A microbial metabolite remodels the gut-liver axis following bariatric surgery
Snehal N Chaudhari, James N Luo, David A Harris, Hassan Aliakbarian, Lina Yao, Donggi Paik, Renuka Subramaniam, Arijit A Adhikari, Ashley H Vernon, Ayse Kiliç, Scott T Weiss, Jun R Huh, Eric G Sheu, A Sloan Devlin, Snehal N Chaudhari, James N Luo, David A Harris, Hassan Aliakbarian, Lina Yao, Donggi Paik, Renuka Subramaniam, Arijit A Adhikari, Ashley H Vernon, Ayse Kiliç, Scott T Weiss, Jun R Huh, Eric G Sheu, A Sloan Devlin
Abstract
Bariatric surgery is the most effective treatment for type 2 diabetes and is associated with changes in gut metabolites. Previous work uncovered a gut-restricted TGR5 agonist with anti-diabetic properties-cholic acid-7-sulfate (CA7S)-that is elevated following sleeve gastrectomy (SG). Here, we elucidate a microbiome-dependent pathway by which SG increases CA7S production. We show that a microbial metabolite, lithocholic acid (LCA), is increased in murine portal veins post-SG and by activating the vitamin D receptor, induces hepatic mSult2A1/hSULT2A expression to drive CA7S production. An SG-induced shift in the microbiome increases gut expression of the bile acid transporters Asbt and Ostα, which in turn facilitate selective transport of LCA across the gut epithelium. Cecal microbiota transplant from SG animals is sufficient to recreate the pathway in germ-free (GF) animals. Activation of this gut-liver pathway leads to CA7S synthesis and GLP-1 secretion, causally connecting a microbial metabolite with the improvement of diabetic phenotypes.
Keywords: bariatric surgery; bile acids; gut-liver axis; microbiome.
Conflict of interest statement
Declaration of interests CA7S is a subject of patents held by HMS and BWH on which S.N.C., D.A.H., E.G.S., and A.S.D. are inventors. A.S.D. is a consultant for Takeda Pharmaceuticals and HP Hood. E.G.S. is a consultant for Vicarious Surgical, Inc. and was previously on the scientific advisory board of Kitotech, Inc.
Copyright © 2020 Elsevier Inc. All rights reserved.
Figures
References
- Abbasi J (2017). Unveiling the "Magic" of Diabetes Remission After Weight-Loss Surgery. JAMA 317, 571–574.
- Adhikari AA, Seegar TCM, Ficarro SB, McCurry MD, Ramachandran D, Yao L, Chaudhari SN, Ndousse-Fetter S, Banks AS, Marto JA, et al. (2020). Development of a covalent inhibitor of gut bacterial bile salt hydrolases. Nat Chem Biol 16, 318–326.
- Alnouti Y (2009). Bile Acid sulfation: a pathway of bile acid elimination and detoxification. Toxicol Sci 108, 225–246.
- Bachmanov AA, Reed DR, Beauchamp GK, and Tordoff MG (2002). Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet 32, 435–443.
- Besnard P, Landrier JF, Grober J, and Niot I (2004). [Is the ileal bile acid-binding protein (I-BABP) gene involved in cholesterol homeostasis?]. Med Sci (Paris) 20, 73–77.
- Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, and Holmes SP (2016). DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods 13, 581–583.
- Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, et al. (2010). QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7, 335–336.
- Chaudhari SN, Harris DA, Aliakbarian H, Luo JN, Henke MT, Subramaniam R, Vernon AH, Tavakkoli A, Sheu EG, and Devlin AS (2020). Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects. Nat Chem Biol.
- Craddock AL, Love MW, Daniel RW, Kirby LC, Walters HC, Wong MH, and Dawson PA (1998). Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol 274, G157–169.
- Cristina ML, Lehy T, Zeitoun P, and Dufougeray F (1978). Fine structural classification and comparative distribution of endocrine cells in normal human large intestine. Gastroenterology 75, 20–28.
- Damms-Machado A, Mitra S, Schollenberger AE, Kramer KM, Meile T, Konigsrainer A, Huson DH, and Bischoff SC (2015). Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption. Biomed Res Int 2015, 806248.
- Dawson PA, Lan T, and Rao A (2009). Bile acid transporters. J Lipid Res 50, 2340–2357.
