Obesity Clinical Trial
Official title:
Role and Pathogenetic Mechanisms of Intestinal Microbiota in Non-alcoholic Fatty Liver Disease Severity in Obese and Non-obese Subjects
NCT number | NCT02158351 |
Other study ID # | 2943/14.11.2013 |
Secondary ID | |
Status | Completed |
Phase | |
First received | |
Last updated | |
Start date | November 2013 |
Est. completion date | October 2017 |
Verified date | November 2020 |
Source | University of Roma La Sapienza |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Observational |
Several experimental data suggest that gut-derived endotoxin and GM composition can act as a "second hit" or insult to convert hepatic SS to NASH and cause both local hepatic and systemic inflammation.This study's aim is to analyze microbiota diversity, providing information both on intestinal microbial composition and on the metabolic processes linked to them. In addition, we will correlate, for the first time, GM composition to hepatic and white adipose tissue gene expression patterns of interest and serum and fecal markers possibly related to impaired fat storage and inflammation. We aim to provide preliminary data to design future intervention studies with pre- or probiotics or bile acid derivatives to prevent/treat inflammation and fibrosis in NAFLD patients.
Status | Completed |
Enrollment | 44 |
Est. completion date | October 2017 |
Est. primary completion date | June 2014 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 65 Years |
Eligibility | Inclusion Criteria: 1. Male or female, equal or over 18 years old 2. Eligible for Sleeve Gastrectomy for obesity with BMI 35-50 kg/m2 3. Eligible for Cholecystectomy for symptomatic gallstones and bright liver at ultrasounds 4. Alcohol consumption is less than 20 g/d Exclusion Criteria: 1. Having liver disease of other etiology 2. Having advanced liver disease 3. Having abnormal coagulation or other reason contraindicating a Liver Biopsy 4. On regular intake of medications known to cause or exacerbate steatohepatitis or antibiotic, pre- or probiotics in the previous 3 months 5. Use of vitamin E or fish oil supplements in the previous 2 months 6. Alcohol consumption of more than 20 g/dl 7. Inflammatory bowel diseases 8. previous gastrointestinal surgery modifying the anatomy (prior to bariatric surgery) 9. Pregnancy or lactating state |
Country | Name | City | State |
---|---|---|---|
Italy | Stefano Ginanni Corradini | Rome |
Lead Sponsor | Collaborator |
---|---|
University of Roma La Sapienza | Göteborg University |
Italy,
Amigo L, Husche C, Zanlungo S, Lütjohann D, Arrese M, Miquel JF, Rigotti A, Nervi F. Cholecystectomy increases hepatic triglyceride content and very-low-density lipoproteins production in mice. Liver Int. 2011 Jan;31(1):52-64. doi: 10.1111/j.1478-3231.2010.02361.x. Epub 2010 Oct 29. — View Citation
Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):979-84. Epub 2007 Jan 8. — View Citation
Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology. 2014 Jan;59(1):328-39. doi: 10.1002/hep.26494. Epub 2013 Nov 15. Review. — View Citation
Dolce CJ, Russo M, Keller JE, Buckingham J, Norton HJ, Heniford BT, Gersin KS, Kuwada TS. Does liver appearance predict histopathologic findings: prospective analysis of routine liver biopsies during bariatric surgery. Surg Obes Relat Dis. 2009 May-Jun;5(3):323-8. doi: 10.1016/j.soard.2008.12.008. Epub 2009 Jan 23. — View Citation
Frazier TH, DiBaise JK, McClain CJ. Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury. JPEN J Parenter Enteral Nutr. 2011 Sep;35(5 Suppl):14S-20S. doi: 10.1177/0148607111413772. Epub 2011 Aug 1. Review. — View Citation
Glicksman C, Pournaras DJ, Wright M, Roberts R, Mahon D, Welbourn R, Sherwood R, Alaghband-Zadeh J, le Roux CW. Postprandial plasma bile acid responses in normal weight and obese subjects. Ann Clin Biochem. 2010 Sep;47(Pt 5):482-4. doi: 10.1258/acb.2010.010040. Epub 2010 Jul 1. — View Citation
