The sterolbiome is a term that exemplifies the interaction of the intestinal flora and bile as a steroid-based endocrine system. In addition, there are continuous interactions among these essential systems in the gastrointestinal skin, oral, respiratory and reproductive tracts.

“The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an endocrine organ with potential to alter host physiology, perhaps to their own favor’’¹

The sterolbiome alters the function of human cells and tissues for its own advantage, while also having major effects that benefit the host. The focus of this article will be on the sterolbiome’s regulation of host inflammation. Hepatocytes synthesize and secrete the water-soluble primary bile acids—cholic acid and chenodeoxycholic acid. These are conjugated with glycine, taurine, sulfate or glucuronide. The intestinal microbiome metabolizes these into the fat-soluble secondary bile acids—deoxycholic and lithocholic acid. In addition, the bacteria may also deconjugate them.

Bile belongs in the small intestine and typically only 5% enters the colon. Bile salts are present in tiny amounts (or not at all) in the other parts of the digestive tract. Bile flows through the entire 18-20 feet of small intestine and is then reabsorbed in the terminal ileum. The bile returns via enterohepatic recirculation for reprocessing and recycling back to the gall bladder and the process starts over. Diseases in the terminal ileum (eg. Crohn’s disease) or resection of the terminal ileum often lead to bile malabsorption. If too much bile enters the colon, it acts as an irritant and can be a cause of severe diarrhea (bile acid diarrhea). Some irritable bowel syndrome patients are ultrasensitive to even normal amounts of bile in the colon and develop diarrhea. Sometimes bile flows up to the stomach (this is called bile reflux) and causes irritation of the stomach lining (bile gastritis).

Primary bile acids participate in micelle formation with lecithin and cholesterol to expedite absorption of fats and fat soluble vitamins. The secondary bile acid metabolites influence nuclear receptors (such as the farnesoid X receptor) and cell surface receptors (G-protein coupled receptors) exerting major effects on inflammation. Primary and secondary bile acids both activate other nuclear receptors such as the pregnane-x-receptor (PXR),² the constitutive androstane receptor (CAR),³ and the vitamin D receptor (VDR).

Farnesoid X Receptor (FXR)

FXR influences glucose and lipid metabolism, tumor suppression, drug metabolism, cell differentiation and inflammation. FXR is found in the GI/liver axis, cardiac,⁴ endocrine/metabolic,⁵ renal,⁶ pulmonary,⁷ breast,⁸ vascular,⁹ and nervous systems.¹⁰ Research suggests that FXR activation is tissue protective in acute inflammation and appears to reduce intestinal inflammation in digestive diseases. In colitis, FXR activation decreases local IL-1β and increases systemic IL-10 expression.¹¹ FXR activation upregulates physiological hydrogen sulfide production, important for the maintenance of gastrointestinal mucosa in the presence of NSAIDs.¹² In chronic inflammatory states, FXR activation reduces colitis and inhibits pro-inflammatory cytokines in humans.¹³ Single-nucleotide polymorphisms in the FXR gene are significantly associated with altered barrier function and upregulation of inflammation of Crohn’s and ulcerative colitis.¹⁴ When ligands activate FXR nuclear receptors, metabolic changes within cells are rapidly sensed leading to transcriptional responses. Responding to elevations in intracellular bile acid concentration, FXR induces protective gene expression. This induces bile salt export pumps, avoiding bile acid toxicity in the liver and intestine.¹⁵ This signaling also prevents bacterial overgrowth in the ileum.¹⁶ Impaired bile flow may down-regulate FXR signaling, leading to enterocyte damage, increased bacterial translocation and systemic infections.

Fecal microbiota transplantation is associated with increased FXR activity.¹⁷ Similar results are seen with supplementation with the anti-inflammatory bile acid ursodeoxycholic acid (UCDA) in murine C. diff models. UDCA administration leads to increased expression of the FXR pathway in both cecal and colonic tissue, likely through its salutary microbiome effects.¹⁸

FXR knockout mice were found to have lower expression of the tight junction proteins ZO-1 and claudin-1. Chenodeoxycholic acid, the primary bile acid that is considered the strongest endogenous FXR ligand, has been found to prevent decreases in ZO-1, occludin, and claudin-1 in response to lipopolysaccharide.¹⁹

G protein coupled receptors (GPCRs)

G protein coupled receptors are a superfamily of cell surface receptors. They are found on immune cells and enteric nerves as well as epithelial cells in the intestine and biliary tracts. They support functional intestinal permeability, anti-inflammatory activity in dendritic cells, monocytes, macrophages, and natural killer cells and also mediate motility via enteric nerves.²⁰ Bile acids and short chain fatty acids activate GPCRs, which are found in the gallbladder, spleen, some intestinal and white blood cells, bile duct, and fat cells. When stimulated, GPCR increases levels of incretins, glucagon, and insulin.²¹

