Investigating the Association Between Diet-Induced “Leaky Gut” and the Development of Prediabetes

Abstract

Introduction Chronic consumption of a high-calorie diet compromises the gut microbiota and the integrity of the intestinal wall, which causes translocation of bacterial lipopolysaccharides (LPS) into the blood. This elicits the secretion of pro-inflammatory cytokines, resulting in inflammation. However, how a high-fat high carbohydrate diet affects intestinal permeability and its possible role in the development of prediabetes have not been investigated. This study investigated the effects of HFHC diet-induced prediabetes on gut microbiota and intestinal permeability in male Sprague Dawley rats.

Methods The animals were randomly assigned into the non-prediabetic (NPD) and diet-induced prediabetic (PD) groups (n=6) for 20 weeks. Then, the fecal samples were analyzed to measure the gut microbiota level of Firmicutes, Bacteroidetes, and Proteobacteria in both animal groups. Blood glucose, plasma insulin, serum zonulin, plasma LPS, soluble CD14, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and intestinal fatty-acid binding protein (IFABP) concentrations were measured.

Results The PD group had a reduction in the Firmicutes and an increase in Bacteroidetes and Proteobacteria levels compared to those in the NPD group. Blood glucose, insulin concentration, serum zonulin, and plasma sCD14 concentrations in the PD group increased significantly, while plasma LPS concentrations were similar to the NPD group. Concentrations of plasma TNF-α, IL-6, CRP, and IFABP, an intracellular protein expressed in the intestine, increased in PD compared to the NPD group.

Conclusions the study results cumulatively suggest that chronic consumption of the HFHC diet may be associated with the dysregulation of gut microbiota, leading to increased intestinal permeability.

Key words

prediabetes - high-fat high carbohydrate - gut microbiota - zonulin - lipopolysaccharides - intestinal permeability

