Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases

Abstract

Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.

Keywords: AS, atherosclerosis; ASBT, apical sodium-dependent bile salt transporter; BAs, bile acids; BSEP, bile salt export pump; BSH, bile salt hydrolases; Bile acid; CA, cholic acid; CAR, constitutive androstane receptor; CCs, cholesterol crystals; CDCA, chenodeoxycholic acid; CMD, cardiometabolic disease; CVDs, cardiovascular diseases; CYP7A1, cholesterol 7 alpha-hydroxylase; CYP8B1, sterol 12α-hydroxylase; Cardiometabolic diseases; DAMPs, danger-associated molecular patterns; DCA, deoxycholic acid; DCs, dendritic cells; ERK, extracellular signal-regulated kinase; FA, fatty acids; FFAs, free fatty acids; FGF, fibroblast growth factor; FMO3, flavin-containing monooxygenase 3; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide 1; HCA, hyocholic acid; HDL, high-density lipoprotein; HFD, high fat diet; HNF, hepatocyte nuclear receptor; IL, interleukin; IR, insulin resistance; JNK, c-Jun N-terminal protein kinase; LCA, lithocholic acid; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPS, lipopolysaccharide; NAFLD, non-alcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor-κB; NLRP3, NLR family pyrin domain containing 3; Nuclear receptors; OCA, obeticholic acid; PKA, protein kinase A; PPARα, peroxisome proliferator-activated receptor alpha; PXR, pregnane X receptor; RCT, reverses cholesterol transportation; ROR, retinoid-related orphan receptor; S1PR2, sphingosine-1-phosphate receptor 2; SCFAs, short-chain fatty acids; SHP, small heterodimer partner; Systemic immunometabolism; TG, triglyceride; TGR5, takeda G-protein receptor 5; TLR, toll-like receptor; TMAO, trimethylamine N-oxide; Therapeutic opportunities; UDCA, ursodeoxycholic acid; VDR, vitamin D receptor; cAMP, cyclic adenosine monophosphate; mTOR, mammalian target of rapamycin; ox-LDL, oxidated low-density lipoprotein.

Graphical abstract

Figure 1

Dysregulated metabolic adaptation and the aberrant systemic immunometabolism in CMD. Metabolic homeostasis involves the coordination of multiple levels of crosstalk and communication at the organ system, tissue, and cell levels. Endogenous metabolites serve as both nutrients and signal molecules to coordinate the organismal homeostasis. The target organs of CMD include but not limit to the liver, gut, pancreatic islet, adipose tissue, heart, and blood vessels. However, this homeostasis is disrupted in conditions of CMD due to dysregulated metabolic adaptation and thereby the aberrant systemic immunometabolism.

Figure 2

BAs play central roles in orchestrating lipid and glucose metabolism. BAs are important metabolic regulators of lipids and glucose via targeting FXR and other nuclear receptors. BAs activate hepatic FXR–SHP pathway, preventing hepatic triglyceride (TG) accumulation via inhibiting hepatic lipogenesis by interfering with the promoters (carbohydrate response elements, ChOREs) of glucose-regulated genes and SREBP-1C. SREBP-1C induces acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl CoA desaturase (SCD). In addition, FXR-SHP pathway acts on de novo cholesterol synthesis by inhibiting SREBP-2. FXR activation regulates cholesterol uptake by inhibiting PCSK9; alleviates the very low-density lipoprotein (VLDL) and TG secretion by repressing the expression of microsomal TG transfer protein (MTP); induces phospholipid transfer protein (PLTP) and angiopoietin-like protein 3 (ANGPTL3); promotes FA β-oxidation though engaging PPARα. Intestinal FXR activation leads to FGF15/19 secretion and thereby inhibiting expression of NPC1-like intracellular cholesterol transporter 1 (NPC1L1) in intestine and cholesterol absorption. In addition, FXR induces ApoE but suppresses hepatic ApoC-III expression and thus inhibiting lipoprotein lipase (LPL). For glucose metabolism, BA–FXR signaling inhibits gluconeogenesis and promotes glycogen synthesis by negative regulation of G6Pase and carbohydrate responsive element-binding protein (ChREBP). In intestinal L cells, BA–TGR5 signaling leads to GLP-1 expression and secretion, whereas BA–FXR signaling inhibits GLP-1 production. Activation of TGR5 in brown adipocytes positively regulates cAMP–D2 signaling pathway, promoting mitochondrial fission and beige remodeling of white adipose tissue as well as provoking FFAs release. FXR in β cell stimulates insulin secretion via K_ATP channel inhibition. TGR5 activation augmented a hyperglycemia-induced switch from glucagon to GLP-1 synthesis in islet α cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of polycystin-1 (PC1) to promote glucose homeostasis.

Figure 3

BAs and other relevant lipids serve as DAMPs and direct inflammatory triggers. BAs (such as DCA and CDCA) are metabolic DAMPs that can activate both signal 1 and 2 of the NLRP3 inflammasome and thereby promoting the secretion of IL-1β, and at high levels, BAs can further open the mitochondrial permeability transition pore and facilitates a very fast pryoprototic death of immune cells. In contrast, some BA species like LCA can also repress NLRP3 inflammasome via activation of TGR5 signals through the cAMP–NF-κB signaling pathway, and can decrease oxidized LDL uptake in macrophages and thereby protecting against on atherosclerotic plaque. Cholesterol crystal (CC) and oxLDL, both of which are regulated by BA signals, are also important DAMPs in activating NLRP3 inflammasome. CC causes lysosomal damage, and thereby activating NLRP3 inflammasome; CC also activate the complement system, which promotes macrophage priming (signal 1) as well as CC phagocytosis and hence, NLRP3 activation. Besides, BAs associated metabolites such as ox-LDL, palmitic acid and saturated fatty acid (SFA) contribute to the pro-inflammation of macrophages through TLR2/4 mediated activation of NLRP3 inflammasome.