Resveratrol Attenuates Trimethylamine- N -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota

In the paper

“Additionally, tempol, an antioxidant and protective agent against radiation, can alter the gut microbiome, leading to the accumulation of intestinal T-βMCA, thereby inhibiting intestinal FXR signaling and decreasing obesity (12).”

What the sources say

• Supported

  The Introduction (page unavailable) describes tempol as an antioxidant and radiation protector. The Abstract and Discussion (pages unavailable) report that, in mice, tempol alters the gut microbiome, increases intestinal T-β-MCA, inhibits intestinal FXR signalling, and reduces obesity. (LLM, conf=0.93)

  cites [12] Li F, Jiang CT, Krausz KW, Li YF, Albert I, Hao HP, Fabre KM, Mitchell JB, Patterson AD, Gonzalez FJ 2013 Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 4: 2384. doi: 10.1038/ncomms3384. 24064762 PMC6595219 source

In the paper

“It has been demonstrated that the gene encoding FMO3 is a direct FXR target gene, and FXR has been found to be a target of sirtuin 1 (SIRT1) in metabolic regulation (23, 34, 35).”

What the sources say

• ?Could not verify

  The Results section, “Regulation of FMO3 by FXR” (page unavailable), identifies FMO3 as a direct FXR target, but does not address whether FXR is a SIRT1 target. Searches for SIRT1, sirtuin, and FXR deacetylation found no passage in our copy supporting the attributed relationship. (LLM, conf=0.76)

  cites [23] Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ 2013 Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17: 49– 60. doi: 10.1016/j.cmet.2012.12.011. 23312283 PMC3771112 sourceExperimental — accuracy not yet measured
• Supported

  The Introduction explicitly states that FXR is a target of SIRT1 in metabolic regulation. The Results further report that reducing SIRT1 increases FXR acetylation in mouse liver. (LLM, conf=0.95)

  cites [34] Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, Tsang S, Wu SY, Chiang CM, Veenstra TD 2009 FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 10: 392– 404. doi: 10.1016/j.cmet.2009.09.009. 19883617 PMC2785075 source
• Supported

  The section “Hepatic deletion of SIRT1 reduces the expression of FXR” reports that SIRT1 positively regulates FXR signaling in hepatocytes. The Discussion also reports that SIRT1 regulates FXR expression and contributes to its activation through deacetylation. No page numbers are provided in the supplied passages. (LLM, conf=0.93)

  cites [35] Purushotham A, Xu Q, Lu J, Foley JF, Yan X, Kim DH, Kemper JK, Li X 2012 Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1 alpha/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice. Mol Cell Biol 32: 1226– 1236. doi: 10.1128/MCB.05988-11. 22290433 PMC3302441 source

In the paper

“Additionally, via a direct ex vivo assay, we found that the production of TMA from choline was higher in cecal content from choline-treated mice and that the effect was reversed by RSV administration (Fig. 7I).”

In the paper

“Finally, we observed a reduction in the mRNA levels of the BA transporters organic solute transporter alpha (OSTα) and beta (OSTβ) in RSV-treated mice”

In the paper

“As shown in Fig. 4G to I and in Table S4 in the supplemental material, RSV increased the bile TCA/TβMCA ratio and induced CYP7A1 mRNA and protein expression and the effects were inhibited by Abs treatment.”

In the paper

“For RSV-treated mice given TMA, TMAO levels were higher and TMA levels were lower than those in the control group (Fig. 1D)”

In the paper

“The atherosclerotic lesion area and the cholesterol content in the whole aorta, as indexes of AS severity, were much higher in mice fed with choline than in chow-fed mice, and the effects were markedly reversed by RSV or Abs administration (Fig. 6).”

In the paper

“We found that RSV significantly decreased the liver cholesterol level and increased the BA pool size and the gallbladder and SI luminal BA content; these effects were reversed by treatment with Abs (Fig. 4A to D).”

In the paper

“RSV also markedly increased FMO activity in the liver (Fig. 2C).”

In the paper

“Moreover, compared to chow-fed ApoE−/− mice, choline significantly increased the number of Prevotella and decreased the concentrations of Bacteroides, Lactobacillus, and Bifidobacterium (see Fig. S4B).”