- Dawson PA, and Setchell KDR (2017). Will the real bile acid sulfotransferase please stand up? Identification of Sult2a8 as a major hepatic bile acid sulfonating enzyme in mice. J Lipid Res 58, 1033–1035.
- Ding L, Sousa KM, Jin L, Dong B, Kim BW, Ramirez R, Xiao Z, Gu Y, Yang Q, Wang J, et al. (2016). Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice. Hepatology 64, 760–773.
- Duboc H, Tache Y, and Hofmann AF (2014). The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 46, 302–312.
- Elam MB, Cowan GS Jr., Rooney RJ, Hiler ML, Yellaturu CR, Deng X, Howell GE, Park EA, Gerling IC, Patel D, et al. (2009). Hepatic gene expression in morbidly obese women: implications for disease susceptibility. Obesity (Silver Spring) 17, 1563–1573.
- Feng L, Yuen YL, Xu J, Liu X, Chan MY, Wang K, Fong WP, Cheung WT, and Lee SS (2017). Identification and characterization of a novel PPARalpha-regulated and 7alpha-hydroxyl bile acid-preferring cytosolic sulfotransferase mL-STL (Sult2a8). J Lipid Res 58, 1114–1131.
- Ferruzza S, Rossi C, Scarino ML, and Sambuy Y (2012). A protocol for differentiation of human intestinal Caco-2 cells in asymmetric serum-containing medium. Toxicol In Vitro 26, 1252–1255.
- Fiorucci S, and Distrutti E (2015). Bile Acid-Activated Receptors, Intestinal Microbiota, and the Treatment of Metabolic Disorders. Trends Mol Med 21, 702–714.
- Fukushima K, Okada A, Hayashi Y, Ichikawa H, Nishimura A, Shibata N, and Sugioka N (2015). Enhanced oral bioavailability of vancomycin in rats treated with long-term parenteral nutrition. Springerplus 4, 442.
- Funabashi M, Grove TL, Wang M, Varma Y, McFadden ME, Brown LC, Guo C, Higginbottom S, Almo SC, and Fischbach MA (2020). A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Nature 582, 566–570.
- Ghosh A, Chen F, Banerjee S, Xu M, and Shneider BL (2014). c-Fos mediates repression of the apical sodium-dependent bile acid transporter by fibroblast growth factor-19 in mice. Am J Physiol Gastrointest Liver Physiol 306, G163–171.
- Gralka E, Luchinat C, Tenori L, Ernst B, Thurnheer M, and Schultes B (2015). Metabolomic fingerprint of severe obesity is dynamically affected by bariatric surgery in a procedure-dependent manner. Am J Clin Nutr 102, 1313–1322.
- Hall AB, Yassour M, Sauk J, Garner A, Jiang X, Arthur T, Lagoudas GK, Vatanen T, Fornelos N, Wilson R, et al. (2017). A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med 9, 103.
- Han S, and Chiang JY (2009). Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. Drug Metab Dispos 37, 469–478.
- Heshmati K, Harris DA, Aliakbarian H, Tavakkoli A, and Sheu EG (2019). Comparison of early type 2 diabetes improvement after gastric bypass and sleeve gastrectomy: medication cessation at discharge predicts 1-year outcomes. Surg Obes Relat Dis 15, 2025–2032.
- Jahansouz C, Staley C, Bernlohr DA, Sadowsky MJ, Khoruts A, and Ikramuddin S (2017). Sleeve gastrectomy drives persistent shifts in the gut microbiome. Surg Obes Relat Dis 13, 916–924.
- Jahansouz C, Staley C, Kizy S, Xu H, Hertzel AV, Coryell J, Singroy S, Hamilton M, DuRand M, Bernlohr DA, et al. (2018). Antibiotic-induced Disruption of Intestinal Microbiota Contributes to Failure of Vertical Sleeve Gastrectomy. Ann Surg.
- Kakizaki S, Takizawa D, Tojima H, Yamazaki Y, and Mori M (2009). Xenobiotic-sensing nuclear receptors CAR and PXR as drug targets in cholestatic liver disease. Curr Drug Targets 10, 1156–1163.
- Kaska L, Sledzinski T, Chomiczewska A, Dettlaff-Pokora A, and Swierczynski J (2016). Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome. World J Gastroenterol 22, 8698–8719.
