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Exp Clin Endocrinol Diabetes 2022; 130(04): 237-247
DOI: 10.1055/a-1643-1689
Article

Reductions in Intestinal Taurine-Conjugated Bile Acids and Short-Chain Fatty Acid-Producing Bacteria Might be Novel Mechanisms of Type 2 Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats

Xiaoyun Yang‡
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
2   Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
,
Wenhui Jiang‡
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
3   Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine of Hebei Province, Hebei Province, China
,
Jingli Cheng‡
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Jintong Hao
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Fei Han
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Yi Zhang
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Jie Xu
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Chunyan Shan
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Jingyu Wang
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Yanhui Yang
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Juhong Yang
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
,
Baocheng Chang
1   NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
› Author Affiliations Funding Statement This work was supported by the National Key R&D Program of China (2018YCF1314000), the National Natural Science Foundation of China (81774043, 82074253, 81700631), and Tianjin Science and Technology Program (17ZXMFSY00140).
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Abstract

Background The pathogenesis of spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, among the best models for human type 2 diabetes mellitus (T2DM), remains poorly defined. Therefore, we investigated the dynamic changes in taurine-conjugated bile acids (T-BAs) and intestinal microbiota during T2DM development in OLETF rats.

Methods OLETF rats and corresponding diabetes-resistant Long Evans Tokushima Otsuka (LETO) rats were fed a normal baseline diet. The progress of T2DM was divided into four phases, including normal glycemia-normal insulinemia (baseline), normal glycemia-hyperinsulinemia, impaired glucose tolerance, and DM. Body weight, liver function, blood lipids, fasting plasma glucose, fasting plasma insulin, fasting plasma glucagon-like peptide (GLP)-1 and GLP-2, serum and fecal T-BAs, and gut microbiota were analyzed during the entire course of T2DM development.

Results There were reductions in fecal T-BAs and short-chain fatty acids (SCFAs)-producing bacteria including Phascolarctobacterium and Lactobacillus in OLETF rats compared with those in LETO rats at baseline, and low levels of fecal T-BAs and SCFAs-producing bacteria were maintained throughout the whole course of the development of T2DM among OLETF rats compared with those in corresponding age-matched LETO rats. Fecal taurine-conjugated chenodeoxycholic acid correlated positively with Phascolarctobacterium. Fecal taurine-conjugated deoxycholic acid correlated positively with Lactobacillus and fasting plasma GLP-1 and inversely with fasting plasma glucose.

Conclusion The fecal BAs profiles and microbiota structure among OLETF rats were different from those of LETO rats during the entire course of T2DM development, indicating that reductions in intestinal T-BAs and specific SCFA-producing bacteria may be potential mechanisms of T2DM in OLETF rats.

Key words

Short-chain fatty acid - Taurine-conjugated bile acids - Bacteria - OLETF Rats - Type 2 diabetes mellitus


