Microbiota & Obesity; Type-2 Diabetes and Cancer PDF

Microbiota & Obesity; Type- 2 Diabetes and Cancer Asst. Prof. Dr. Ayhan MEHMETOĞLU [email protected]  At the end of this lecture students need to know: Relation between dysbiosis...

Microbiota & Obesity; Type- 2 Diabetes and Cancer Asst. Prof. Dr. Ayhan MEHMETOĞLU [email protected]  At the end of this lecture students need to know: Relation between dysbiosis and obesity Learning objectives Role of microbiota in development of diabetes disease Role of microbiota in development of some cancers  Worldwide, obesity has more than doubled since 1980 according to the World Health Organization. Obesity 1980 2014 In 2014, more than 1.9 billion adults were overweight, and over 600 million of those people were obese.  Obesity results from a positive energy balance, which occurs when the amount of Obesity and energy ingested exceeds the amount type 2 expended, and it is a strong risk factor for other metabolic complications such as type 2 diabetes diabetes. Type 2 diabetes is increasing in prevalence in low-income countries, and in 2014, approximately 422 million adults worldwide had diabetes. Type 2 diabetes The condition is characterized by high blood sugar, resistance to insulin and a relative lack of insulin. Insulin resistance is also associated with an increased flux of free fatty acids that contribute to diabetic dyslipidaemia, which is characterized by a high concentration of triglycerides in blood plasma, a low concentration of high-density lipoprotein (HDL) cholesterol and an increased concentration of small, dense low-density lipoprotein cholesterol particles. Dyslipidaemia is one of the major risk factors for cardiovascular disease in people with diabetes. https://www.ndss.com.au/about-diabetes/type-2-diabetes/ Metabolic syndrome Accordingly, abnormal metabolism of glucose and lipids is the hallmark of metabolic syndrome, which is defined by central (abdominal) obesity and the presence of two or more of four factors Elevated triglycerides Reduced HDL cholesterol High blood pressure Increased fasting blood glucose https://www.elitelearning.com/resource-center/rehabilitation-therapy/metabolic-syndrome- risks-and-innovative-solutions/  Germ-free mice are protected from diet- induced obesity when fed a Western-style diet, which further supports a link between the gut microbiota and the host Microbiota metabolism. and The altered microbiota that is observed in adiposity genetically obese mice is sufficient to promote increased adiposity in lean mice that receive a microbiota transplant, demonstrating that the microbiota contributes to the regulation of adiposity. How strongly microbes are linked and associated, both positively and negatively, with the fundamental and essential parts of diabetes in humans The main mechanism of gut microbiota affecting insulin resistance and diabetes Gut microbes are influenced by diet, genetics and medication, and common types of interventions in humans include fecal microbiota transplantation, metformin and probiotics. The main mechanism of gut microbiota affecting insulin resistance and diabetes Lipopolysaccharide (LPS), short-chain fatty acids (SCFAs) and bile acids are major regulators of diabetes. LPS binds to the Toll-like receptor 4 to induce low-grade inflammation and insulin resistance. Bile acids are synthesized by the liver and transformed into secondary bile acids through the metabolism of gut microbiota. The main mechanism of gut microbiota affecting insulin resistance and diabetes Secondary bile acids activate Farnesoid X receptor to induce increased secretion of fibroblast growth factor 15/19. Secondary bile acids activate Takeda G protein-coupled receptor to stimulate intestinal L cells to secrete glucagon-like peptide-1 (GLP-1). SCFAs activate L cells to promote the release of GLP-1 and peptide YY to increase insulin sensitivity. SCFAs also have a regulatory effect on T cells. Microbiota and Cancer Two populations living in peace and solidarity When there is a threat for various reasons, the state of "symbiosis" turns into "dysbiosis" and peaceful bacteria turn into "pathobionts" that cause disease. Prof. Dr. Nurdan