Microbial derived-short chain fatty acids and bile acids influence the immune system as ligands for GPRCs. Intestinal bacteria produce hormones (e.g. serotonin, dopamine and somatostatin), as well as responding to and regulating host hormones. Examples include inhibiting genes that transcribe prolactin or converting glucocorticoids to androgens). There are regulatory effects from these receptors on intestinal permeability and possibly autoimmune pathology. Gut microbial dysbiosis may be an etiological factor in autoimmune disease by this mechanism. Treating dysbiosis with dietary interventions such as botanicals, prebiotics and probiotics may prevent or treat autoimmunity.³² A meta-analysis found that compared to patients in remission, patients with active ulcerative colitis had decreased abundance of Clostridium coccoides and leptum, Faecalibacterium prausnitzii and Bifidobacterium spp. Patients with active Crohn’s disease had fewer C. leptum, F. prausnitzii, and Bifidobacterium, but no decrease in C. coccoides.²³ In a second meta-analysis, the abundance of F. prausnitzii was reduced in both active CD patients and active UC patients when compared with the patients with CD or UC in remission, respectively.²⁴

Bile Salts as Therapy for Inflammatory Conditions

In a mouse model of Clostridium difficile enterocolitis, ursodeoxycholic acid (UDCA) improved NF-KB signaling and reduced inflammation in the colon. It was given early in the course of the disease, acting through FXR and TGR5, the major G-protein-coupled membrane receptor.²⁵ In the World Journal of Hepatology, researchers studied bile therapies and non-alcoholic steatohepatitis: “Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid with immunomodulatory, anti-inflammatory, antiapoptotic, antioxidant and anti-fibrotic properties. UDCA can improve insulin resistance and modulate lipid metabolism through its interaction with nuclear receptors such as, TGR5, (and the) farnesoid X receptor….”²⁶ UDCA is perhaps best known for preventing eosinophilic degranulation and reducing eosinophil counts in primary biliary cholangitis. It is standard therapy for preventing progression to cirrhosis in this autoimmune disorder. It has also been found to reduce eosinophilic inflammation beyond the GI tract. In a ovalbumin-induced model of asthma in mice, UDCA was found to modulate dendritic cell/T cell interactions, reducing eosinophilic inflammation in vivo.²⁷

Brazilian researchers found that UDCA had a local protective effect of in murine ileitis induced by indomethacin. They found that this unique bile salt protected against intestinal barrier dysfunction and oxidative stress and suggest it as a possible treatment for Crohn’s disease.²⁸ UDCA has also been studied for symptom amelioration in bile gastritis. A small prospective placebo-controlled study in men and women found 1000 mg of oral ursodeoxycholic acid daily resulted in a highly significant decrease in the intensity and frequency of the epigastric pain. In addition, nausea and vomiting were all but abolished. During bile acid therapy the proportion of the anti-inflammatory bile salt rose from 2% to 50% of total bile acids.²⁹

Over the last twenty years, research—most of which is murine based—reveals that bile can significantly reduce neurodegeneration, accumulation of amyloid material and markedly prevent memory loss in Alzheimer’s disease. Both UDCA and its taurine conjugated form—tauroursodeoxycholic acid (TUDCA)—are inhibitors of apoptosis. This cellular protection is achieved by reducing the mitochondrial pathway of cell death, reducing ER stress, inhibiting the production of oxygen-radicals and stabilizing protein unfolding.³⁰ Protection of essential nerve tissue has been shown in amyotrophic lateral sclerosis, Parkinson’s, Huntington’s, stroke and retinitis pigmentosa.³¹ The stroke research did not employ oral bile salt treatment, but rather injection into the carotid one hour post ischemic event. The fascinating results included significantly increased bile acid levels in the brain, improved neurologic functioning, and a 50% reduction in the area of the stroke.³² Rats given IV UDCA prior to ligation-induced myocardial infarction had significantly smaller areas of infarction and caspase 3 activity.³³

In human studies of overweight men and women, oral supplementation of bile salts increased insulin sensitivity by 30% with no increase seen in the placebo group. There were also improvements in blood sugar, insulin, and transaminases in the bile-treated group, but not in controls.³⁴ A small prospective, double-blind, randomized, placebo-controlled crossover study of UDCA in male CHF patients used 500 mg UDCA twice daily for four weeks and placebo for an additional four weeks. The treatment was well tolerated and increased peripheral circulation and lowered GGT and AST compared to placebo.³⁵

In summary, preliminary research shows that bile may be important in reduction of inflammation, apoptosis and necrosis in the liver, intestine, CNS, myocardium and retina. It appears to be important in maintaining insulin sensitivity. Bile starts in the liver but appears to have systemic inflammation modulating effects!

References

Ridlon JM, Bajaj JS. The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics. Acta Pharm Sin B. 2015 Mar;5(2):99-105.

Staudinger JL, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA. 2001;98:3369–3374.

Moore LB, et al. Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Mol Endocrinol. 2002;16:977–986.

Li C, et al, Bile Acids and Farnesoid X Receptor: Novel Target for the Treatment of Diabetic Cardiomyopathy. Curr Protein Pept Sci. 2019;20(10):976-983.

Chávez-Talavera O, et al. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. Gastroenterology. 2017 May;152(7):1679-1694.e3.