Helling TS, Helzberg JH, Nachnani JS, Gurram K. Predictors of nonalcoholic steatohepatitis in patients undergoing bariatric surgery: when is liver biopsy indicated? Surg Obes Relat Dis. 2008 Sep-Oct;4(5):612-7. doi: 10.1016/j.soard.2007.11.007. Epub 2008 Jan 28. — View Citation
Júnior WS, Nonino-Borges CB. Clinical predictors of different grades of nonalcoholic fatty liver disease. Obes Surg. 2012 Feb;22(2):248-52. doi: 10.1007/s11695-011-0438-6. — View Citation
Karlsson FH, Fåk F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, Bäckhed F, Nielsen J. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun. 2012;3:1245. doi: 10.1038/ncomms2266. — View Citation
Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, Nielsen J, Bäckhed F. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013 Jun 6;498(7452):99-103. doi: 10.1038/nature12198. Epub 2013 May 29. — View Citation
Keitel V, Häussinger D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol. 2012 Oct;36(5):412-9. doi: 10.1016/j.clinre.2012.03.008. Epub 2012 Apr 18. Review. — View Citation
Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006 Dec 21;444(7122):1022-3. — View Citation
Lima ML, Mourão SC, Diniz MT, Leite VH. Hepatic histopathology of patients with morbid obesity submitted to gastric bypass. Obes Surg. 2005 May;15(5):661-9. — View Citation
Ma Y, Huang Y, Yan L, Gao M, Liu D. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res. 2013 May;30(5):1447-57. doi: 10.1007/s11095-013-0986-7. Epub 2013 Feb 1. — View Citation
Mande SS, Mohammed MH, Ghosh TS. Classification of metagenomic sequences: methods and challenges. Brief Bioinform. 2012 Nov;13(6):669-81. doi: 10.1093/bib/bbs054. Epub 2012 Sep 8. Review. — View Citation
Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, McGilvray ID, Allard JP. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013 Jul;58(1):120-7. doi: 10.1002/hep.26319. Epub 2013 May 14. — View Citation
Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013 Sep;145(3):574-82.e1. doi: 10.1053/j.gastro.2013.05.042. Epub 2013 May 30. — View Citation
Musso G, Gambino R, Cassader M. Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: mechanisms and implications for metabolic disorders. Curr Opin Lipidol. 2010 Feb;21(1):76-83. doi: 10.1097/MOL.0b013e3283347ebb. Review. — View Citation
Nervi F, Arrese M. Cholecystectomy and NAFLD: does gallbladder removal have metabolic consequences? Am J Gastroenterol. 2013 Jun;108(6):959-61. doi: 10.1038/ajg.2013.84. — View Citation
Ramos-De la Medina A, Remes-Troche JM, Roesch-Dietlen FB, Pérez-Morales AG, Martinez S, Cid-Juarez S. Routine liver biopsy to screen for nonalcoholic fatty liver disease (NAFLD) during cholecystectomy for gallstone disease: is it justified? J Gastrointest Surg. 2008 Dec;12(12):2097-102; discussion 2102. doi: 10.1007/s11605-008-0704-7. Epub 2008 Sep 30. — View Citation
Ruhl CE, Everhart JE. Relationship of non-alcoholic fatty liver disease with cholecystectomy in the US population. Am J Gastroenterol. 2013 Jun;108(6):952-8. doi: 10.1038/ajg.2013.70. Epub 2013 Apr 2. — View Citation
Shalhub S, Parsee A, Gallagher SF, Haines KL, Willkomm C, Brantley SG, Pinkas H, Saff-Koche L, Murr MM. The importance of routine liver biopsy in diagnosing nonalcoholic steatohepatitis in bariatric patients. Obes Surg. 2004 Jan;14(1):54-9. — View Citation
Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology. 2011 Mar;140(3):976-86. doi: 10.1053/j.gastro.2010.11.049. Epub 2010 Dec 1. — View Citation
