Serological markers of intestinal barrier impairment do not correlate with duration of diabetes and glycated hemoglobin in adult patients with type 1 and type 2 diabetes mellitus
Language English Country Czech Republic Media print-electronic
Document type Journal Article
PubMed
35616045
PubMed Central
PMC9470092
DOI
10.33549/physiolres.934874
PII: 934874
Knihovny.cz E-resources
- MeSH
- Biomarkers MeSH
- Diabetes Mellitus, Type 1 * diagnosis metabolism MeSH
- Diabetes Mellitus, Type 2 * diagnosis MeSH
- Adult MeSH
- Glycated Hemoglobin analysis MeSH
- Hyperglycemia * MeSH
- Humans MeSH
- Lipopolysaccharide Receptors MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Biomarkers MeSH
- Glycated Hemoglobin A MeSH
- Lipopolysaccharide Receptors MeSH
Growing evidence suggests that diabetes mellitus is associated with impairment of the intestinal barrier. However, it is not clear so far if the impairment of the intestinal barrier is a consequence of prolonged hyperglycemia or the consequence of external factors influencing the gut microbiota and intestinal mucosa integrity. Aim of the study was to perform an estimation of relationship between serological markers of impairment of the intestinal barrier: intestinal fatty acid-binding protein (I-FABP), cytokeratin 18 caspase-cleaved fragment (cCK-18), and soluble CD14 (sCD14) and markers of prolonged hyperglycemia, such as the duration of diabetes mellitus and glycated hemoglobin (HbA1c) via a correlation analysis in patients with diabetes mellitus. In 40 adult patients with type 1 diabetes mellitus and 30 adult patients with type 2 diabetes mellitus the estimation has been performed. Statistically significant positive correlation was found between cCK-18 and HbA1c (r=0.5047, p=0.0275) in patients with type 1 diabetes mellitus with fading insulitis (T1D). In patients with type 1 diabetes mellitus with ongoing insulitis (T1D/INS) and in patients with type 2 diabetes mellitus (T2D), no statistically significant positive correlations were found between serological markers of intestinal barrier impairment (I-FABP, cCK-18, sCD14) and duration of diabetes or levels of HbA1c. Similarly, in cumulative cohort of patients with T1D/INS and patients with T1D we revealed statistically positive correlation only between HbA1c and cCK-18 (r=0.3414, p=0.0311). Surprisingly, we found statistically significant negative correlation between the duration of diabetes mellitus and cCK-18 (r=-0.3050, p=0.0313) only in cumulative group of diabetic patients (T1D, T1D/INS, and T2D). Based on our results, we hypothesize that the actual condition of the intestinal barrier in diabetic patients is much more dependent on variable interactions between host genetic factors, gut microbiota, and environmental factors rather than effects of long-standing hyperglycemia (assessed by duration of diabetes mellitus or HbA1c).
