HOW THE MICROBIOME AFFECTS OUR HEALTH

HOW THE MICROBIOME AFFECTS OUR HEALTH

THE INTESTINAL BARRIER AND INTESTINAL PERMEABILITY Intestinal Barrier: a functional body Defense from translocation of dietary antigens, bacteria or bacterial endotoxins Physical barrier = vascular endothelium, epithelial cell lining, mucus layer Chemical barrier = digestive secretions, immune molecules, cytokines, inflammatory mediators Intestinal Permeability: a functional feature Altered via modifications gut microbiota with epithelial damage and alteration to the mucus layer Affected by diet (Western-style diet, EtOH) Loss of barrier function can be acute (via trauma) or chronic (from chronic inflammation)

INTESTINAL PERMEABILITY Barrier of epithelial cells Paracellular space sealed by tight junctions (TJ) TJ comprised of several intramembrane proteins If tight junctions or mucus layer are impaired, it leads to increased intestinal permeability and leakage occurs Impaired TJ associated with Crohn s Disease and Ulcerative Colitis

WHAT AFFECTS INTESTINAL PERMEABILITY Pathogens and antibiotics may impair the mucus layer Butyrate helps maintain the barrier Deficiency in butyrate may cause lesions to the TJ and impair permeability Fructose increases intestinal permeability and is associated with the loss of TJ proteins High-fat diet leads to alterations of the gut microbiota which increases intestinal permeability and results in endotoxemia Prebiotics, probiotics and fecal microbiota transplant may have beneficial effects to help modulate intestinal permeability

MICROBIOTA AND ENDOTOXEMIA High-Fat Diet (HFD) modulates gut microbiota and increases plasma lipopolysaccharide (LPS) leading to endotoxemia LPS is a major component of the outer membrane of gram-negative bacteria Gram-Neg : Gram-Pos ratio increases with a HFD and decreases with a High Fiber Diet HFD increases intestinal permeability by reducing the expression of TJ proteins When given antibiotics to correct the dysbiosis caused by a HFD, endotoxemia and inflammation decreased and glucose tolerance improved

INFLAMMATION High-fat diet increases LPS and increases inflammation Decreased bacterial diversity and dysbiosis can lead to increased intestinal permeability and inflammation Low-grade chronic inflammation is associated with obesity and T2D

Cani et al., 2008, Diabetes 57(6) INTESTINAL PERMEABILITY AND METABOLIC CHANGES

OBESITY Obesity is associated with metabolic disorders including elevated fasting glucose, hypertriglyceridemia, dyslipidemia and hypertension Metabolic syndrome increases the risk of T2D Chronic low-grade inflammation is associated with obesity Inflammation and impaired insulin action are connected

OBESITY Relationship with weight has been known for 3 decades Bidirectional Relationship Dysbiosis can increase energy harvest, regulate energy expenditure and increase fat storage Dysbiosis affects lipid metabolism, increases fasting glucose and increases insulin resistance A high-fat, high-sugar diet may lead to dysbiosis Overfeeding in lean individuals increases Firmicutes & decreases Bacteroidetes, increasing energy harvest

Obese humans and mice have decreased richness and diversity Obese individuals more likely to have a low gene count MICROBIOTA & OBESITY Obese individuals shown to have higher proportion of Firmicutes and lower proportion of Bacteroides than lean individuals High-fat, high-sugar diet increases Firmicutes Ratio can shift through weight loss via diet or surgery (wt loss increases diversity, increases Bacteroides & decreases Firmicutes)

TYPE 2 DIABETES Individuals with T2D have compositional and functional differences in gut microbiota compared to those with normal glucose tolerance Fewer butyrate producing bacteria T2D links to microbiota Intestinal permeability Endotoxemia SCFA Gut hormones BCAA Bile acid metabolism

GLUCOSE METABOLISM Intestinal Permeability Dysbiosis leads to increased intestinal permeability Increased intestinal permeability leads to endotoxemia at subsepticemia levels and is associated with chronic disease Endotoxemia Increased lipopolysaccharide (LPS) levels & increased intestinal permeability are associated with low-grade chronic inflammation, metabolic syndrome and T2D Endotoxin levels 20% in those with obesity and glucose intolerance and 125% in those with T2D compared to lean individuals LPS cross mucosa through leaky tight junctions or infiltrates chylomicrons after a high-fat meal