Svensson PA, Olsson M, Andersson-Assarsson JC, Taube M, Pereira MJ, Froguel P, Jacobson P. The TGR5 gene is expressed in human subcutaneous adipose tissue and is associated with obesity, weight loss and resting metabolic rate. Biochem Biophys Res Commun. 2013 Apr 19;433(4):563-6. doi: 10.1016/j.bbrc.2013.03.031. Epub 2013 Mar 22. — View Citation
Teixeira AR, Bellodi-Privato M, Carvalheira JB, Pilla VF, Pareja JC, D'Albuquerque LA. The incapacity of the surgeon to identify NASH in bariatric surgery makes biopsy mandatory. Obes Surg. 2009 Dec;19(12):1678-84. doi: 10.1007/s11695-009-9980-x. — View Citation
Teodoro JS, Rolo AP, Palmeira CM. Hepatic FXR: key regulator of whole-body energy metabolism. Trends Endocrinol Metab. 2011 Nov;22(11):458-66. doi: 10.1016/j.tem.2011.07.002. Epub 2011 Aug 19. Review. — View Citation
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011 Aug;34(3):274-85. doi: 10.1111/j.1365-2036.2011.04724.x. Epub 2011 May 30. Review. — View Citation
Vincent RP, Omar S, Ghozlan S, Taylor DR, Cross G, Sherwood RA, Fandriks L, Olbers T, Werling M, Alaghband-Zadeh J, le Roux CW. Higher circulating bile acid concentrations in obese patients with type 2 diabetes. Ann Clin Biochem. 2013 Jul;50(Pt 4):360-4. doi: 10.1177/0004563212473450. Epub 2013 Jun 14. — View Citation
Watanabe M, Horai Y, Houten SM, Morimoto K, Sugizaki T, Arita E, Mataki C, Sato H, Tanigawara Y, Schoonjans K, Itoh H, Auwerx J. Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem. 2011 Jul 29;286(30):26913-20. doi: 10.1074/jbc.M111.248203. Epub 2011 Jun 1. — View Citation
Wong VW, Tse CH, Lam TT, Wong GL, Chim AM, Chu WC, Yeung DK, Law PT, Kwan HS, Yu J, Sung JJ, Chan HL. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis--a longitudinal study. PLoS One. 2013 Apr 25;8(4):e62885. doi: 10.1371/journal.pone.0062885. Print 2013. — View Citation
Yilmaz Y. NAFLD in the absence of metabolic syndrome: different epidemiology, pathogenetic mechanisms, risk factors for disease progression? Semin Liver Dis. 2012 Feb;32(1):14-21. doi: 10.1055/s-0032-1306422. Epub 2012 Mar 13. Review. — View Citation
Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, Gill SR. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013 Feb;57(2):601-9. doi: 10.1002/hep.26093. Epub 2013 Jan 8. — View Citation
* Note: There are 32 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | In each group, overall gut microbiota composition, and serum fasting and (only in the obese patients) post-prandial bile acid levels, serum markers of inflammation and liver damage and white adipose tissue mRNA expression of relevant genes | In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition, and serum fasting and (only in patients submitted to bariatric surgery) post-prandial bile acid levels.In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition, and serum markers of inflammation and liver damage (endotoxin, TNF-alfa, IL-6, aspartate aminotransferase (AST), alanine aminotransferase (ALT), cytokeratin 18.In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition and white adipose tissue mRNA expression of relevant genes chosen on the base of the mRNA expression results on liver specimens. | 18 months | |
Primary | gut microbiota composition | In patients with simple steatosis SS vs those with NASH the gut microbiota composition is different even after BMI normalization | 12 months | |
Secondary | In each patient group overall gut microbiota composition, and hepatic and (only in the obese patients submitted to bariatric surgery) adipose tissue mRNA expression of relevant lipid and inflammatory response pathways | In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition, and hepatic and (only in patients submitted to bariatric surgery) adipose tissue messenger ribonucleic acid (mRNA) expression of relevant lipid and inflammatory response pathways: Acetyl-coenzyme A-carboxylase (ACC1), Fatty acid Synthase (FAS), Sterol regulatory element-binding protein (SREBP1c), apolipoprotein B (ApoB), farnesoid X receptor (FXR), Carbohydrate-responsive element-binding protein (ChREBP), TGR5, Sterol regulatory element-binding protein (SREBP2a), liver X receptor (LXR), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), low density lipoprotein receptor (LDLR) , Proprotein-convertase-subtilisin/kexin type 9 (PCSK9), tumor necrosis factor a (TNF-a), toll-like receptor 4 (TLR-4), NLRP3 (NOD-like receptor 3), c-Jun N-terminal kinase (JUN-K) | 12 months | |