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Sharma S, Tripathi P. Gut microbiome and type 2 diabetes: where we are and where to go? J Nutr Biochem. 2019;63:101–108. doi: 10.1016/j.jnutbio.2018.10.003. PubMed DOI
Grega T, Vojtechova G, Gregova M, Zavoral M, Suchanek S. Pathophysiological characteristics linking type 2 diabetes mellitus and colorectal neoplasia. Physiol Res. 2021;70:509–522. doi: 10.33549/physiolres.934631. PubMed DOI PMC
Auricchio R, Paparo F, Maglio M, Franzese A, Lombardi F, Valerio G, Nardone G, Percopo S, Greco L, Troncone R. In vitro-deranged intestinal immune response to gliadin in type 1 diabetes. Diabetes. 2004;53:1680–1683. doi: 10.2337/diabetes.53.7.1680. PubMed DOI
Watts T, Berti I, Sapone A, Gerarduzzi T, Not T, Zielke R, Fasano A. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci U S A. 2005;102:2916–2921. doi: 10.1073/pnas.0500178102. PubMed DOI PMC
Tlaskalová-Hogenová H, Stěpánková R, Kozáková H, Hudcovic T, Vannucci L, Tučková L, Rossmann P, Hrnčíř T, Kverka M, Zákostelská Z, et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell Mol Immunol. 2011;8:110–120. doi: 10.1038/cmi.2010.67. PubMed DOI PMC
Kverka M, Tlaskalova-Hogenova H. Two faces of microbiota in inflammatory and autoimmune diseases: triggers and drugs. APMIS. 2013;121:403–421. doi: 10.1111/apm.12007. PubMed DOI
Vaarala O. Is the origin of type 1 diabetes in the gut? Immunol Cell Biol. 2012;90:271–276. doi: 10.1038/icb.2011.115. PubMed DOI
Sorini C, Cosorich I, Lo Conte M, De Giorgi L, Facciotti F, Lucianò R, Rocchi M, Ferrarese R, Sanvito F, Canducci F, Falcone M. Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes. Proc Natl Acad Sci U S A. 2019;116:15140–15149. doi: 10.1073/pnas.1814558116. PubMed DOI PMC
Abdellatif AM, Sarvetnick NE. Current understanding of the role of gut dysbiosis in type 1 diabetes. J Diabetes. 2019;11:632–644. doi: 10.1111/1753-0407.12915. PubMed DOI
Huml M, Kobr J, Siala K, Varvařovská J, Pomahačová R, Karlíková M, Sýkora J. Gut peptide hormones and pediatric type 1 diabetes mellitus. Physiol Res. 2011;60:647–658. doi: 10.33549/physiolres.931995. PubMed DOI
Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res. 2020;9 doi: 10.12688/f1000research.20510.1. F1000 Faculty Rev-69. PubMed DOI PMC
Binienda A, Twardowska A, Makaro A, Salaga M. Dietary carbohydrates and lipids in the pathogenesis of leaky gut syndrome: An overview. Int J Mol Sci. 2020;21:8368. doi: 10.3390/ijms21218368. PubMed DOI PMC
Allam-Ndoul B, Castonguay-Paradis S, Veilleux A. Gut microbiota and intestinal trans-epithelial permeability. Int J Mol Sci. 2020;21:6402. doi: 10.3390/ijms21176402. PubMed DOI PMC
Tilg H, Zmora N, Adolph TE, Elinav E. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol. 2020;20:40–54. doi: 10.1038/s41577-019-0198-4. PubMed DOI
Régnier M, Van Hul M, Knauf C, Cani PD. Gut microbiome, endocrine control of gut barrier function and metabolic diseases. J Endocrinol. 2021;248:R67–R82. doi: 10.1530/JOE-20-0473. PubMed DOI
Secondulfo M, Iafusco D, Carratù R, de Magistris L, Sapone A, Generoso M, Mezzogiomo A, Sasso FC, Cartenì M, De Rosa R, Prisco F, Esposito V. Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients. Dig Liver Dis. 2004;36:35–45. doi: 10.1016/j.dld.2003.09.016. PubMed DOI
Min XH, Yu T, Qing Q, Yuan YH, Zhong W, Chen GC, Zhao LN, Deng N, Zhang LF, Chen QK. Abnormal differentiation of intestinal epithelium and intestinal barrier dysfunction in diabetic mice associated with depressed Notch/NICD transduction in Notch/Hes1 signal pathway. Cell Biol Int. 2014;38:1194–1204. doi: 10.1002/cbin.10323. PubMed DOI
Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes. 2017;8:249–269. doi: 10.4239/wjd.v8.i6.249. PubMed DOI PMC
Thaiss CA, Levy M, Grosheva I, Zheng D, Soffer E, Blacher E, Braverman S, et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science. 2018;359:1376–1383. doi: 10.1126/science.aar3318. PubMed DOI
Hoffmanová I, Sánchez D, Hábová V, Anděl M, Tučková L, Tlaskalová-Hogenová H. Serological markers of enterocyte damage and apoptosis in patients with celiac disease, autoimmune diabetes mellitus and diabetes mellitus type 2. Physiol Res. 2015;64:537–546. doi: 10.33549/physiolres.932916. PubMed DOI
Doggui R, Sahli CA, Aissa WL, Hammami M, Ben Sedrine M, Mahjoub R, Zouaoui K, Daboubi R, Siala H, Messaoud T, Bibi A. Capillarys 2 Flex Piercing: Analytical performance assessment according to CLSI protocols for HbA1c quantification. Electrophoresis. 2017;38:2210–2218. doi: 10.1002/elps.201600423. PubMed DOI
Carneiro L, Leloup C. Mens Sana in Corpore Sano: Does the glycemic index have a role to play? Nutrients. 2020;12:2989. doi: 10.3390/nu12102989. PubMed DOI PMC
Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93:137–188. doi: 10.1152/physrev.00045.2011. PubMed DOI
Natarajan R. Epigenetic mechanisms in diabetic vascular complications and metabolic memory: The 2020 Edwin Bierman Award Lecture. Diabetes. 2021;70:328–337. doi: 10.2337/dbi20-0030. PubMed DOI PMC
de Kort S, Keszthelyi D, Masclee AAM. Leaky gut and diabetes mellitus: what is the link? Obes Rev. 2011;12:449–458. doi: 10.1111/j.1467-789X.2010.00845.x. PubMed DOI
Rouland M, Beaudoin L, Rouxel O, Bertrand L, Cagninacci L, Saffarian A, Pedron T, Gueddouri D, Guilmeau S, Burnol AF, Rachdi L, Tazi A, Mouriès J, Rescigno M, Vergnolle N, Sansonetti P, Rogner UC, Lehuen A. Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia. Gut. 2022;71:296–308. doi: 10.1136/gutjnl-2020-323664. PubMed DOI
Lalande C, Drouin-Chartier JP, Tremblay AJ, Couture P, Veilleux A. Plasma biomarkers of small intestine adaptations in obesity-related metabolic alterations. Diabetol Metab Syndr. 2020;12:31. doi: 10.1186/s13098-020-00530-6. PubMed DOI PMC
Verdam FJ, Greve JWM, Roosta S, van Eijk H, Bouvy N, Buurman WA, Rensen SS. Small intestinal alterations in severely obese hyperglycemic subjects. J Clin Endocrinol Metab. 2011;96:E379–E383. doi: 10.1210/jc.2010-1333. PubMed DOI
Wang Y, Ding L, Yang J, Liu L, Dong L. Intestinal fatty acid-binding protein, a biomarker of intestinal barrier dysfunction, increases with the progression of type 2 diabetes. PeerJ. 2021;9:e10800. doi: 10.7717/peerj.10800. PubMed DOI PMC
Lau E, Marques C, Pestana D, Santoalha M, Carvalho D, Freitas P, Calhau C. 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. PubMed DOI PMC
Camilleri M. Leaky gut: Mechanisms, measurement and clinical implications in humans. Gut. 2019;68:1516–1526. doi: 10.1136/gutjnl-2019-318427. PubMed DOI PMC
Paray BA, Albeshr MF, Jan AT, Rather IA. Leaky gut and autoimmunity: An intricate balance in individuals health and the diseased state. Int J Mol Sci. 2020;21:9770. doi: 10.3390/ijms21249770. PubMed DOI PMC
Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol. 2017;11:821–834. doi: 10.1080/17474124.2017.1343143. PubMed DOI PMC
Zhang Q, Hu N. Effects of metformin on the gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Metab Syndr Obes. 2020;13:5003–5014. doi: 10.2147/DMSO.S286430. PubMed DOI PMC