In the paper

“Via liquid chromatography-tandem mass spectrometry (LC/MS), we found that peak concentrations of TMA and TMAO occurred 4 h after choline administration and 1 h after TMA administration (Fig. 1A and B).”

In the paper

“In contrast, there was a significant decrease in the fecal conjugated/unconjugated BA ratio, along with an increase in bile salt hydrolase (BSH) enzyme activity, in the feces of RSV-treated mice (Fig. 3C and D; see also Table S4).”

In the paper

“Via qPCR and sequencing 16S rRNA assays, we found that choline administration markedly increased the bacterial concentrations of Bacteroidetes phyla and decreased the concentrations of Firmicutes phyla compared to the control group (see Fig. S4A in the supplemental material).”

In the paper

“Genus-level analysis showed that RSV induced an increase in the relative abundances of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia in mice (Fig. 2E and F).”

In the paper

“Moreover, the addition of 1% choline over 30 days significantly increased the levels of TMA and TMAO in mice; however, this was reversed by RSV administration (Fig. 1E).”

In the paper

“As shown in Fig. 7A to D, RSV administration markedly decreased TMA and TMAO contents and increased the expression levels of liver FMO3 and FMO activity.”

In the paper

“In the liver, RSV treatment appeared to have no significant effect on the mRNA level of the SHP gene and the mRNA and protein levels of FXR (see Fig. S3A and B in the supplemental material).”

In the paper

“RSV significantly enhanced fecal BA loss, which was inhibited by Abs (Fig. 3A).”

In the paper

“RSV also increased the relative abundances of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia and decreased the relative abundances of Prevotella, Ruminococcaceae_unclassified, and Biophila in choline-fed ApoE−/− mice (Fig. 7F and G).”

In the paper

“Moreover, we found that the same mice fed with RSV could show markedly decreased TMA and TMAO levels after choline treatment; however, after washout with a chow diet for 1 month, they failed to reduce TMA and TMAO contents after choline administration (Fig. 2J).”

In the paper

“Additionally, plasma RSV content was higher in mice fed RSV than in mice fed a standard diet (Fig. 1F).”

In the paper

“Via a direct ex vivo assay, we found that the production of TMA from choline was lower in cecal content from RSV-treated mice”

In the paper

“RSV treatment resulted in a significant decrease in ileal FGF15 mRNA and protein levels; however, ileal FXR mRNA and protein levels were unchanged (Fig. 5A and B).”

In the paper

“The proportion of sequences assigned to Bacteroidetes was significantly increased in metagenomes of RSV-fed animals at the expense of Firmicutes (Fig. 2D).”

In the paper

“The mRNA level of the SHP gene and the mRNA and protein levels of FXR in the liver were unchanged by RSV (Fig. 9A and B).”

In the paper

“We observed that RSV significantly increased the expression of CYP7A1, subsequently inducing BA synthesis in the liver.”

In the paper

“We also found that RSV decreased the activity of ileal FXR and the expression of FGF15 by decreasing the levels of FXR agonists (TCA and CDCA) in SI tissues (45, 46).”

What the sources say

• Not checked yetcites [45] De Aguiar Vallim TQ, Tarling EJ, Edwards PA 2013 Pleiotropic roles of bile acids in metabolism. Cell Metab 17: 657– 669. doi: 10.1016/j.cmet.2013.03.013. 23602448 PMC3654004 source
• Not checked yetcites [46] Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F 2013 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225– 235. doi: 10.1016/j.cmet.2013.01.003. 23395169 source

In the paper

“When Z-Gug, a natural antagonist of FXR, was administered, RSV failed to reduce FGF15 expression and to induce the expression of CYP7A1 in mice.”

In the paper

“TMAO generation is dependent on the gut microbiota, which first metabolizes dietary choline to trimethylamine (TMA). Thereafter, the TMA is metabolized to TMAO by enzymes of the flavin monooxygenase (FMO) family in the liver (4).”

