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, #Polyphenols] [#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] 
  - 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
• [1.25] [#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.
• [1.26] [#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.
• [1.27] 
  - 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.
• [1.28] [#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.
• [1.29] [#Secondary bile acids] 
  - BSH activity fuels the production of MCBAs (microbial conjugated bile acids)
• [#Clostridium difficile associated disease] [#Clostridioides difficile] - Conjugated BAs may suppress the expression of C. difficile’s toxin A.
• [#Clostridium difficile associated disease] [#Clostridioides difficile] - #Taurine conjugates inhibit growth less, while #Glycine conjugates and deconjugated BAs are much more toxic to C. difficile.
• - #Lactobacillaceae BSHs display a clear bias for either #Glycine or #Taurine-conjugated BAs.
• [#Mild Cognitive Impairment] [#Curcumin, #Mediterranean Ketogen Diet] - MCI individuals with #Curcumin in their diet had lower levels of #Bile Salt hydrolase-containing microbes and an altered bile acid pool, suggesting reduced gut motility.
• [1.31] 
  - #Veillonella is acid-sensitive, the abundance of #Veillonella heightens when aldafermin-mediated suppressions of bile acid synthesis, particularly toxic bile acids, are inhibited.
• [1.32] 
  - #TMAO can reduce the production of #Cholesterol 7α-hydroxylase, thereby reducing the production of bile acids, causing #Cholesterol to accumulate in cells. - At the same time, up-regulating the expression of the vascular cellular adhesion molecule-1 (VCAM-1) can promote monocyte adhesion, activate protein kinase C (PKC) and p-NF-κB, and further lead to the formation of atherosclerotic plaque.
• [1.33] 
  - Different bile acids activate G-protein-coupled bile acid receptor (TGR5) that impairs inflammation and increases energy expenditure.
• - Different bile acids may upregulate the expression of FGF15, inhibiting hepatic triglycerides and bile acid synthesis.
• [1.34] 
  - short- and long-term myalgic encephalomyelitis/#Chronic fatigue syndrome > reduced microbial #Butyrate biosynthesis and a reduction in plasma #Butyrate, bile acids, and #Benzoate.
• [1.35] 
  - exposure to the fungicide propamocarb, which similarly to thymol targets disruption of the cell membrane, increased #Propionate, #Isobutyrate and bile acids in faeces of exposed mice according to a faecal metabolomics analysis.
• [1.36] 
  - The majority of the #Bacteroidetes species fall into three genera: #Prevotella (bile-sensitive, moderately saccharolytic, with pigmented and nonpigmented species), #Porphyromonas (bile-sensitive, pigmented, asaccharolytic species), and #Bacteroides (bile-resistant, nonpigmented, saccharolytic species).
• [#Serotonin, #Short Chain Fatty Acid] - gut microbiota may promote the development of functional #Constipation through microbial metabolites, including bile acids, SCFAs, 5-hydroxytryptamine, and #Methane.
• [1.37] 
  - #High ambient temperature of 36 °C increases host resistance to viral pathogens including #Influenza virus and severe acute respiratory syndrome #Coronavirus 2 (SARS-CoV-2). - High heat-exposed mice increase basal body temperature over 38 °C to enable more bile acids production in a gut microbiota-dependent manner. - The gut microbiota-derived #Deoxycholic acid (DCA) and its plasma membrane-bound receptor Takeda G-protein-coupled receptor 5 (TGR5) signaling increase host resistance to #Influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage. - the DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamsters from lethal SARS-CoV-2 infection. certain bile acids are reduced in the plasma of COVID-19 patients who develop moderate I/II disease compared with the minor severity of illness group.
• [1.38] 
  - The BAs increase the production of GLP-1 and promote #Glucose homeostasis.
• [1.39] 
  - bile acid receptors, Farnesoid X receptor and G-protein coupled bile acid receptor 1, regulate various elements of #Glucose, lipid, and energy metabolism
• - Most gram-positive bacteria, like #Ruminococcus and #Clostridium, and some gram-negative bacteria can metabolize bile acids .