Funderburg NT, Boucher M, Sattar A, Kulkarni M, Labbato D, Kinley BI, McComsey GA. Rosuvastatin decreases intestinal fatty acid binding protein (I-FABP), but does not alter zonulin or lipopolysaccharide binding protein (LBP) levels, in HIV-infected subjects on antiretroviral therapy. Pathog Immun. 2016;1:118–128. doi: 10.20411/pai.v1i1.124. PubMed DOI PMC
Vieira-Silva S, Falony G, Belda E, Nielsen T, Aron-Wisnewsky J, Chakaroun R, Forslund SK, Assmann K, Valles-Colomer M, Nguyen TTD, et al. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature. 2020;581:310–315. doi: 10.1038/s41586-020-2269-x. PubMed DOI
Kobayashi K, Sasase T, Maekawa T, Shinozaki Y, Sano R, Yamada T, Ohta T. Immune disorders and sex differences in spontaneously diabetic Torii rats, type 2 diabetic model. Physiol Res. 2022;71:113–123. doi: 10.33549/physiolres.934825. PubMed DOI PMC
Adamičková A, Gažová A, Adamička M, Chomaničová N, Valašková S, Červenák Z, Šalingová B, Kyselovič J. Molecular basis of the effect of atorvastatin pretreatment on stem cell therapy in chronic ischemic diseases – critical limb ischemia. Physiol Res. 2021;70(Suppl 4):S527–S533. doi: 10.33549/physiolres.934718. PubMed DOI PMC
Li W, Abdul Y, Ward R, Ergul A. Endothelin and diabetic complications: A brain-centric view. Physiol Res. 2018;67(Suppl 1):S83–S94. doi: 10.33549/physiolres.933833. PubMed DOI
Derikx JPM, Luyer MDP, Heineman E, Buurman WA. Non-invasive markers of gut wall integrity in health and disease. World J Gastroenterol. 2010;16:5272–5279. doi: 10.3748/wjg.v16.i42.5272. PubMed DOI PMC
Grootjans J, Thuijls G, Verdam F, Derikx JP, Lenaerts K, Buurman WA. Non-invasive assessment of barrier integrity and function of the human gut. World J Gastrointest Surg. 2010;2:61–69. doi: 10.4240/wjgs.v2.i3.61. PubMed DOI PMC
Wells JM, Brummer RJ, Derrien M, MacDonald TT, Troost F, Cani PD, Theodorou V, Dekker J, Méheust A, de Vos WM, Mercenier A, Nauta A, Garcia-Rodenas CL. Homeostasis of the gut barrier and potential biomarkers. Am J Physiol Gastrointest Liver Physiol. 2017;312:G171–G193. doi: 10.1152/ajpgi.00048.2015. PubMed DOI PMC
Škrha J, Šoupal J, Škrha J, Jr, Prázný M. Glucose variability, HbA1c and microvascular complications. Rev Endocr Metab Disord. 2016;17:103–110. doi: 10.1007/s11154-016-9347-2. PubMed DOI
Natividad JMM, Petit V, Huang X, de Palma G, Jury J, Sanz Y, Philpott D, Garcia Rodenas CL, McCoy KD, Verdu EF. Commensal and probiotic bacteria influence intestinal barrier function and susceptibility to colitis in Nod1−/−; Nod2−/− mice. Inflamm Bowel Dis. 2012;18:1434–1446. doi: 10.1002/ibd.22848. PubMed DOI
Natividad JMM, Verdu EF. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol Res. 2013;69:42–51. doi: 10.1016/j.phrs.2012.10.007. PubMed DOI
Rinninella E, Cintoni M, Raoul P, Lopetuso LR, Scaldaferri F, Pulcini G, Miggiano GAD, Gasbarrini A, Mele MC. Food components and dietary habits: Keys for a healthy gut microbiota composition. Nutrients. 2019;11:2393. doi: 10.3390/nu11102393. PubMed DOI PMC
Brunkwall L, Orho-Melander M. The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: from current human evidence to future possibilities. Diabetologia. 2017;60:943–951. doi: 10.1007/s00125-017-4278-3. PubMed DOI PMC
Stols-Gonçalves D, Tristão LS, Henneman P, Nieuwdorp M. Epigenetic markers and microbiota/metabolite-induced epigenetic modifications in the pathogenesis of obesity, metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease. Curr Diab Rep. 2019;19:31. doi: 10.1007/s11892-019-1151-4. PubMed DOI PMC