Zhu J.-B., et al. Farnesoid X Receptor agonist obeticholic acid inhibits renal inflammation and oxidative stress during lipopolysaccharide-induced acute kidney injury. Eur J Pharmacol. 2018;838:60–68.

Fei J, et al. Obeticholic acid alleviate lipopolysaccharide-induced acute lung injury via its anti-inflammatory effects in mice. Int Immunopharmacol. 2019;66:177–184.

Giaginis C, et al. High Farnesoid X Receptor (FXR) expression is a strong and independent prognosticator in invasive breast carcinoma. Neoplasma. 2017;64:633–639.

Zhang R J, et al. Farnesoid X receptor regulates vascular reactivity through nitric oxide mechanism. Physiol Pharmacol. 2012 Aug;63(4):367-72.

Huang C, et al. Identification of functional Farnesoid X Receptors in brain neurons. FEBS Lett. 2016;590: 3233–3242.

Massafra V, et al. Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis. Biochim Biophys Acta (BBA)-Mol. Basis Dis. 2016;1862:166–173.

Fiorucci S, et al. Activation of the Farnesoid-X Receptor protects against gastrointestinal injury caused by non-steroidal anti-inflammatory drugs in mice. Br J Pharmacol. 2011;164:1929–1938.

Nijmeijer RM, et al. Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease. PLoS ONE. 2011;6:e23745.

Attinkara R, et al. The Swiss IBD Cohort Study Group Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease. BMC Res Notes. 2012;5:461.

Eloranta JJ, Kullak-Ublick GA. The role of FXR in disorders of bile acid homeostasis. Physiology (Bethesda) 2008;23:286–295.

Inagaki T, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A. 2006;103:3920–3925.

Monaghan T, et al. Effective fecal microbiota transplantation for recurrent Clostridioides difficile infection in humans is associated with increased signalling in the bile acid-Farnesoid X Receptor-fibroblast growth factor pathway. Gut Microbes. 2019;10:142–148.

Winston JA, et al. Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids. Infect Immun. 2020;88:e00045-20.

Liu H-M, Liao J-F, Lee T-Y. Farnesoid X Receptor agonist GW4064 ameliorates lipopolysaccharide-induced ileocolitis through TLR4/MyD88 pathway related mitochondrial dysfunction in mice. Biochem Biophys Res. Commun. 2017;490:841–848.

Fiorucci S, et al, Bile Acid Signaling in Inflammatory Bowel Diseases. Dis Sci. 2021; 66(3): 674–693.

Kuhre RE, et al.Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metab. 2018 May;11:84-95.

Rizzetto L, Fava F, Tuohy KM, Selmi C, Connecting the immune system, systemic chronic inflammation and the gut microbiome: The role of sex. J Autoimmun. 2018 Aug;92:12-34.

Prosberg M, et al. The association between the gut microbiota and the inflammatory bowel disease activity: a systematic review and meta-analysis. Scand J Gastroenterol. 2016 Dec;51(12):1407-1415.

Zhao H, et al. Systematic review and meta-analysis of the role of Faecalibacterium prausnitzii alteration in inflammatory bowel disease. J Gastroenterol Hepatol. 2021 Feb;36(2):320-328.

Winston JA, et al. Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids. Infect Immun. 2020;88:e00045-20.

Higuera-de la Tijera F, Servin-Caamano AI. Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets. World J Hepat. 2015 Jun 8;7(10):1297-301.

Willart MAM, et al. Ursodeoxycholic acid suppresses eosinophilic airway inflammation by inhibiting the function of dendritic cells through the nuclear farnesoid X receptor. Allergy. 2012 Dec;67(12):1501-10.

Bernardes-Silva CF, et al. Ursodeoxycholic acid ameliorates experimental ileitis counteracting intestinal barrier dysfunction and oxidative stress. Dig Dis Sci. 2004 Oct;49(10):1569-74.

Stefaniwsky AB, et al. Ursodeoxycholic acid treatment of bile reflux gastritis. Gastroenterology. 1985 Nov;89(5):1000-4.

Vang S, et al. The Unexpected Uses of Urso- and Tauroursodeoxycholic Acid in the Treatment of Non-liver Diseases. Glob Adv Health Med. 2014 May;3(3):58-69.

Zangerolamo L, et al. The bile acid TUDCA and neurodegenerative disorders: An overview. Life Sci. 2021 May 1;272:119252.

Rodrigues CMP, et al. Neuroprotection by a bile acid in an acute stroke model in the rat. J Cereb Blood Flow Metab. 2002 Apr;22(4):463-71.

Rivard AL, et al. Administration of tauroursodeoxycholic acid (TUDCA) reduces apoptosis following myocardial infarction in rat. Am J Chin Med. 2007;35(2):279-95.

Rodrigues CMP, et al. Neuroprotection by a bile acid in an acute stroke model in the rat. J Cereb Blood Flow Metab. 2002 Apr;22(4):463-71.

von Haehling S, et al. Ursodeoxycholic acid in patients with chronic heart failure: a double-blind, randomized, placebo-controlled, crossover trial. J Am Coll Cardiol. 2012 Feb 7;59(6):585-92.