Bile acids act as signaling molecules to boost intestinal regeneration


Researchers at EPFL have made a surprising discovery about how bile acids act as signaling molecules to boost intestinal regeneration.

The discovery sheds light on the role of bile acids as hormone-like molecules and opens new ways for regenerative therapies of the gut.

Intestinal stem cells replenish the cells lining the gut epithelium, which usually renews itself every week.

These cells also generate all the specialized cells of the gut that carry out different functions e.g. antimicrobial protection, mucus secretion, and the release of nutrient-induced hormones.

When injury occurs, the intestinal stem cells become activated and coordinate the repair of the damaged epithelium and the recovery of intestinal function.

A team of scientists led by Kristina Schoonjans at EPFL have discovered that exposing stem cells to physiological concentrations of bile acids can boost the growth of miniature “guts” called organoids.

On the cutting-edge of bio-engineering, gut organoids are grown from isolated intestinal stem cells in the lab as tiny, three-dimensional tissues that simulate the anatomy and function of many cell types found in the actual gut.

The scientists found that exposing intestinal cells to bile acids not only helped them grow into organoid intestines, but also preserved their ability to differentiate into specialized cell types. Bile acids even increased the number of cells that secrete glucagon like peptide-1 (GLP-1), an important gut hormone with established antidiabetic actions.

In addition, they discovered that the bile acid-activated membrane receptor, called TGR5, is enriched in intestinal stem cells, and that it contributes to their activation when bile acid levels accumulate in the gut, e.g. after eating a meal.

Looking deeper into their findings, the researchers generated genetically modified mice to disrupt the function of TGR5 specifically in intestinal stem cells.

The result was that bile acids not only increased the number of intestinal stem cells in the mice’s gut, but also protected mice from acute colitis by promoting intestinal regeneration through a mechanism that involves TGR5.

“The results of our work imply that every time we eat—a process that triggers the secretion of bile acids into the gut—we are stimulating the regeneration and the proper functions of the intestine, through the action of bile acids on intestinal stem cells,” says Schoonjans.

“However, our study also includes a warning: dietary habits known to chronically increase the levels of bile acids into the gut, such as the consumption of high-fat food, might exacerbate intestinal stem cell proliferation and transform the homeostatic intestinal regeneration into cancer development.”

The researchers hope that, in the future, the administration of synthetic molecules that can activate TGR5 specifically in the gut, might become a pharmacological strategy to acutely stimulate the regeneration of damaged intestinal epithelium in patients with inflammatory bowel disease.

Roughly a liter of bile is produced by human hepatocytes daily.1 Bile acids constitute about 50% of the organic component of bile.1 The primary bile acids produced in humans are cholic acid (CA) and chenodeoxycholic acid (CDCA).

Once primary bile acids enter the gastrointestinal tract, over 50 chemically distinct secondary bile acids are produced.2 The chemical diversification of bile acids is a collaborative effort by the host (production of primary bile acids) and the gut microbiota (production of secondary bile acids).

Some postulate that the gut microbiota act as an “endocrine organ” by altering host physiology via the production of metabolites, such as microbially derived secondary bile acids.3 Recently, interest in the gut microbiota-bile acid-host axis is expanding in diverse fields including gastroenterology, endocrinology, oncology, and infectious disease.1,3–12

Host bile acid metabolism
Bile acids are water-soluble, cholesterol derived amphipathic molecules of saturated hydroxylated C-24 sterols that are synthesized by hepatocytes.13

The liver is the only organ that contains all 14 enzymes that are required for de novo synthesis of bile acids.14,15 Cholic acid and CDCA are the main primary bile acids synthesized in humans and rodents (Figure 1).13,16,17 In rodents, a significant quantity of CDCA is converted by 6β-hydroxylation to muricholic acids, which are not detected in humans (Figure 1).3,18

These primary bile acids are further metabolized via N-acyl amidation to glycine or taurine producing conjugated bile acids, such as taurocholic acid (TCA).13 Conjugation is important for solubility of bile acids; at physiologic pH, unconjugated bile acids are only sparingly soluble.1,19 The ratio of glycine to taurine conjugated bile acids varies across mammals.16,20,21

Conjugated bile acids are actively secreted across the canalicular membranes into the bile ducts, which converge and empty into the gallbladder (except in species that lack a gallbladder such as horses, rats, and rabbits). Bile acids are just one component in bile, which also includes phospholipids, biliverdin/bilirubin, immunoglobulin A, mucus, various endogenous products (such as lipovitamins, corticosteroids, progesterone, testosterone), trace metals, and xenobiotics.1

Within the gallbladder, bile is concentrated 5–10 times, via removal of water and electrolytes, and acidified via Na+/H+ exchangers.1,22 Only about 50% of bile enters into the gallbladder, the remaining enters directly into the gastrointestinal tract.1 During a meal, cholecystokinin from the duodenum causes contraction of the gallbladder and concentrated bile is released into the proximal gastrointestinal tract.