- Kastl AJ Jr., Terry NA, Wu GD, and Albenberg LG (2020). The Structure and Function of the Human Small Intestinal Microbiota: Current Understanding and Future Directions. Cell Mol Gastroenterol Hepatol 9, 33–45.
- Kohli R, Bradley D, Setchell KD, Eagon JC, Abumrad N, and Klein S (2013). Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. J Clin Endocrinol Metab 98, E708–712.
- Lamp KC, Freeman CD, Klutman NE, and Lacy MK (1999). Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet 36, 353–373.
- Larraufie P, Roberts GP, McGavigan AK, Kay RG, Li J, Leiter A, Melvin A, Biggs EK, Ravn P, Davy K, et al. (2019). Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery. Cell Rep 26, 1399–1408 e1396.
- Lea T (2015). Caco-2 Cell Line. In The Impact of Food Bioactives on Health: in vitro and ex vivo models, Verhoeckx K, Cotter P, Lopez-Exposito I, Kleiveland C, Lea T, Mackie A, Requena T, Swiatecka D, and Wichers H, eds. (Cham (CH)), pp. 103–111.
- Lespessailles E, and Toumi H (2017). Vitamin D alteration associated with obesity and bariatric surgery. Exp Biol Med (Maywood) 242, 1086–1094.
- Li YC, Amling M, Pirro AE, Priemel M, Meuse J, Baron R, Delling G, and Demay MB (1998). Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocrinology 139, 4391–4396.
- Liu H, Hu C, Zhang X, and Jia W (2018). Role of gut microbiota, bile acids and their cross-talk in the effects of bariatric surgery on obesity and type 2 diabetes. J Diabetes Investig 9, 13–20.
- Magouliotis DE, Tasiopoulou VS, Sioka E, Chatedaki C, and Zacharoulis D (2017). Impact of Bariatric Surgery on Metabolic and Gut Microbiota Profile: a Systematic Review and Meta-analysis. Obes Surg 27, 1345–1357.
- Manchanda PK, and Bid HK (2012). Vitamin D receptor and type 2 diabetes mellitus: Growing therapeutic opportunities. Indian J Hum Genet 18, 274–275.
- Marion S, Studer N, Desharnais L, Menin L, Escrig S, Meibom A, Hapfelmeier S, and Bernier-Latmani R (2019). In vitro and in vivo characterization of Clostridium scindens bile acid transformations. Gut Microbes 10, 481–503.
- Martinez-Augustin O, and Sanchez de Medina F (2008). Intestinal bile acid physiology and pathophysiology. World J Gastroenterol 14, 5630–5640.
- Martinez-Guryn K, Hubert N, Frazier K, Urlass S, Musch MW, Ojeda P, Pierre JF, Miyoshi J, Sontag TJ, Cham CM, et al. (2018). Small Intestine Microbiota Regulate Host Digestive and Absorptive Adaptive Responses to Dietary Lipids. Cell Host Microbe 23, 458–469 e455.
- McGavigan AK, Garibay D, Henseler ZM, Chen J, Bettaieb A, Haj FG, Ley RE, Chouinard ML, and Cummings BP (2017). TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut 66, 226–234.
- Medina DA, Pedreros JP, Turiel D, Quezada N, Pimentel F, Escalona A, and Garrido D (2017). Distinct patterns in the gut microbiota after surgical or medical therapy in obese patients. PeerJ 5, e3443.
- Out C, Patankar JV, Doktorova M, Boesjes M, Bos T, de Boer S, Havinga R, Wolters H, Boverhof R, van Dijk TH, et al. (2015). Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4. J Hepatol 63, 697–704.
- Patti ME, Houten SM, Bianco AC, Bernier R, Larsen PR, Holst JJ, Badman MK, Maratos-Flier E, Mun EC, Pihlajamaki J, et al. (2009). Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity (Silver Spring) 17, 1671–1677.
- Pournaras DJ, Glicksman C, Vincent RP, Kuganolipava S, Alaghband-Zadeh J, Mahon D, Bekker JH, Ghatei MA, Bloom SR, Walters JR, et al. (2012). The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology 153, 3613–3619.
- Ridlon JM, Kang DJ, and Hylemon PB (2006). Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47, 241–259.