What the sources say

• Not checked yetcites [4] Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH 2013 Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576– 585. doi: 10.1038/nm.3145. 23563705 PMC3650111 source

In the paper

“Primary BAs are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary BAs via deconjugation, dehydrogenation, and dehydroxylation in the gut (6).”

What the sources say

• Not checked yetcites [6] Jones ML, Tomaro-Duchesneau C, Prakash S 2014 The gut microbiome, probiotics, bile acids axis, and human health. Trends Microbiol 22: 306– 308. doi: 10.1016/j.tim.2014.04.010. 24836108 source

In the paper

“These findings highlighted that RSV downregulated the ileal FXR-FGF15 axis, which might result from RSV-induced significant reduction in FXR agonists (TCA, DCA, CA, and CDCA) in SI tissues (see Table S4).”

In the paper

“Researchers have confirmed that a polyphenol-rich cranberry extract and metformin attenuate diet-induced metabolic syndrome in mice in a gut microbiota-dependent manner (16, 17).”

What the sources say

• Not checked yetcites [16] Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW 2014 An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63: 727– 735. doi: 10.1136/gutjnl-2012-303839. 23804561 source
• Not checked yetcites [17] Anhê FF, Roy D, Pilon G, Dudonné S, Matamoros S, Varin TV, Garofalo C, Moine Q, Desjardins Y, Levy E, Marette A 2015 A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 64: 872– 883 doi: 10.1136/gutjnl-2014-307142. 25080446 source

In the paper

“In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis.”

In the paper

“VSL#3 probiotics can induce hepatic BA neosynthesis via downregulation of the gut-liver FXR-FGF15 axis (10).”

What the sources say

• Not checked yetcites [10] Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A 2014 Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the FXR-FGF15 axis in mice. Cell Rep 7: 12– 18. doi: 10.1016/j.celrep.2014.02.032. 24656817 source

In the paper

“Sayin et al. found that the gut microbiota can reduce the levels of tauro-beta-muricholic acid (T-βMCA), a naturally occurring FXR antagonist. This subsequently inhibits cholesterol 7a-hydroxylase (CYP7A1), the rate-limiting enzyme in BA synthesis, by activating FXR-FGF15 signaling and ultimately regulating BA metabolism in the liver (5, 11).”

What the sources say

• Not checked yetcites [5] Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F 2013 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225– 235. doi: 10.1016/j.cmet.2013.01.003. 23395169 source
• Not checked yetcites [11] Miyata M, Sakaida Y, Matsuzawa H, Yoshinari K, Yamazoe Y 2011 Fibroblast growth factor 19 treatment ameliorates disruption of hepatic lipid metabolism in farnesoid X receptor (FXR)-null mice. Biol Pharm Bull 34: 1885– 1889. doi: 10.1248/bpb.34.1885. 22130247 source

In the paper

“These results suggested that RSV could be a good candidate for prebiotics and could be used to promote the growth of beneficial commensals and thus to confer health benefits to the host.”

In the paper

“Resveratrol (RSV) is a natural polyphenol that mainly occurs in grapes, berries, and other dietary constituents and is beneficial for treatment of many metabolic diseases, including AS (13).”

What the sources say

• Not checked yetcites [13] Chung JH, Manganiello V, Dyck JR 2012 Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 22: 546– 554. doi: 10.1016/j.tcb.2012.07.004. 22885100 PMC3462230 source

In the paper

“These results indicated that RSV remodeled the gut microbiome in mice, which might contribute to decreased gut microbial TMA production, thereby inhibiting TMAO synthesis.”

In the paper

“This process is controlled by a negative-feedback loop through the activation of the nuclear farnesoid X receptor (FXR) in the ileum and liver (7, 8).”

What the sources say

• Not checked yetcites [7] Li-Hawkins J, Gåfvels M, Olin M, Lund EG, Andersson U, Schuster G, Björkhem I, Russell DW, Eggertsen G 2002 Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J Clin Invest 110: 1191– 1200. doi: 10.1172/JCI16309. 12393855 PMC150802 source
• Not checked yetcites [8] Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P 2009 Bile acids as regulatory molecules. J Lipid Res 50: 1509– 1520. doi: 10.1194/jlr.R900007-JLR200. 19346331 PMC2724047 source

In the paper

“Previous investigations have shown that the physiological effects of dietary RSV are in striking contrast to its poor bioavailability, which is a major concern for the development of this class of compounds into therapeutic agents (14, 15).”

