Bile Acids {90000131}

Shared Reference Notes

• [1.1] 
  - Bile acids that enter the large intestine are converted by the microbiota (largely by those in Clostridium clusters XIVa and XI) into secondary bile acids—deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA). - Lithocholic acid and DCA are hydrophobic bile acids that are cytotoxic at elevated physiological concentrations. - Increases in LCA and DCA have been implicated in intestinal inflammation, liver injury, cholestasis, and gallstone formation.
• [1.2] 
  - Lactobacillus plantarum strains have the selective ability to alter BA signatures in favour of receptor activation that would be beneficial to humans.
• [1.3] 
  - The blood–brain barrier allows the access of bile acids.
• [1.4] [#Inflamatory bowel disease] [#High satureted fat diet] 
  - Diet rich in high saturated fats promotes chronic inflammation. - One explanation is that the amino acid #Taurine, present in saturated fats, linked to bile acids, seems to increase substrate availability for sulfur-reducing bacteria like #Bilophila wadsworthia, highly prevalent in the dysbiotic microbiota of IBD patients.
• [1.5] [#Western-style diet] 
  - WD consumption in conjunction with #Clostridium spp. increased the secondary bile acid deoxycholic acid levels in the ileum, which in turn inhibited Paneth cell function.
• [1.6] 
  - Bile acids bind to and activate nuclear hormone receptors, such as the farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR), as well as G-protein-coupled bile acid receptor-1 (TGR5) - FXR is a nuclear hormone receptor that is expressed in the liver, intestines, kidney, and several other tissues where it regulates bile acid homeostasis in addition to lipid and glucose metabolism in response to both 1BAs and 2BAs. - PXR was shown to upregulate a detoxification network in response to LCA. - VDR was also shown to be activated by LCA, albeit at a concentration 1000-fold greater than active vitamin D. - VDR activation by LCA was found to affect T cell activation. - Bile acid-driven activation of TGR5 in adipose tissue can promote thyroid hormone action thereby increasing energy expenditure
• [#Diabetes Type 2] - In diabetic mice, the administration of a synthetic FXR agonist markedly reduced plasma glucose, triglycerides, free fatty acids, and cholesterol as well as hepatic steatosis. - Conversely, intestine-specific knockout of FXR in mice was shown to reduce insulin resistance and hepatic triglyceride accumulation
• [#Diabetes Type 2] - TGR5, unlike the nuclear receptors discussed above, is a GPCR, expressed by digestive, immune, and adipose tissues where it is preferentially activated by LCA and DCA. - In the gut, TGR5 activation leads to secretion of GLP-1 and PYY, thereby having beneficial effects on insulin secretion and satiety. - TGR5 knockout in macrophages and myeloid-lineage cells was found to exacerbate adipose tissue inflammation and insulin resistance, suggesting a protective role in T2DM pathogenesis
• [1.7] [#Pregnancy] [#Probiotic (Bifidobacter and Lactobacilus)] 
  - Probiotic supplementation > significantly reduced the severity of nausea, vomiting, constipation, and improved life quality in pregnant women. - Probiotic intake increased fecal bsh (bile salt hydrolase) > free bile acids > facilitate intestinal mobility and metabolism > associated with lower vomiting scores.
• [1.8] 
  - Bile acids > interact with bile acid receptors Farnesoid X Receptor (FXR) and Takeda G protein Receptor 5 (TGR-5) > regulate hepatic energy metabolism, adipocyte differentiation and dampen immune activation.
• [1.9] 
  - #Grape powder consumption > decreased the total #Cholesterol by 6.1% and HDL #Cholesterol by 7.6%. - There was also a trend of decreasing LDL #Cholesterol by 5.9%, and decreasing total bile acid by 40.9%.
• - Microbiota > higher levels of the microbiota-derived secondary bile acid #Deoxycholic acid and Gram-positive gut microbial component, #Lipoteichoic acid > These compounds induced senescence of hepatic stellate cells (HSCs) and the secretion of pro-inflammatory SASP > creating a pro-tumorigenic microenvironment.