Tüzün TÜBA Mikrobiyota İnsan Sağlığı Sempozyumu Microbiota and Cancer At least 15-20% of cancers are caused by infectious agents 20-30% tobacco products, 30-35% due to diet, lack of physical activity and/or is associated with energy balance disorder (obesity) Prof. Dr. Nurdan Tüzün TÜBA Mikrobiyota İnsan Sağlığı Sempozyumu Microbiota and Cancer On the other hand, the inflammation triggered by the microbiome also leads to cancer by stimulating many cytokines and chemokines that increase cell proliferation and suppress apoptosis. Diet: The foods we ingest are important both in terms of microbiota content and cancer development. Namely, microbial metabolism products contribute to the development of cancer. Prof. Dr. Nurdan Tüzün TÜBA Mikrobiyota İnsan Sağlığı Sempozyumu Microbiota and Cancer In one study, when fresh stool samples were given to patients with colon cancer by gavage to healthy germ-free rats, cell proliferation, an early indicator of cancer, and adenomatous polyp-like aberrant crypt foci (ACF) in humans occurred. Prof. Dr. Nurdan Tüzün TÜBA Mikrobiyota İnsan Sağlığı Sempozyumu Stomach 5 major phylums were detected in the stomach: Firmicutes, Bacteroides, Actinobacteri, Fusobacterium and Proteobacteri. Long-term Hylicobacter pylori infection changes the structure of the microbiota by raising the pH, and various bacteria colonization. Also the constant use of PPI (proton pump inhibitor) leads to the development of non-Hp flora and atrophic gastritis. In this context, it has been reported that using PPI for a long time poses a risk for stomach cancer in experimental animals. The microbiota of the large intestine also contributes to the development of cancer in Hp(+) people. Colon The thick mucus layer covering the epithelium protects enterocytes along the intestinal mucosa against bacterial or food antigens and prevents hypersensitivity reactions. The ratio of anaerobes to aerobics in the mucosal face is lower than in luminal flora. The fact that the rat gut microbiota is similar to that of humans has made experimental studies valuable.  Colon Early studies on the relationship between colon cancer and bacteria An association has been noted between Streptococcus bovis (new name Streptococcus gallolyticus). S. bovis has been reported in 33%-100% of colorectal cancer patients. B. fragilis E. faecalis, Clostrioides septicum, Fusobacterium spp. Beside Escherichia coli (E. coli ) Peptostreptococcus, Prevotella, Parvimonas, Leptotrichia and Campylobacter Colon It has been reported that immune cells (IL-17) are increased in tumor samples where there is a higher population of Bacteroides/Prevotella in patients with colonoscopy compared to people with normal colonoscopy Colon It should not be forgotten that other environmental factors (smoking, age, obesity, alcohol, excessive fatty diet, genetics, drugs, immune system, etc.), especially the damage caused by harmful substances (especially secondary bile acids) released as a result of microbiota interaction with the components in the diet, are the main factors involved in the formation of cancer. Liver The liver does not have a unique microbiota. However, intestinal intercourse through the portal vein again leads to exposure to various antigens and bacterial metabolites. Obesity also creates a dysbiosis that leads to cancer, and the production of secondary bile acid: deoxycholic acid (DCA) by Clostridia is increased, which facilitates HCC. Antibiotics can act by reducing LPS and TLR4, while probiotics can reduce LPS and the toxicity of aflatoxin. Probiotics?? Bifidobacterium breve and Lactobacillus rhamnosus are known to suppress pro-inflammatory cytokines and reduce the DNA methylation of the host. Promising References Sonnenburg JL, Bäckhed F. Diet-microbiota interactions as moderators of human metabolism. Nature. 2016 Jul 7;535(7610):56- 64. doi: 10.1038/nature18846. PMID: 27383980; PMCID: PMC5991619. Li WZ, Stirling K, Yang JJ, Zhang L. Gut microbiota and diabetes: From correlation to causality and mechanism. World J Diabetes. 2020 Jul 15;11(7):293-308. doi: 10.4239/wjd.v11.i7.293. PMID: 32843932; PMCID: PMC7415231.  For any question [email protected]