What the sources say

• Not checked yetcites [14] Subramanian L, Youssef S, Bhattacharya S, Kenealey J, Polans AS, van Ginkel PR 2010 Resveratrol: challenges in translation to the clinic—a critical discussion. Clin Cancer Res 16: 5942– 5948. doi: 10.1158/1078-0432.CCR-10-1486. 21045084 PMC3057445 source
• Not checked yetcites [15] Asensi M, Medina I, Ortega A, Carretero J, Baño MC, Obrador E, Estrela JM 2002 Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic Biol Med 33: 387– 398. doi: 10.1016/S0891-5849(02)00911-5. 12126761 source

In the paper

“These results suggested that RSV-induced modulation of the gut microbiome contributed to increased BSH activity and subsequently promoted the generation of unconjugated BAs from conjugated BAs, thereby enhancing fecal BA loss.”

In the paper

“These results were consistent with our findings in C57BL/6J mice, suggesting the important role of the gut microbiota in the RSV-induced decrease of TMAO levels.”

In the paper

“These results indicated that chronic choline supplementation might alter cecal microbial composition, thereby enhancing the synthesis of TMA and TMAO and ultimately increasing AS.”

In the paper

“We found that RSV reduced TMAO levels by inhibiting gut microbial TMA formation via remodeling gut microbiota, thereby attenuating TMAO-induced AS.”

• Also stated in: § DISCUSSION · plain

  “Here, we found that RSV inhibited TMAO synthesis by decreasing gut microbial TMA production through gut microbiota modulation, which subsequently attenuated TMAO-induced AS.”

In the paper

“Bacterial BSH activity affects systemic metabolic processes and adiposity in the host.”

What the sources say

• Not checked yetcites [42] Joyce SA, MacSharry J, Casey PG, Kinsella M, Murphy EF, Shanahan F, Hill C, Gahan CG 2014 Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci U S A 111: 7421– 7426. doi: 10.1073/pnas.1323599111. 24799697 PMC4034235 source

In the paper

“The gut microbiota is important for BA metabolism, as it mediates primary BA deconjugation and subsequent conversion to secondary BAs, which are responsible for BA synthesis in the liver (5).”

What the sources say

• Not checked yetcites [5] Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F 2013 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225– 235. doi: 10.1016/j.cmet.2013.01.003. 23395169 source

In the paper

“Our results contradict those previously published, possibly because we were experimenting in vivo, which is a more complex environment than that in vitro.”

In the paper

“Dietary RSV has been shown to increase the expression of hepatic CYP7A1 and to ameliorate hypercholesterolemia in high-fat-fed C57BL/6J mice (43).”

What the sources say

• Not checked yetcites [43] Chen Q, Wang E, Ma L, Zhai P 2012 Dietary resveratrol increases the expression of hepatic 7alpha-hydroxylase and ameliorates hypercholesterolemia in high-fat fed C57BL/6J mice. Lipids Health Dis 11: 56. doi: 10.1186/1476-511X-11-56. 22607622 PMC3439360 source

In the paper

“RSV promotes the degradation of ASBT in vitro, which might have some clinical relevance with regard to the observed cholesterol-lowering effects of RSV (44).”

What the sources say

• Not checked yetcites [44] Chothe PP, Swaan PW 2014 Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2). Biochem J 459: 301– 312. doi: 10.1042/BJ20131428. 24498857 source

In the paper

“It has been demonstrated that the gene encoding FMO3 is a direct FXR target gene, and FXR has been found to be a target of sirtuin 1 (SIRT1) in metabolic regulation (23, 34, 35).”