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Figure 1.
Overview of bile acid metabolism and enterohepatic recirculation.
Host-derived primary bile acids are synthesized by heptocytes (CA and CDCA in humans, and CA, CDCA, αMCA, and βMCA in rodents) and conjugated with either taurine or glycine. Primary bile acids are then secreted into the bile and stored in the gallbladder until secreted in the duodenum. Resident gut microbiota biotransform primary bile acids into secondary bile acids such as LCA, UDCA, and DCA (green shaded circles) and HCA, MDCA, ωMCA, and HDCA in rodents (gray-shaded circles). Abbreviations: CA, cholate; CDCA, chenodeoxycholate; DCA, deoxycholate; HCA, hyocholate; HDCA, hyodeoxycholate; LCA, lithocholate; MDCA, murideoxycholate; UDCA, ursodeoxycholate; αMCA, α-muricholate; βMCA, β-muricholate; ωMCA, ω-muricholate.

High concentrations of conjugated primary bile acids are noted within the duodenum, jejunum, and proximal ileum.13 The primary role of bile acids in the small intestine is to aid in fat emulsification and absorption. Bile acids undergo enterohepatic recirculation, a process which involves:

(1). Passive absorption of conjugated and unconjugated bile acids in the small intestine and colon;

(2) High-affinity active transport in the distal ileum.1,17,23 Absorbed bile acids enter into the portal bloodstream and are rapidly taken up by hepatocytes and resecreted into bile (Figure 1).

A small fraction of bile acids escape enterohepatic recirculation and spill into systemic circulation, which allows bile signaling to occur in other organs and tissues.24,25 Enterohepatic recirculation is extremely efficient, with 95% of bile acids reabsorbed and only 5% lost into the feces.1 Hepatocytes maintain the bile acid pool by synthesizing bile acids to make up for fecal loss. In healthy humans, the total bile acid pool cycles about 10 times each day, which requires enterocytes and hepatocytes to transport about 20 g of bile acids every hour.5,26

Bile acids regulate their own synthesis and transport via the nuclear farnesoid X receptor (FXR; NR1H4), thus acting as hormones.27–30 Binding of bile acids to ileal FXR induces expression of fibroblast growth factor (FGF15/19).31 FGF15/19 travels via the portal bloodstream and binds to cell surface receptors on hepatocytes to repress bile acid synthesis (feedback inhibition) by inhibiting the rate-limiting enzyme cholesterol 7α- hydroxylase (CYP7A1) which allows the host to synthesize primary bile acids from cholesterol.28 Different bile acids have varying affinities to FXR.3,28,32 The bile acid-FXR pathway is also important for glucose homeostasis, lipid metabolism, protein synthesis, inflammation, and liver regeneration; however, this is beyond the scope of this review.6,27,28,33 Bile acids also interact with pregnane X receptors (PXR; NR1I2) and vitamin D receptors (VDR; NR1I1), which are reviewed elsewhere.4,28,34

Bile acids are biological detergents and can act as a host physicochemical defense system within the gut directly against both commensal resident microbes and enteric pathogens.1 Bile acids, via stimulation of FXR, can also induce expression of antimicrobial peptides.31 Therefore, bile acids are a major survival and colonization challenge to gut microbes. Regardless, gut commensals and some pathogens can elude the detrimental effects of bile acids and in some cases secure a fitness advantage.1

Diversification of host bile acids by gut microbes

The gastrointestinal microbiome is the most densely populated natural ecosystem and is comprised of over 1014 bacterial cells.14,35 Originally it was thought that microbial cells outnumbered human cells in the body by a ratio of 10:1;14,35 however, recent revised estimates suggest closer to 1.3–2.3:1.36 There are thousands of different bacterial species in the human gut.37 In healthy humans and animals, over 90–99% of the microbial community are dominated by two phyla, Firmicutes and Bacteroidetes, with fewer members in Proteobacteria, Actinobacteria, Verrucomicrobia, and Cyanobacteria.38,39 Diversity within this community is mainly at the genus, species, and strain level.14 It is estimated that 99% of functional genes in the human body are of microbial origin.40 By acting in an endocrine fashion, the gut microbiome can alter host physiology by producing metabolites, such as secondary bile acids.3,41

Secondary bile acids are produced by gut microbes via biotransformation of host-derived primary bile acids (Figure 2). When the small fraction (approximately 5%) of unabsorbed bile acids enters the distal ileum, cecum, and colon they undergo chemical diversification via three main microbial pathways: deconjugation, dehydrogenation, and dehydroxylation reactions.13

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Figure 2.
Microbial metabolism of host-derived primary bile acids.
Primary bile acids are synthesized from cholesterol by hepatocytes. Primary bile acids are then biotransformed by resident bacteria in the gastrointestinal tract to secondary bile acids, such as LCA and DCA, which predominate in humans. Abbreviations: CA, cholate; CDCA, chenodeoxycholate; DCA, deoxycholate; HCA, hyocholate; HDCA, hyodeoxycholate; LCA, lithocholate; MDCA, murideoxycholate; UDCA, ursodeoxycholate; αMCA, α-muricholate; βMCA, β-muricholate; ωMCA, ω-muricholate.