Publication History

Article published online:
20 December 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Danaei G, Finucane MM, Lu Y. et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. The Lancet 2011; 378: 31-40
    CrossrefPubMedGoogle Scholar
  • 2 Zimmet PZ, Magliano DJ, Herman WH. et al. Diabetes: A 21st century challenge. Lancet Diabetes Endocrinol 2014; 2: 56-64
    CrossrefPubMedGoogle Scholar
  • 3 Amini M, Janghorbani M. Diabetes and impaired glucose regulation in first-degree relatives of patients with type 2 diabetes in Isfahan, Iran: Prevalence and risk factors. Review Diabet Stud 2007; 4: 169-176
    CrossrefPubMedGoogle Scholar
  • 4 Sircana A, Framarin L, Leone N. et al. Altered gut microbiota in type 2 diabetes: Just a coincidence?. Curr Diab Rep 2018; 18: 98
    CrossrefPubMedGoogle Scholar
  • 5 Fiorucci S, Distrutti E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med 2015; 21: 702-714
    CrossrefPubMedGoogle Scholar
  • 6 Chen D, Wang MW. Development and application of rodent models for type 2 diabetes. Diabetes Obes Metab 2015; 7: 307-317
    CrossrefPubMedGoogle Scholar
  • 7 Moran TH, Bi S. Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1211-1218
    CrossrefPubMedGoogle Scholar
  • 8 Yamada T, Kose H, Ohta T. et al. Genetic dissection of complex genetic factor involved in NIDDM of OLETF rat. Exp Diabetes Res 2012; 2012: 582546
    CrossrefPubMedGoogle Scholar
  • 9 Kawano K, Hirashima T, Mori S. et al. OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain. Diabetes Res Clin Pract 1994; 24: S317-S320
    CrossrefPubMedGoogle Scholar
  • 10 Bi S, Moran TH. Actions of CCK in the controls of food intake and body weight: lessons from the CCK-A receptor deficient OLETF rat. Neuropeptides 2002; 36: 171-181
    CrossrefPubMedGoogle Scholar
  • 11 Bi S, Moran TH. Obesity in the Otsuka Long Evans Tokushima Fatty Rat: Mechanisms and discoveries. Front Nutr 2016; 3: 21
    PubMedGoogle Scholar
  • 12 Watanabe TK, Okuno S, Oga K. et al. Genetic dissection of "OLETF," a rat model for non-insulin-dependent diabetes mellitus: quantitative trait locus analysis of (OLETF x BN) x OLETF. Genomics 1999; 58: 233-239
    CrossrefPubMedGoogle Scholar
  • 13 Takiguchi S, Takata Y, Takahashi N. et al. A disrupted cholecystokinin A receptor gene induces diabetes in obese rats synergistically with ODB1 gene. Am J Physiol 1998; 274: E265-E270
    PubMedGoogle Scholar
  • 14 Thomas C, Gioiello A, Noriega L. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009; 10: 167-177
    CrossrefPubMedGoogle Scholar
  • 15 Watanabe M, Houten SM, Mataki C. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006; 439: 484-489
    CrossrefPubMedGoogle Scholar
  • 16 Culnan DM, Albaugh V, Sun M. et al. Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat. Am J Physiol Gastrointest Liver Physiol 2010; 299: G751-G760
    CrossrefPubMedGoogle Scholar
  • 17 Kohli R, Kirby M, Setchell KD. et al. Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities. Am J Physiol Gastrointest Liver Physiol 2010; 299: G652-G660
    CrossrefPubMedGoogle Scholar
  • 18 Kashihara H, Shimada M, Kurita N. et al. Duodenal-jejunal bypass improves diabetes and liver steatosis via enhanced glucagon-like peptide-1 elicited by bile acids. J Gastroenterol Hepatol 2015; 30: 308-315
    CrossrefPubMedGoogle Scholar
  • 19 Brighton CA, Rievaj J, Kuhre RE. et al. Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G rotein-coupled bile acid receptors. Endocrinology 2015; 156: 3961-3970
    CrossrefPubMedGoogle Scholar
  • 20 Ferrannini E, Camastra S, Astiarraga B. et al. Increased bile acid synthesis and deconjugation after biliopancreatic diversion. Diabetes 2015; 64: 3377-3385
    CrossrefPubMedGoogle Scholar
  • 21 Wewalka M, Patti ME, Barbato C. et al. Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin. J Clin Endocrinol Metab 2014; 99: 1442-1451
    CrossrefPubMedGoogle Scholar
  • 22 Shonsey SM, Wheeler J, Johnson M. et al. Synthesis of bile acid coenzyme A thioesters in the amino acid conjugation of bile acids. Methods Enzymol 2005; 400: 360-373
    CrossrefPubMedGoogle Scholar
  • 23 de Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids in metabolism. Cell Metab 2013; 17: 657-669
    CrossrefPubMedGoogle Scholar
  • 24 Chavez-Talavera O, Tailleux A, Lefebvre P. et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 2017; 152: 1679-1694e3
    CrossrefPubMedGoogle Scholar
  • 25 Human Microbiome Project Consortium Structure, function and diversity of the healthy human microbiome. Nature 2012; 486: 207-214
    CrossrefPubMedGoogle Scholar
  • 26 Joyce SA, Gahan CG. Disease-associated changes in bile acid profiles and links to altered gut microbiota. Dig Dis 2017; 35: 169-177
    CrossrefPubMedGoogle Scholar
  • 27 Qin J, Li Y, Cai Z. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490: 55-60
    CrossrefPubMedGoogle Scholar
  • 28 Karlsson FH, Tremaroli V, Nookaew I. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498: 99-103
    Google Scholar
  • 29 Rabot S, Membrez M, Bruneau A. et al. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. Faseb J 2010; 24: 4948-4959