What the sources say

• Not checked yetcites [23] Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ 2013 Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17: 49– 60. doi: 10.1016/j.cmet.2012.12.011. 23312283 PMC3771112 source
• Not checked yetcites [34] Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, Tsang S, Wu SY, Chiang CM, Veenstra TD 2009 FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 10: 392– 404. doi: 10.1016/j.cmet.2009.09.009. 19883617 PMC2785075 source
• Not checked yetcites [35] Purushotham A, Xu Q, Lu J, Foley JF, Yan X, Kim DH, Kemper JK, Li X 2012 Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1 alpha/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice. Mol Cell Biol 32: 1226– 1236. doi: 10.1128/MCB.05988-11. 22290433 PMC3302441 source

In the paper

“Moreover, RSV is a well-known activator of SIRT1 and our previous study also found that RSV improved hepatic steatosis partially by inducing autophagy via the SIRT1 signaling pathway in vitro and in vivo (36–38).”

What the sources say

• Not checked yetcites [36] Kulkarni SS, Cantó C 2015 The molecular targets of resveratrol. Biochim Biophys Acta 1852: 1114– 1123. doi: 10.1016/j.bbadis.2014.10.005. 25315298 source
• Not checked yetcites [37] El-Mowafy AM, El-Mesery ME, Salem HA, Al-Gayyar MM, Darweish MM 2010 Prominent chemopreventive and chemoenhancing effects for resveratrol: unraveling molecular targets and the role of C-reactive protein. Chemotherapy 56: 60– 65. doi: 10.1159/000298821. 20299793 source
• Not checked yetcites [38] Zhang Y, Chen ML, Zhou Y, Yi L, Gao YX, Ran L, Chen SH, Zhang T, Zhou X, Zou D, Wu B, Wu Y, Chang H, Zhu JD, Zhang QY, Mi MT 2015 Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Mol Nutr Food Res 59: 1443– 1457. doi: 10.1002/mnfr.201500016. 25943029 source

In the paper

“It also represents a key mechanistic target for the control of obesity and hypercholesterolemia, acting by deconjugating BAs to generate unconjugated BAs (42).”

What the sources say

• Not checked yetcites [42] Joyce SA, MacSharry J, Casey PG, Kinsella M, Murphy EF, Shanahan F, Hill C, Gahan CG 2014 Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci U S A 111: 7421– 7426. doi: 10.1073/pnas.1323599111. 24799697 PMC4034235 source

In the paper

“Meanwhile, we found that RSV increased BSH activity, thereby enhancing BA deconjugation.”

In the paper

“Recently, it was found that ASBT plays a key role in the enterohepatic recycling of BAs and indirectly contributes to cholesterol homoeostasis (26).”

What the sources say

• Not checked yetcites [26] Alrefai WA, Gill RK 2007 Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 24: 1803– 1823. doi: 10.1007/s11095-007-9289-1. 17404808 source

In the paper

“Overall, we came to the conclusion that RSV attenuated TMAO-induced AS, partially by regulating BA synthesis through the enterohepatic FXR-FGF15 axis in a gut microbiota-dependent manner.”

In the paper

“BAs are synthesized from cholesterol by CYP7A1 in the liver and play a central role in cholesterol homoeostasis (8).”

What the sources say

• Not checked yetcites [8] Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P 2009 Bile acids as regulatory molecules. J Lipid Res 50: 1509– 1520. doi: 10.1194/jlr.R900007-JLR200. 19346331 PMC2724047 source

In the paper

“Moreover, RSV is a well-known activator of SIRT1 and our previous study also found that RSV improved hepatic steatosis partially by inducing autophagy via the SIRT1 signaling pathway in vitro and in vivo (36–38).”

What the sources say

• Not checked yetcites [36] Kulkarni SS, Cantó C 2015 The molecular targets of resveratrol. Biochim Biophys Acta 1852: 1114– 1123. doi: 10.1016/j.bbadis.2014.10.005. 25315298 source
• Not checked yetcites [37] El-Mowafy AM, El-Mesery ME, Salem HA, Al-Gayyar MM, Darweish MM 2010 Prominent chemopreventive and chemoenhancing effects for resveratrol: unraveling molecular targets and the role of C-reactive protein. Chemotherapy 56: 60– 65. doi: 10.1159/000298821. 20299793 source
• Not checked yetcites [38] Zhang Y, Chen ML, Zhou Y, Yi L, Gao YX, Ran L, Chen SH, Zhang T, Zhou X, Zou D, Wu B, Wu Y, Chang H, Zhu JD, Zhang QY, Mi MT 2015 Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Mol Nutr Food Res 59: 1443– 1457. doi: 10.1002/mnfr.201500016. 25943029 source

In the paper

“Previous studies have shown that FXR activation induces SHP and FGF15, thereby suppressing CYP7A1 expression and ultimately inhibiting BA synthesis (31, 32).”