• - The #Bile Salt hydrolase of probiotics is thought to play an important role in bile acid homeostasis because it hydrolyzes the bound bile salts to form amino acids and less soluble free bile acids, which bind to #Cholesterol to reduce serum #Cholesterol levels
• - lipid-lowering of probiotics and #Lactobacillus oris may be associated with HMGR inhibition to suppress the synthesis of endogenous #Cholesterol; bile acids reabsorption, and intestinal FXR-FGF15 signaling pathways promoting the #Cholesterol conversion into bile acids secretion.
• [#Metabolic associated fatty liver disease] - Bile acids may participate in the regulation of gene transcription because they are endogenous ligands for the nuclear receptor Farnesoid X receptor (FXR). - FXR agonists have been used to treat nonalcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids
• [1.41] 
  - #Lentils (LEN) and #Chickpeas (CKP) increase #Butyrate, while #Inulin (INU) promotes #Propionate. - bile acids and #Cholesterol are reduced in #Prebiotic groups along with suppressed #Choline-to-trimethylamine conversion by LEN and CKP
• [#Resistant starch] - The bile acids-binding capacity of RS could aid in weight management, glycemic index modulation, and #Cholesterol reduction
• [1.42] 
  - certain #Bifidobacterium, #Bacteroides, and #Lactobacillus species that have high activities of #Bile Salt hydrolase, the enzyme responsible for the deconjugation of bile acids.
• [#Hypercholesterolaemia] - bile acids can be deconjugated by certain microbiota, which inhibits their reabsorption > elevation of bile acid synthesis inliver > reducing of Blood #Cholesterol
• [1.43] 
  - #Walnut consumption also decreased pro-inflammatory bile acids #Deoxycholic acid and #Lithocholic acid and serum LDL #Cholesterol
• [1.44] 
  - Recent technological advances have led to the characterization of more than 170 BAs, of which more than 60 have been directly observed in human fecal samples.
• [#Colorectal cancer] - potential gut microbes capable of conjugating CAs including #Ileibacterium valens. - #Ileibacterium valens has been recently implicated in microbial-induced #Obesity and intestinal inflammation through its production of interleukin-17 - enrichment of #Ileibacterium valens strains in adenocarcinoma mouse models, suggesting that this species may promote tumorigenesis.
• [#Colorectal cancer] [#High Fat Diet] - 7 non-classic amino acid-conjugated BAs enriched in HFD-fed mice, > microbially modified #Cholic acid derivatives appear restricted to the gut, distinguishing them from host-conjugated BAs. - non-classic amino acid conjugation selectively modulates #Cholic acid signaling via FXR and TGR5, as well as its ability to promote Wnt signaling and intestinal stem cell proliferation, key steps in CRC initiation and progression.
• [1.45] 
  - BA levels, especially of the secondary BAs modulated by gut microbiota, are negatively correlated with the severity of depressive symptoms,35 suggesting a protective role of higher BA levels for #Depression. - Turicibacterales, Turicibacteraceae, and #Turicibacter were related to the increased production of BAs. - this taxa has been reported to reduce in #Depression state.
• [1.46] [#Berberine] 
  - BBR can cause an increase in serum BA, total BA, and primary BA content
• [1.47] [#Parkinson’s Disease] 
  - microbially derived toxic bile acids such as #Deoxycholic acid and #Lithocholic acid are heightened in PD
• [1.48] [#Taurinivorans muris] 
  - Colonization of T. muris in gnotobiotic mice increased deconjugation of #Taurine-conjugated bile acids and transcriptional activity of a #Sulfur metabolism gene-encoding prophage in other commensals, and slightly decreased the abundance of #Salmonella enterica
• [1.49] [#Cancer] [#Deoxycholic acid, #Lithocholic acid] 
  - Secondary BA, DCA, and LCA can cause DNA damage
• [#Eggerthella lenta] [#Deoxycholic acid, #Lithocholic acid] - E. lenta gavage also altered BA metabolism as observed by increased primary and secondary BA including DCA and lithocholate (LCA)
• [#Chronic liver disease] - patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity.