Deconjugation of host-derived primary bile acids occurs rapidly and via bile salt hydrolases (BSH), which are widespread in members of the gut microbiota.1,13,42 Based on metagenomic screening, three major phyla have BSHs: Firmicutes (30%), Bacteroidetes (14.4%), and Actinobacteria (8.9%).42 Within these phyla, the following genera are heavily studied: Clostridium, Bacteroides, Lactobacillus, Bifidobacterium, and Enterococcus (reviewed in Begley et al., 2005).1

The physiologic function of BSH is debated and the current three hypotheses are: (1) BSHs provide a nutritional advantage by liberating amino acids that can be used for carbon/nitrogen sources and energy generation via taurine as a terminal electron acceptor; (2) BSHs aid in incorporation of cholesterol and bile components into bacterial membranes; (3) BSHs provide a detoxification mechanism to diminish the inherent detergent properties of bile acids.1,43 Bile salt hydrolases appear to enhance bacterial colonization within the lower gastrointestinal tract, but appears to be strain specific.13

Some probiotic Lactobacillus strains have several BSH genes, thus highlighting the importance of deconjugation of bile acids for gut microbes.44–46 For the host, deconjugation of bile acids by gut microbes has several consequences. Unconjugated bile acids result in less effective emulsification of fat, less efficient enterohepatic recirculation of bile acids due to reduced distal ileal transporter affinity, and lowering of serum cholesterol levels.1,47,48 Despite the host impacts of microbial BSH activity, the bacterial physiologic advantage of BSHs remains elusive.13

Three distinct microbial hydroxysteroid dehydrogenases (HSDH), 3α-, 7α-, and 12α-, which result in oxidization and epimerization of specific hydroxyl groups on bile acids are present in gut microbes.13 These HSDHs can lead to the formation of over 20 diverse metabolites from the host-derived primary bile acids alone.13,14 Ridlon et al. speculated that these bile acid metabolites evolved as signaling molecules for microbes to communicate with other gut microbes (via microbe–microbe interactions) and/or alter host physiology (via microbe–host interactions).3

In the colon, nearly 100% of bile acids are microbially derived, and unconjugated bile acids undergo dehydrogenation carried out by a broad spectrum of bacteria.13,49 However, 7α-dehydroxylation is performed by only a few anaerobic species representing less than 0.025% of total gut microbiome and 0.0001% of total colonic microbiota.3,13,50 These are largely Clostridium spp. (C. hiranonis, C. hylemonae, C. sordelli, and C. scindens), which are members of the Firmicutes phyla.13,14,51–57

Removal of the 7α-hydroxyl group from host-derived primary bile acids requires multiple intracellular enzyme steps, which are encoded on the bai (bile acid inducible) operon.4,13,14,56,58,59 These reactions ultimately lead to formation of the secondary bile acids, deoxycholate (DCA) from CA and lithocholate (LCA) from CDCA (Figure 2).5,49,60

Additionally, DCA and LCA can be modified into other secondary bile acids by microbes, such as isoDCA (iDCA) and isoLCA (iLCA),49 however it is only partially understood which microbes conduct this conversion (Figures 2 and 3).5,60,62 Secondary bile acids can also undergo enterohepatic recirculation by passive colonic absorption and thus can be found in the liver and bile.3,23 In human feces, although secondary bile acids DCA and LCA predominate, there are over 50 different microbially derived secondary bile acids present.2

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Figure 3.
Directions of 7α/7β-HSDH reactions form UDCA-producing bacteria.
Epimerization reaction from CDCA to UDCA, which is catalyzed by the 7α-HSDH and 7β-HSDH enzymes. ND: Not determined; *: Found in the gastrointestinal tract. Dashed line denotes weak reaction. Figure modified from Lee et al. 2013.61

The microbial physiologic role of secondary bile acids remains elusive. It is suggested that microbially derived secondary bile acids are used in energy production as terminal electron acceptors, aid in formation of less membrane damaging bile acid pools, and alter enteric pathogen virulence, such as germination and outgrowth of Clostridioides difficile.1,9,13,63–65 In the host, secondary bile acids such as DCA and LCA can be cytotoxic molecules leading to oxidative stress, membrane damage, and colonic carcinogenesis (reviewed in Barrasa et al.).66

However, the secondary bile acid UDCA can protect colonic cells against apoptosis and oxidative damage.66 Additionally, in a colitis model, UDCA and LCA exerted anti-inflammatory properties.67 Thus, collectively highlighting the diverse and potentially divergent roles of microbially derived secondary bile acids. It is remarkable how little is known about secondary bile acids, including which gut microbes produce them, their microbial biologic function, and their impacts on host health and disease.

reference link :

More information: Giovanni Sorrentino et al. Bile Acids Signal via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration, Gastroenterology (2020). DOI: 10.1053/j.gastro.2020.05.067


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