• [1.11] 
  - Primary bile acids by the intestinal flora > secondary bile acid #Deoxycholic acid > cause inflammatory reactions
• [1.12] 
• [1.13] 
  - #Castalagin induced metabolic changes > resulting in an increase in #Taurine conjugated bile acids. Oral supplementation of #Castalagin following fecal microbiota transplantation from ICI-refractory patients into mice supported anti-PD-1 activity.
• [#Cancer] [#Castalagin] [#Polyphenol-rich supplementation] - oral supplementation with the #Polyphenol-rich berry camu-camu (CC, Myrciaria dubia) in mice > shifted gut microbial composition, which translated into antitumor activity and a stronger anti-PD-1 response.
• [1.14] [#Clostridioides difficile] 
  - #Odoribacteraceae > produces a bile acid called #Isoallolithocholic acid > inhibit the growth of Clostridium difficile (C. difficile) in a lab culture > preventing illness.
• [1.15] 
  - All secondary bile acids identified in plasma were significantly associated with the gut microbiome.
• [1.16] [#Inflamatory bowel disease] 
  - Bile acid > gut-residing bacteria produce metabolite #3-oxolithocholic acid (3-oxoLCA) > inhibits TH17 (inhibitory) cell differentiation. - Secondary bile acid #Lithocholic acid > gut bacteria > 3-oxoLCA as well as the abundant gut metabolite #Isolithocholic acid (isoLCA). - IsoLCA suppressed TH17 differentiation by inhibiting RORγt (retinoic acid receptor-related orphan nuclear receptor γt), a key TH17 cell-promoting transcription factor. - Levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase (3α-HSDH) genes required for their biosynthesis were significantly reduced in patients with inflammatory bowel diseases (IBD). - levels of these bile acids were inversely correlated with expression of TH17 cell-associated genes. - bacterially produced TH17 cell-inhibitory bile acids may reduce the risk of autoimmune and inflammatory disorders such as IBD
• [1.17] [#Inflamatory bowel disease] 
  - Inflammatory Bowel Disease > increased Primary bile acids
• [1.18] 
  - Butyrate producing bacteria such as #Eubacterium spp. are capable of transforming primary BAs to secondary BAs such as: #Lithocholic acid and #Deoxycholic acid, which are potentially cytotoxic and have been linked to #Colorectal cancer and cholesterol GS formation.
• [1.19] [#Reduced cholesterol] 
  - #Arabinoxylan decreases #Cholesterol in part through increased bile acid synthesis. - AX consumption associates with a significant #Reduction in LDL and an increase in bile acids, contributing to its observed #Cholesterol reduction.
• [#Primary bile acids, #Secondary bile acids] - Both primary BAs and secondary BAs have been shown to interact agonistically or antagonistically with a family of nuclear (FXR) and G-protein-coupled receptors, collectively known as BA-activated receptors (BAR), influencing cellular signaling as well as immunological response
• [1.21] 
  - free #Taurine has a largely protective impact on the host, serves as a source of energy for microbiota, regulates bacterial colonization and defends from pathogens. - #Taurine is also crucial as a molecule used to conjugate bile acids (BAs). In the gastrointestinal tract, BAs deconjugation by enteric bacteria results in high levels of unconjugated BAs and free #Taurine.
• [1.22] [#Primary bile acids, #Secondary bile acids] 
  - Intestinal bacteria will deconjugate primary BAs that fail reabsorption in the terminal ileum and thereby convert them to secondary BAs by microbial biotransformation, including dehydroxylation, epimerization, and oxidation of hydroxyl groups. - Free BAs, such as cholic acid, deoxycholic acid, and chenodeoxycholic acid, can stimulate apoptosis and reduce interleukin 6 (IL-6) production, while conjugated BAs such as glycolic acid, glycodeoxycholic acid, and glycochenodeoxycholic acid promote cell growth and induce IL-6 production.