GLUCOSE METABOLISM SCFAs & Gut Hormones SCFAs help regulate glucose metabolism via regulation of GLP-1 secretion which mediates insulin secretion SCFAs increase postprandial PYY SCFAs stimulate fatty acid oxidation & inhibit lipogenesis BCAAs Branched chain amino acids (BCAA) are associated with obesity and insulin resistance; gut bacteria can synthesize all 20 amino acids Bile Acids Secondary bile acids (bile salts fermented by bacteria in the large intestine) are also involved in insulin sensitivity and glucose metabolism Microbiota composition affects both the type and amount of secondary bile acids produced

Boulangé et al., 2016, Genome Medicine 8(42) GUT MICROBIOTA & METABOLIC DYSFUNCTION LEADING TO DISEASE

HOW WE AFFECT THE MICROBIOME

WHAT FACTORS DETERMINE YOUR MICROBE MIX? Vaginal delivery vs. C-section and breastfeeding Age/Lifecycle Hygiene The Hygiene Hypothesis Geography (Italy vs. Germany and Africa vs. Europe) Environment Diet (fiber-rich foods vs. processed foods) Medication Sleep Exercise Fecal Microbiota Transplants Genetics

DIET

DIETARY EFFECT ON MICROBIOME by shifting to a diet that is fundamentally different to the diet under which the human microbiome interrelationship evolved, we might have disrupted this symbiosis, reducing or removing the evolutionary routed benefits provided by the microbes. The notion that this process might have contributed to the rise of NCDs [chronic non-communicable diseases]and a substantial degree of morbidity and mortality provides a strong incentive to consider attempts to conserve and potentially restore the gut microbiome. Deehan, E., and Walters, J., 2016, Trends in Endocrinology & Metabolism 27(5)

DIET & GUT MICROBIOTA Diet influences gut microbiota composition Diet changes microbiome rapidly Study: Plant-based diet (PBD) or Animal-based diet (ABD) x 5 days with washout period between switch Saw change in gut microbiota after 1 day Microbiota returned to baseline composition within 2 days after stopping intervention diet ABD decreased products of carbohydrate fermentation and increased products of amino acid fermentation Microbiota fluctuate rapidly, but dominant genera are relatively stable over time, therefore long-term dietary patterns may be more important David et al., 2014, Nature 505

DIET NEGATIVES Western Diet Artificial Sweeteners POSTIVES Fiber Prebiotics Probiotics

Western Diet: High-fat, highsugar/high-refined carbs (low fiber) High-fat diet associated with: Increased adiposity Increased Firmicutes Decreased Bacteroides Increased LPS levels gut permeability Incorporation of LPS into chylomicrons in the small intestine after a high-fat meal Saccharolytic activity decreases (due to change in microbiota function) THE WESTERN DIET

Bischoff et al., 2014, BMC Gastroenterology 14 THE WESTERN DIET

ARTIFICIAL SWEETENERS 32% adults consume non-caloric artificial sweeteners (NAS) Mixed results: Some studies show efficacy in weight control, others show weight gain Link to weight gain, CVD, type 2 diabetes Associated with impaired glucose homeostasis and hyperinsulinemia (mice) Other studies show anti-hyperglycemic effect Chicken or the egg? Are they a contributor to metabolic derangement or are they consumed more frequently by those with overweight/obesity and dysglycemia? Pass through GI tract undigested to the colon

ARTIFICIAL SWEETENERS, GLUCOSE INTOLERANCE & GUT MICROBIOTA Study (lean mice) Given water sweetened with saccharin, sucralose, aspartame, sucrose or glucose (control: water) Compared glucose tolerance Marked glucose intolerance from all 3 NAS; effect greatest with saccharin Glucose intolerance improved after antibiotic treatment suggesting a role by gut microbiota Fecal microbiota transplant (FMT) from mice drinking saccharin induced glucose tolerance in recipients Dysbiosis found in mice consuming saccharin Oral glucose tolerance test after consuming all sweeteners before & after antibiotic treatment Suez et al., 2014, Nature 514

NAS, GLUCOSE INTOLERANCE & MICROBIOTA 7 healthy subjects who did not normally consume NAS (human) Gave max-dose saccharin allowed by FDA on days 2 7 Daily glucose tolerance test 4 of 7 developed worsened glycemic response Compared microbiota of responders vs. nonresponders Those who responded to NAS had pronounced compositional changes, whereas non-responders had little change to microbiota FMT from responders & non-responders into mice produced glucose intolerance in those who received stool from NAS responders - Our findings suggest that NAS may have directly contributed to enhancing the exact epidemic that they themselves were intended to fight. Suez et al., 2014, Nature 514