets and arhythmic eating may impair BA homeostasis by disrupting circadian rhythm signaling. The impact of diet and other drug therapies on circadian rhythm signaling should be considered in future preclinical studies and translational research.

Global prevalence of obesity, MetS, T2D, non-alcoholic fatty liver disease (NAFLD), and CVD are all increasing (Le et al., 2022; Organization WH, 2016; Organization WH, 2017; Roth et al., 2020). CVD is the most common non-communicable disease globally; in 2019, the WHO reported CVD was associated with 18.6 million deaths globally (Depommier et al., 2019b) with 80% of deaths occurring in low to middle income countries (Chambers et al., 2019b). The increased incidence of cardiometabolic disease during this time is largely due to increased consumption of highly processed foods that are rich in sugars and seed oils, but low in fiber and phytonutrients, combined with more sedentary lifestyles (Kopp, 2019). Evidence suggests that whole and minimally processed foods rich in dietary polyphenols and fiber is protective against metabolic disease in a manner involving the gut bacteria (Villa-Rodriguez et al., 2019).

Polyphenols are secondary metabolites produced by plants to protect against oxidative and environmental stressors; however, humans benefit from consumption of polyphenols as well (Cory et al., 2018; Pandey and Rizvi, 2009; Vauzour et al., 2010). Polyphenols are categorized into several families and comprised of a diversity of monomeric and polymeric subunits containing one or more phenolic rings in their chemical structure (Abbas et al., 2017). Plant foods rich in polyphenols (e.g., fruits, berries, vegetables, tea, coffee, spices, nuts, legumes, and whole grains) have been reported to promote metabolic resilience and may protect against developing cardiometabolic diseases, such as T2D, hepatobiliary diseases, and CVD (Amiot et al., 2016; Cao et al., 2019; Chiva-Blanch and Badimon, 2017). Diet is the main determinant of gut microbial composition (Rowland et al., 2018). Polyphenols generally have poor bioavailability, and their metabolic benefits appear to be mediated by their modulation of the gut microbiota and polyphenol-derived microbial metabolites (Liu et al., 2019a; Roopchand et al., 2015a; Tomás-Barberán et al., 2016). In addition, many studies suggest polyphenols alter a gut microbiome-BA signaling axis to promote metabolic health (Table 2).

Polyphenol-induced alterations of BA pathways represent novel mechanisms of action with respect to resilience against metabolic disease (Anhê et al., 2019; Han et al., 2020; Li et al., 2021a; Tveter et al., 2020). SHP and FXR are orphan receptors that may respond to ligands other than BAs (Denson et al., 2001; Parks et al., 1999). Research suggests polyphenols may act as ligands for BA nuclear receptors (Li et al., 2012), while other studies indicate polyphenol metabolites do not bind BA receptors (Del Bas et al., 2009; Han et al., 2020). Other studies report polyphenols modulate cholesterol metabolism by interacting directly with BA receptors or through indirect promotion of BA synthesis (Chambers et al., 2019a; Del Bas et al., 2009; Huang et al., 2018a). Moreover, there is evidence that polyphenols may act as co-agonists of BA receptor activity in the presence of known BA agonists, such as CDCA (Alfaro-Viquez et al., 2018a; Del Bas et al., 2009). Based on preclinical and clinical studies, the metabolic benefits of polyphenols may be mediated through modulation of gut microbial communities (Anhê et al., 2015a; Roopchand et al., 2015a; Yang et al., 2021a; Zhao et al., 2019) and BA signaling (Anhê et al., 2019; Ezzat-Zadeh et al., 2021; Han et al., 2020; Li et al., 2021a; Rodríguez-Morató et al., 2018; Tveter et al., 2020; Zhao et al., 2021). The following sections review the literature covering the relationships between polyphenol-induced changes in gut microbial communities, BA profiles, and signaling to BA receptors in the context of MetS, T2D, hepatobiliary diseases, and CVD.