Secondary | In each patient group overall gut microbiota composition, and hepatic and (only in the obese patients submitted to bariatric surgery) adipose tissue mRNA expression of relevant lipid and inflammatory response pathways | In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition, and hepatic and (only in patients submitted to bariatric surgery) adipose tissue mRNA expression of relevant lipid and inflammatory response pathways: ACC1 (Acetyl-CoA carboxylase), FAS (Fatty acid Synthase), SREBP1c (Sterol regulatory element-binding protein), ApoB (apolipoprotein B), FXR (farnesoid X receptor), ChREBP (Carbohydrate-responsive element-binding protein), TGR5, SREBP2a (Sterol regulatory element-binding protein), LXR (liver X receptor), HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), LDLR (low density lipoprotein receptor) , PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9), TNF-a (tumor necrosis factor a), TLR-4 toll-like receptor 4), NLRP3 (NOD-like receptor 3), JUN-K (c-Jun N-terminal kinase) | 12 months |
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT04243317 -
Feasibility of a Sleep Improvement Intervention for Weight Loss and Its Maintenance in Sleep Impaired Obese Adults
|
N/A | |
Recruiting |
NCT04101669 -
EndoBarrier System Pivotal Trial(Rev E v2)
|
N/A | |
Terminated |
NCT03772886 -
Reducing Cesarean Delivery Rate in Obese Patients Using the Peanut Ball
|
N/A | |
Completed |
NCT03640442 -
Modified Ramped Position for Intubation of Obese Females.
|
N/A | |
Completed |
NCT04506996 -
Monday-Focused Tailored Rapid Interactive Mobile Messaging for Weight Management 2
|
N/A | |
Recruiting |
NCT06019832 -
Analysis of Stem and Non-Stem Tibial Component
|
N/A | |
Active, not recruiting |
NCT05891834 -
Study of INV-202 in Patients With Obesity and Metabolic Syndrome
|
Phase 2 | |
Active, not recruiting |
NCT05275959 -
Beijing (Peking)---Myopia and Obesity Comorbidity Intervention (BMOCI)
|
N/A | |
Recruiting |
NCT04575194 -
Study of the Cardiometabolic Effects of Obesity Pharmacotherapy
|
Phase 4 | |
Completed |
NCT04513769 -
Nutritious Eating With Soul at Rare Variety Cafe
|
N/A | |
Withdrawn |
NCT03042897 -
Exercise and Diet Intervention in Promoting Weight Loss in Obese Patients With Stage I Endometrial Cancer
|
N/A | |
Completed |
NCT03644524 -
Heat Therapy and Cardiometabolic Health in Obese Women
|
N/A | |
Recruiting |
NCT05917873 -
Metabolic Effects of Four-week Lactate-ketone Ester Supplementation
|
N/A | |
Active, not recruiting |
NCT04353258 -
Research Intervention to Support Healthy Eating and Exercise
|
N/A | |
Completed |
NCT04507867 -
Effect of a NSS to Reduce Complications in Patients With Covid-19 and Comorbidities in Stage III
|
N/A | |
Recruiting |
NCT03227575 -
Effects of Brisk Walking and Regular Intensity Exercise Interventions on Glycemic Control
|
N/A | |
Completed |
NCT01870947 -
Assisted Exercise in Obese Endometrial Cancer Patients
|
N/A | |
Recruiting |
NCT06007404 -
Understanding Metabolism and Inflammation Risks for Diabetes in Adolescents
|
||
Recruiting |
NCT05972564 -
The Effect of SGLT2 Inhibition on Adipose Inflammation and Endothelial Function
|
Phase 1/Phase 2 | |
Recruiting |
NCT05371496 -
Cardiac and Metabolic Effects of Semaglutide in Heart Failure With Preserved Ejection Fraction
|
Phase 2 |