• [1.51] [#Diabetes Type 1] [#Deoxycholic acid] 
  - stool concentrations of secondary BAs, particularly UDCA, DCA, HDCA, and their #Glycine and/or #Taurine conjugates, were downregulated in P2Ab versus P1Ab and/or CTR groups.
• [#Diabetes Type 1] [#Tauroursodeoxycholic acid] - TUDCA, a conjugated secondary BA, was observed to reduce the incidence of diabetes development by improving the #Glucose utilization and metabolism in streptozotocin-treated C57BL/6 mice
• [#Diabetes Type 1] [#Lithocholic acid] - administration of secondary BAs, specifically LCA, a secondary BA, causes downregulation of circulating lipids, similar to previous findings in progression to T1D. - two distinct derivatives of LCA, including 3-oxoLCA and isoallo LCA, were found to affect host immune responses by directly modulating T cell differentiation, potentially via gut microbial activity.
• [#Diabetes Type 1] - #Children who progressed to multiple islet autoantibodies later in life had decreased concentrations of conjugated BAs in early life.
• [#Diabetes Type 1] - #Eggerthella lenta was associated with the stool concentrations of TLCA and GLCA in the P2Ab study group. - #Eggerthella lenta hydroxysteroid dehydrogenases is capable of using both tauro- and glyco-conjugated BAs as substrates. - #Eggerthella lenta has previously been associated with human disease and found to activate T-helper type 17 (Th17) immune cells. - #Eggerthella lenta as an immunomodulatory microbe.
• [1.52] [#Secondary bile acids] 
  - BAs serve as signaling molecules with the ability to bind to receptors such as farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), constitutive androstane receptor (CAR), and more. - Each BA is able to bind with multiple receptor types with varying degrees of effec.t. - bile acids can be conjugated with #Glycine, #Taurine, and to a lesser studied extent, other amino acids, which can affect the ability of BAs to act as substrates for specific receptors in the body.
• [1.53] [#Crohn’s disease] [#Deoxycholic acid, #Lithocholic acid] 
  - Individuals with CD had lower plasma concentrations of the majority of secondary BA compared to controls, in total CD/CC ratio 0.60. - The most prominent observations were lower levels of deoxycolic acid derivates and lithocolic acid derivates among participants with CD. - plasma concentration for secondary BA among participants with active CD was significantly lower compared to those with CD in remission, CD active/CD remission ratio 0.65
• [1.54] [#Parkinson’s Disease] 
  - #Taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with PD incidence in the general population
• [1.55] 
  - bile acids and gut microbiota are reciprocally regulated and collaboratively control #GLP-1 production mainly through the binding of BAs to their receptors, FXR. - The activation of FXR decreases #GLP-1 secretion.
• [#High temperature and humidity] - ambient HTH affected the crosstalk between gut microbiota and BAs and thereby caused an aberrant FXR activation and #GLP-1 suppression.
• [#High temperature and humidity] - BAs (like CA, CDCA, and CA) are FXR agonizts, and all of them reduced slightly after HTH treatment, the intestinal FXR signaling pathway was activated.
• [1.56] 
  - BAs interact with FXR in the intestines, affecting BA absorption, transport, hepatic lipogenesis, lipid metabolism, and inflammation regulation.
• [#Metabolic associated fatty liver disease] - patients with lean NAFLD displayed elevated levels of total, primary, and secondary BAs compared to their nonlean counterparts, with statistical significance observed specifically for secondary BAs
• [#Metabolic associated fatty liver disease] - Patients with MAFLD show elevated levels of total fecal BAs, including #Cholic acid and #Chenodeoxycholic acid, along with an altered balance of primary and secondary BAs.
• [#Metabolic associated fatty liver disease] [#High Fat Diet] - high-fat diets (HFD) have been found to increase specific #Lactobacillus species resistant to BAs, which may influence lipid metabolism and contribute to MAFLD development.

References Notes