What the sources say

• Not checked yetcites [31] Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA 2005 Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217– 225. doi: 10.1016/j.cmet.2005.09.001. 16213224 source
• Not checked yetcites [32] Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ 2000 Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6: 507– 515. doi: 10.1016/S1097-2765(00)00050-2. 11030331 source

In the paper

“The gut microbiome produces potent ligands corresponding to BA receptors; probiotics or prebiotics could act as therapeutics of BA dysmetabolism, indicating that microbiota-targeted therapies could be effective in preventing and/or treating gut-related diseases, including AS (40).”

What the sources say

• Not checked yetcites [40] Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, Holmes E 2011 Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A 108: 4523– 4530. doi: 10.1073/pnas.1006734107. 20837534 PMC3063584 source

In the paper

“Interestingly, the SI lumenal BA content was higher upon RSV treatment, which was presumably a result of increased biliary output.”

In the paper

“Meanwhile, a recent report showed that 3,3-dimethyl-1-butanol can reduce TMAO levels by inhibiting the formation of TMA from microbes in mice, thereby attenuating choline diet-enhanced AS (39).”

What the sources say

• Not checked yetcites [39] Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, Zamanian-Daryoush M, Culley MK, DiDonato AJ, Fu X, Hazen JE, Krajcik D, DiDonato JA, Lusis AJ, Hazen SL 2015 Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163: 1585– 1595. doi: 10.1016/j.cell.2015.11.055. 26687352 PMC4871610 source

In the paper

“FXR is required for the negative-feedback regulation of BA biosynthesis and the enterohepatic cycle (30).”

What the sources say

• Not checked yetcites [30] Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ 2000 Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731– 744. doi: 10.1016/S0092-8674(00)00062-3. 11030617 source

In the paper

“Our findings were the first to indicate the crucial role of the gut microbiota in RSV-induced cholesterol metabolism in the liver, indicating that RSV could attenuate TMAO-caused AS, partially by inducing BA synthesis in a gut microbiota-dependent manner.”

In the paper

“whereas TMA has been reported to influence signal transduction by direct interaction with a family of G protein-coupled receptors (47).”

What the sources say

• Not checked yetcites [47] Liberles SD, Buck LB 2006 A second class of chemosensory receptors in the olfactory epithelium. Nature 442: 645– 650. doi: 10.1038/nature05066. 16878137 source

In the paper

“TMAO, a small quaternary amine with an aliphatic character, is reportedly capable of directly inducing conformational changes in proteins and of stabilizing protein folding and acting as a small-molecule protein chaperone (48, 49).”

What the sources say

• Not checked yetcites [48] Bai C, Biwersi J, Verkman AS, Matthay MA 1998 A mouse model to test the in vivo efficacy of chemical chaperones. J Pharmacol Toxicol Methods 40: 39– 45. doi: 10.1016/S1056-8719(98)00034-3. 9920533 source
• Not checked yetcites [49] Mello CC, Barrick D 2003 Measuring the stability of partly folded proteins using TMAO. Protein Sci 12: 1522– 1529. doi: 10.1110/ps.0372903. 12824497 PMC2323936 source

In the paper

“BA synthesis and modulation of the enterohepatic FXR-FGF15 axis are seen in germ-free, gnotobiotic, and antibiotic-treated animals (5).”

What the sources say

• Not checked yetcites [5] Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F 2013 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225– 235. doi: 10.1016/j.cmet.2013.01.003. 23395169 source

In the paper

“Results from a recent study demonstrate that probiotic VSL#3 affects hepatic BA synthesis by downregulating the gut-liver FXR-FGF15 axis.”

What the sources say

• Not checked yetcites [10] Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A 2014 Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the FXR-FGF15 axis in mice. Cell Rep 7: 12– 18. doi: 10.1016/j.celrep.2014.02.032. 24656817 source