- Roda A, Cappelleri G, Aldini R, Roda E, and Barbara L (1982). Quantitative aspects of the interaction of bile acids with human serum albumin. J Lipid Res 23, 490–495.
- Runge-Morris M, Kocarek TA, and Falany CN (2013). Regulation of the cytosolic sulfotransferases by nuclear receptors. Drug Metab Rev 45, 15–33.
- Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Perez HE, Sandoval DA, Kohli R, Backhed F, et al. (2014). FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509, 183–188.
- Samczuk P, Ciborowski M, and Kretowski A (2018). Application of Metabolomics to Study Effects of Bariatric Surgery. J Diabetes Res 2018, 6270875.
- Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, Lesniewski RA, Oakley BB, Parks DH, Robinson CJ, et al. (2009). Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 75, 7537–7541.
- Shang Q, Saumoy M, Holst JJ, Salen G, and Xu G (2010). Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing the release of GLP-1. Am J Physiol Gastrointest Liver Physiol 298, G419–424.
- Sisley SR, Arble DM, Chambers AP, Gutierrez-Aguilar R, He Y, Xu Y, Gardner D, Moore DD, Seeley RJ, and Sandoval DA (2016). Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight. Diabetes 65, 2732–2741.
- Sun AQ, Balasubramaniyan N, Chen H, Shahid M, and Suchy FJ (2006). Identification of functionally relevant residues of the rat ileal apical sodium-dependent bile acid cotransporter. J Biol Chem 281, 16410–16418.
- Tan HY, Trier S, Rahbek UL, Dufva M, Kutter JP, and Andresen TL (2018). A multi-chamber microfluidic intestinal barrier model using Caco-2 cells for drug transport studies. PLoS One 13, e0197101.
- Tremaroli V, Karlsson F, Werling M, Stahlman M, Kovatcheva-Datchary P, Olbers T, Fandriks L, le Roux CW, Nielsen J, and Backhed F (2015). Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation. Cell Metab 22, 228–238.
- Wahlstrom A, Kovatcheva-Datchary P, Stahlman M, Khan MT, Backhed F, and Marschall HU (2017). Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota. J Lipid Res 58, 412–419.
- Wahlstrom A, Sayin SI, Marschall HU, and Backhed F (2016). Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab 24, 41–50.
- Wang W, Cheng Z, Wang Y, Dai Y, Zhang X, and Hu S (2019). Role of Bile Acids in Bariatric Surgery. Front Physiol 10, 374.
- Weber N, Liou D, Dommer J, MacMenamin P, Quinones M, Misner I, Oler AJ, Wan J, Kim L, Coakley McCarthy M, et al. (2018). Nephele: a cloud platform for simplified, standardized and reproducible microbiome data analysis. Bioinformatics 34, 1411–1413.
- Wells JE, Williams KB, Whitehead TR, Heuman DM, and Hylemon PB (2003). Development and application of a polymerase chain reaction assay for the detection and enumeration of bile acid 7alpha-dehydroxylating bacteria in human feces. Clin Chim Acta 331, 127–134.
- Wu WK, Hsu CC, Sheen LY, and Wu MS (2019). Measurement of gut microbial metabolites in cardiometabolic health and translational research. Rapid Commun Mass Spectrom.
- Xie G, Wang X, Jiang R, Zhao A, Yan J, Zheng X, Huang F, Liu X, Panee J, Rajani C, et al. (2018). Dysregulated bile acid signaling contributes to the neurological impairment in murine models of acute and chronic liver failure. EBioMedicine 37, 294–306.
- Yalcin EB, More V, Neira KL, Lu ZJ, Cherrington NJ, Slitt AL, and King RS (2013). Downregulation of sulfotransferase expression and activity in diseased human livers. Drug Metab Dispos 41, 1642–1650.
- Yao L, Seaton SC, Ndousse-Fetter S, Adhikari AA, DiBenedetto N, Mina AI, Banks AS, Bry L, and Devlin AS (2018). A selective gut bacterial bile salt hydrolase alters host metabolism. Elife 7.
- Ye ZQ, Niu S, Yu Y, Yu H, Liu BH, Li RX, Xiao HS, Zeng R, Li YX, Wu JR, et al. (2010). Analyses of copy number variation of GK rat reveal new putative type 2 diabetes susceptibility loci. PLoS One 5, e14077.
Source: PubMed