Publication History

Received: 22 April 2023
Received: 21 June 2023

Accepted: 26 September 2023

Accepted Manuscript online:
26 September 2023

Article published online:
31 October 2023

• References

• 1 Khan MAB, Hashim MJ, King JK. et al. Epidemiology of type 2 diabetes – global burden of disease and forecasted trends. J Epidemiol Glob Health 2019; 10: 107
• 2 Mutyambizi C, Pavlova M, Hongoro C. et al. Inequalities and factors associated with adherence to diabetes self-care practices amongst patients at two public hospitals in Gauteng, South Africa. BMC Endocr Disord 2020; 20: 15
• 3 Fareed M, Salam N, Khoja AT. et al. Life style related risk factors of type 2 diabetes mellitus and its increased prevalence in Saudi Arabia: A brief review. Int J Med Res Health Sci 2017; 6: 125-132
• 4 Huang Y, Shi X, Li Z. et al. Possible association of Firmicutes in the gut microbiota of patients with major depressive disorder. Neuropsychiatr Dis Treat 2018; 14: 3329
• 5 Alizadeh A, Akbari P, Garssen J. et al. Epithelial integrity, junctional complexes, and biomarkers associated with intestinal functions. Tissue Barriers 2022; 10: 1996830
• 6 de La Serre CB, Ellis CL, Lee J. et al. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol-Gastrointest Liver Physiol 2010; 299: G440-G448
• 7 Devaraj S, Dasu MR, Jialal I. Diabetes is a proinflammatory state: A translational perspective. Expert Rev Endocrinol Metab 2010; 5: 19-28
• 8 Liu Z, Li N, Neu J. Tight junctions, leaky intestines, and pediatric diseases. Acta Paediatrica 2007; 94: 386-393
• 9 Lozupone CA, Stombaugh JI, Gordon JI. et al. Diversity, stability and resilience of the human gut microbiota. Nature 2012; 489: 220-230
• 10 Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers 2016; 4: e1251384
• 11 Shive CL, Jiang W, Anthony DD. et al. Soluble CD14 is a nonspecific marker of monocyte activation. AIDS (London, England) 2015; 29: 1263
• 12 Wisniewski PJ, Dowden RA, Campbell SC. Role of dietary lipids in modulating inflammation through the gut microbiota. Nutrients 2019; 11: 117
• 13 Ghody P, Shikha D, Karam J. et al. Identifying prediabetes–Is it beneficial in the long run?. Maturitas 2015; 81: 282-286
• 14 Forouhi N, Luan J, Hennings S. et al. Incidence of type 2 diabetes in England and its association with baseline impaired fasting glucose: The Ely study 1990–2000. Diabet Med 2007; 24: 200-207
• 15 Nathan DM, Davidson MB, DeFronzo RA. et al. Impaired fasting glucose and impaired glucose tolerance: Implications for care. Diabetes Care 2007; 30: 753-759
• 16 Khathi A, Luvuno M, Mabandla MV. Voluntary ingestion of a high-fat high-carbohydrate diet: A model for prediabetes. J Ponte 2018; 74
• 17 Gamede M, Mabuza L, Ngubane P. et al. The effects of plant-derived oleanolic acid on selected parameters of glucose homeostasis in a diet-induced pre-diabetic rat model. Molecules 2018; 23: 794
• 18 Luvuno M, Mbongwa H, Khathi A. Development of a novel prediabetes animal model using a high fat high carbohydrate diet: Implications for type 2 diabetes. PloS One 2017; 13: 8-14
• 19 Mtshali K, Khumalo ZTH, Kwenda S. et al. Exploration and comparison of bacterial communities present in bovine faeces, milk and blood using 16S rRNA metagenomic sequencing. PLoS One 2022; 17: e0273799
• 20 Musabayane C, Tufts M, Mapanga R. Synergistic antihyperglycemic effects between plant-derived oleanolic acid and insulin in streptozotocin-induced diabetic rats. Ren Fail 2010; 32: 832-839
• 21 Wang L, Llorente C, Hartmann P. et al. Methods to determine intestinal permeability and bacterial translocation during liver disease. J Immunol Methods 2015; 421: 44-53
• 22 Thaiss CA, Levy M, Grosheva I. et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science 2018; 359: 1376-1383
• 23 Daniel H, Gholami AM, Berry D. et al. High-fat diet alters gut microbiota physiology in mice. ISME J 2014; 8: 295-308
• 24 Rohr MW, Narasimhulu CA, Rudeski-Rohr TA. et al. Negative effects of a high-fat diet on intestinal permeability: A review. Adv Nutr 2019; 11: 77-91
• 25 De Kort S, Keszthelyi D, Masclee AAM. Leaky gut and diabetes mellitus: What is the link?. Obes Rev 2011; 12: 449-458
• 26 Tai N, Wong FS, Wen L. The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Rev Endocr Metab Disord 2015; 16: 55-65
• 27 Mabuza LP, Gamede MW, Maikoo S. et al. Cardioprotective effects of a ruthenium (II) Schiff base complex in diet-induced prediabetic rats. Diabetes Metab Syndr Obes 2019; 12: 217-223
• 28 Tabák AG, Herder C, Rathmann W. et al. Prediabetes: A high-risk state for diabetes development. Lancet 2012; 379: 2279-2290
• 29 Huang BW, Chiang MT, Yao HT. et al. The effect of high-fat and high-fructose diets on glucose tolerance and plasma lipid and leptin levels in rats. Diabetes Obes Metab 2004; 6: 120-126
• 30 Gummesson A, Carlsson LMS, Storlien LH. et al. Intestinal permeability is associated with visceral adiposity in healthy women. Obesity 2011; 19: 2280-2282
• 31 Shin N-R, Whon TW, Bae J-W. Proteobacteria: Microbial signature of dysbiosis in gut microbiota. Trends Biotechnol 2015; 33: 496-503
• 32 Seethaler B, Basrai M, Neyrinck AM. et al. Biomarkers for assessment of intestinal permeability in clinical practice. Am J Physiol-Gastrointest Liver Physiol 2021; 321: G11-G17
• 33 Kim AS, Ko H-J. Plasma concentrations of zonulin are elevated in obese men with fatty liver disease. Diabetes Metab Syndr Obes 2018; 11: 149-157
• 34 Guo S, Al-Sadi R, Said HM. et al. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am J Pathol 2013; 182: 375-387
• 35 Derikx JP, Luyer MD, Heineman E. et al. Non-invasive markers of gut wall integrity in health and disease. World J Gastroenterol 2010; 16: 5272-5279
• 36 Raetz CRH, Whitfield C. Lipopolysaccharide Endotoxins. Annu Rev Biochem 2002; 71: 635-700
• 37 Jayashree B, Bibin YS, Prabhu D. et al. signify novel biomarkers of proinflammation in patients with type 2 diabetes increased circulatory levels of lipopolysaccharide (LPS) and zonulin. Mol Cell Biochem 2014; 388: 203-210
• 38 Yao Z, Mates JM, Cheplowitz AM. et al. Blood-borne lipopolysaccharide is rapidly eliminated by liver sinusoidal endothelial cells via high-density lipoprotein. J Immunol 2016; 197: 2390-2399
• 39 Sandler NG, Koh C, Roque A. et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 2011; 141: 1220-1230. e1223
• 40 Hawa MI. Immune and metabolic changes leading to diabetes. Queen Mary University of London. 2012
• 41 Amasheh M, Fromm A, Krug SM. et al. TNFα-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFκB signaling. J Cell Sci 2010; 123: 4145-4155
• 42 Shen L, Black ED, Witkowski ED. et al. Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure. J Cell Sci 2006; 119: 2095-2106
• 43 Bruewer M, Utech M, Ivanov AI. et al. Interferon‐γ induces internalization of epithelial tight junction proteins via a macropinocytosis‐like process. FASEB J 2005; 19: 923-933
• 44 Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 2008; 8: 923-934
• 45 Hoshiko H, Feskens EJM, Oosterink E. et al. Identification of leaky gut-related markers as indicators of metabolic health in Dutch adults: The Nutrition Questionnaires plus (NQplus) study. PLoS One 2021; 16: e0252936
• 46 Al-Ayadhi L, Zayed N, Bhat RS. et al. The use of biomarkers associated with leaky gut as a diagnostic tool for early intervention in autism spectrum disorder: A systematic review. Gut Pathogens 2021; 13
• 47 Adriaanse M, Tack G, Passos VL. et al. Serum I‐FABP as marker for enterocyte damage in coeliac disease and its relation to villous atrophy and circulating autoantibodies. Aliment Pharmacol Ther 2013; 37: 482-490
• 48 Funaoka H, Kanda T, Fujii H. Intestinal fatty acid-binding protein (I-FABP) as a new biomarker for intestinal diseases. Rinsho Byori 2010; 58: 162-168