    PubMedGoogle Scholar
  • 30 Swann JR, Want EJ, Geier FM. et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci USA 2011; 108: 4523-4530
    CrossrefPubMedGoogle Scholar
  • 31 Begley M, Gahan CG, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev 2005; 29: 625-651
    CrossrefPubMedGoogle Scholar
  • 32 Nie YF, Hu J, Yan XH. Cross-talk between bile acids and intestinal microbiota in host metabolism and health. J Zhejiang Univ Sci B 2015; 16: 436-446
    CrossrefPubMedGoogle Scholar
  • 33 Kawano K, Hirashima T, Mori S. et al. Spontaneous long-term hyperglycemic rat with diatetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992; 11: 1422-1428
    CrossrefPubMedGoogle Scholar
  • 34 Xiang X, Han Y, Neuvonen M. et al. High performance liquid chromatography-tandem mass spectrometry for the determination of bile acid concentrations in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 51-60
    CrossrefPubMedGoogle Scholar
  • 35 Salonen A, Nikkila J, Jalanka-Tuovinen J. et al. Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis. J Microbiol Methods 2010; 81: 127-134
    CrossrefPubMedGoogle Scholar
  • 36 Zaborska KE, Cummings BP. Rethinking bile acid metabolism and signaling for type 2 diabetes treatment. Curr Diab Rep 2018; 18: 109
    CrossrefPubMedGoogle Scholar
  • 37 Alemi F, Poole DP, Chiu J. et al. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 2013; 144: 145-154
    CrossrefPubMedGoogle Scholar
  • 38 Inagaki T, Moschetta A, Lee YK. et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA 2006; 103: 3920-3925
    CrossrefPubMedGoogle Scholar
  • 39 Bellahcene M, O'Dowd JF, Wargent ET. et al. Male mice that lack the G-protein-coupled receptor GPR41 have low energy expenditure and increased body fat content. Br J Nutr 2013; 109: 1755-1764
    CrossrefPubMedGoogle Scholar
  • 40 Park J, Kim M, Kang SG. et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 2015; 8: 80-93
    CrossrefPubMedGoogle Scholar
  • 41 Zhang X, Zhao Y, Xu J. et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep 2015; 5: 14450
    CrossrefPubMedGoogle Scholar
  • 42 Zhang J, Guo Z, Xue Z. et al. A phylo-functional core of gut microbiota in healthy young Chinese cohorts across lifestyles, geography and ethnicities. ISME J 2015; 9: 1979-1990
    CrossrefPubMedGoogle Scholar
  • 43 Sartor RB. Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis. Gastroenterology 2010; 139: 1816-1819
    CrossrefPubMedGoogle Scholar
  • 44 Maslowski KM, Vieira AT, Ng A. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009; 461: 1282-1286
    CrossrefPubMedGoogle Scholar
  • 45 De Filippo C, Cavalieri D, Di Paola M. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010; 107: 14691-14696
    CrossrefPubMedGoogle Scholar
  • 46 Gao Z, Yin J, Zhang J. et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009; 58: 1509-1517
    CrossrefPubMedGoogle Scholar
  • 47 Roshanravan N, Mahdavi R, Alizadeh E. et al. Effect of butyrate and inulin supplementation on glycemic status, lipid profile and glucagon-like peptide 1 level in patients with type 2 diabetes: A randomized double-blind, placebo-controlled trial. Horm Metab Res 2017; 49: 886-891
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Cabreiro F, Au C, Leung KY. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 2013; 153: 228-239
    CrossrefPubMedGoogle Scholar
  • 49 Xie W, Gu D, Li J. et al. Effects and action mechanisms of berberine and Rhizoma coptidis on gut microbes and obesity in high-fat diet-fed C57BL/6J mice. PLoS One 2011; 6: e24520
    CrossrefPubMedGoogle Scholar
  • 50 Nobaek S, Johansson ML, Molin G. et al. Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol 2000; 95: 1231-1238
    CrossrefPubMedGoogle Scholar
  • 51 Quigley EM. Gut bacteria in health and disease. Gastroenterol Hepatol 2013; 9: 560-569
    PubMedGoogle Scholar
  • 52 von Schillde MA, Hormannsperger G, Weiher M. et al. Lactocepin secreted by Lactobacillus exerts anti-inflammatory effects by selectively degrading proinflammatory chemokines. Cell Host Microbe 2013; 11: 387-396
    CrossrefPubMedGoogle Scholar
  • 53 Yan X, Feng B, Li P. et al. Microflora disturbance during progression of glucose intolerance and effect of sitagliptin: An animal Study. J Diabetes Res 2016; 2016: 2093171
    PubMedGoogle Scholar
  • 54 Lau E, Marques C, Pestana D. et al. The role of I-FABP as a biomarker of intestinal barrier dysfunction driven by gut microbiota changes in obesity. Nutr Metab (Lond) 2016; 13: 31 DOI: 10.1186/s12986-016-0089-7. eCollection 2016
    CrossrefPubMedGoogle Scholar
  • 55 La Frano MR, Hernandez-Carretero A, Weber N. et al. Diet-induced obesity and weight loss alter bile acid concentrations and bile acid-sensitive gene expression in insulin target tissues of C57BL/6J mice. Nutr Res 2017; 46: 11-21
    CrossrefPubMedGoogle Scholar
  • 56 Ridlon JM, Wolf PG, Gaskins HR. Taurocholic acid metabolism by gut microbes and colon cancer. Gut Microbes 2016; 7: 201-215
    CrossrefPubMedGoogle Scholar
  • 57 Nakatani H, Kasama K, Oshiro T. et al. Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery. Metabolism 2009; 58: 1400-1407
    CrossrefPubMedGoogle Scholar