• [#Short Chain Fatty Acid] - SCFAs and secondary bile acids modulate gastric inflammation and immune system activation by reducing NF-κB activation, promoting the secretion of anti-inflammatory cytokines, AMPs, and IgA, and preserving the integrity of the gut barrier
• [#Inflamatory bowel disease] [#Primary bile acids, #Secondary bile acids] - Reduced BA deconjugation is associated with inflammatory bowel diseases (IBD) including #Ulcerative Colitis (UC) and #Crohn’s disease (CD), as well as #Irritable bowel syndrome (IBS).
• [1.23] [#Allergy] [#Inulin] 
  - diet of #Inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. - This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. - dietary #Inulin fibre triggers microbiota-derived #Cholic acid and type 2 inflammation at barrier surfaces
• [1.24] [#CVD] [#Primary bile acids, #Secondary bile acids, #Short Chain Fatty Acid, #TMA, #TMAO] 
• [1.25] 
  - There was a relative enrichment of taurine-conjugated compared to glycine-conjugated and non-conjugated bile acids during #Pregnancy, accompanied by expansion of taurine respirer #Bilophila wadsworthia, which has been linked to colitis and glucose dysmetabolism
• [1.26] [#Diabetes Type 2] [#Gastric bypass surgery] 
  - An increase in #Propionate and bile acids after RYGB was associated with an increase in hormone peptide tyrosine tyrosine (PYY) in humans and, hence, resolution of diabetes.
• [1.27] [#CVD] [#Short Chain Fatty Acid] [#Probiotic, #Probiotic (Bifidobacter and Lactobacilus)] 
  - Short-chain fatty acids and secondary bile acids can decrease #Cholesterol levels by regulating #Cholesterol metabolism. - Microbial #Bile Salt hydrolases can increase #Cholesterol disposal rates by accelerating its conversion to bile acids. - Probiotics from the genera Lactobacillus and Bifidobacterium are efficient reducers of #Cholesterol levels in clinical studies. - Several candidate next-generation probiotics, including #Akkermansia muciniphila, #Bacteroides spp., #Clostridium spp., #Christensenella minuta, Eubacterium spp., and #Faecalibacterium prausnitzii, have been shown to decrease #Cholesterol levels in human or animal studies.
• [1.28] 
  - bile acids promote inflammatory responses in the gut. - Bile acids trigger multiple cellular receptors, such as the farnesoid X receptor (FXR), the pregnane X receptor (PXR), the vitamin D receptor, the G protein-coupled bile acid receptor 1 (TGR5), α5β1 integrin, and the sphingosine-1-phosphate receptor 2. - Bile acids differ in their receptor binding affinity and activation efficiency. - FXR shows bile acid affinities in the order of CDCA>DCA>LCA>CA, while the TGR5 shows affinities in the order of LCA>DCA>CDCA>CA.
• [#Primary bile acids, #Secondary bile acids] - Primary bile acids are conjugated in several different forms and secreted into the intestine. - a small portion (~5%) of the Primary bile acids (about 200 to 800 mg daily in humans) escapes the reabsorption in Ileum and reaches the colon where gut bacteria convert them into secondary bile acids (SBAs), such as #Deoxycholic acid (DCA), #Ursodeoxycholic acid (UDCA), and #Lithocholic acid (LCA). - majority (90% to 95%) of SBAs are reabsorbed into colonocytes to return to the liver for detoxification and recycling.
• [#Colorectal cancer] [#Deoxycholic acid, #Secondary bile acids] - Elevated levels of fecal SBAs, especially DCA, are associated with an increased risk for CRC. - FXR, receptor for bile acids, is downregulated in CRC and low levels of FXR expression correlate with worse clinic outcomes.
• [#Gastric carcinoma] - The bile acid receptor TGR5 is overexpressed in gastric adenocarcinoma, and bile acids can increase cell proliferation via TGR5 signaling.
• [1.29] [#Inflamatory bowel disease] 
  - #Psyllium, a fiber derived from Plantago seeds, can inhibit #inflammation that leads to #Colitis in mice by increasing serum bile acids and activating the farnesoid X receptor (FXR). - This is exciting since it suggests that pharmacologic FXR activation might be an interesting target for the management of inflammation found in IBD.
• [#Clostridium difficile infection] [#Clostridioides difficile] 

References Notes