Microbiota, leaky gut syndrome and gut-related diseases


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Lecture on "Microbiota, Leaky gut Syndrome and gut-related disease" at the 7° International workshop on Immunonutrition "Eating for preventing" Carovigno (BA) May 1st-3th 2014

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Microbiota, leaky gut syndrome and gut-related diseases

  1. 1. Microbiota, leaky gut syndrome and gut-related diseases Dott. Maurizio Salamone Metagenics Academy
  2. 2. Summary 1. Microbiota and Clinical Practice 2. Humans are meta-organisms made of ecosystems 3. Concept of Intestinal Ecosystem & functional levels 4. Where do our symbionts live (in the gut)? 5. Functions of microbiota 6. From balance to dysbiosis to Leaky gut 7. Microbiota and IBS 8. Gut permeability and MICI 9. Gut ecostystem, obesity and diabetes type II 10. Nutrimonium study 11. Innovative approaches: lifestyle modifications , supplementation, faecal transplants
  3. 3. Human Microbiome and Clinical Practice Paradigm shift from linear cause-effect approach (tipical of blockbuster drugs) to a network approach tipical of Ecosystemic Complexity Management cause Intermediate step Effect Public Health Genomics. 2013 ; 16(3): 127–133. doi:10.1159/000350308.
  4. 4. Gut microbioma contains more than: - 1000 species - 1014 bacteria + virus and fungi. Are we only human?
  5. 5. A world inside a world Lee YKL, Science 2010
  6. 6. A complex network of micro-ecosystems ECOLOGICAL APPROACH: - Energy balance - Matter balance - Living organism composition - Limiting factors of each community - Reproductive cycles
  7. 7. Human microbiota start from a sterile environment guaranteed by the mother placental barrier Real colonization of gut fetus starts at birth
  8. 8. Human Microbiome projects: 3 main enterotypes ENTEROTYPE 1: Bacteroides ENTEROTYPE 2: Prevotella ENTEROTYPE 3: Ruminococcus Arumugam – Nature 2011
  9. 9. Human body is almost sterile at birth Diet Environment Native CORE microbiota (4-36 months of life) Vaginal microbiotaFecal microbiota (mother) Skin microbiota (mother/father/parents/ babysitter
  10. 10. Mucus layer Intestinal Lumen Endotelium (enterocites) Enteric immunitary and nervous system 4 functional levels of intestinal ecosystem
  11. 11. Intestinal Barrier Turner JR, Nat Rev Immunol 2009;9:799-809 Salim et al, Inflamm Bowel Dis 2011;17;362-81 • Players: epithelial cells, mucus, microbiota • Task: absorb nutrients/exclude pathogens • Transcellular pathway: (20-30 min) • pinocytosis; R-endocytosis • Paracellular pathway (sec-min) • Tight Junctions (ZO) are protein complexes • claudins, occludin (transmembrane) • ZO1-3 (scaffolding) • actin filaments (activated by MLCK) • Adherens junctions • Desmosomes
  12. 12. Zoom on Tight Junctions
  13. 13. Gut permeability is regulated Mucus Microbiota Junctional complex Enterocytes
  14. 14. Where do our symbionts live (in the gut) Biomed Res Int. 2013;2013:435268. doi: 10.1155/2013/435268. Epub 2013 Aug 7
  15. 15. Effect of gut microbiota on human health Barrier effect Immunocompetence/Tolerance Synthesis (vitamins, metabolic modulators) Metabolic/Trophic function Drug methabolism Behavior conditioning But specific effect on each Gastrointestinal tract !
  16. 16. Human Core Microbiota develops in parallel with GALT • Gut symbiontes • Matter and energy network Gut Microbiota • 60% of immune cells are located in the gut Immunity
  17. 17. Can Nutritional Modulation of Maternal Intestinal Microbiota Influence the Development of the Infant Gastrointestinal Tract? J. Nutr. 142: 1921–1928, 2012.
  18. 18. Many cells participate in maintaining health at the intestinal-lumen interface. ILCs: innate lymphoid cells, AMPs: anti-microbial peptides, sIgA: secretory IgA
  19. 19. The Gastrointestinal Tract as an Immunologic Organ - 400 m2 of surface area - GI-associated lymphoid tissue constitutes the largest immune compartment in the body. - T cells of small intestinal epithelium > 60% of the total body lymphocytes.2
  20. 20. The gut-immune interface Macdonald TT, Monteleone G. Science. 2005 Mar 25;307(5717):1920-5. Review.
  21. 21. How the host-gut microbiota balance is mantained?  Secretion of : Gastric acid Mucus Biliary salts Mucosal Ig  Mucosal pH  Mucosal barrier integrity  Intestinal motility  Local mucosal and systemic immunity  Interactions among different bacteria species
  22. 22. Human (guest) Gut Microbioma Regulatory mechanisms alteration Alteration of gut ecosystem Symbiontic link broken Alteration of relation among symbiontic species Cancer Drugs Radio and chemotherapy Enviromental toxics Diet Lack of physical exercise Stress Infezioni Etiopathogenesis Symbiontic link broken Regulatory mechanisms alteration Genetic predisposition Bad maternal microbioma
  23. 23.  Lifestyle (diet and exercise)  Gastric acid barrier  Local mucosal and systemic immunity  Intestinal clearance Anti H2-PPI Gastric atrophy/Surgery Autoimmune disease Aging Surgery Neuromuscolar diseases Radiation/Inflammation Infectious diseases Drugs Endocrine disorders Selective IgA deficit HIV Immunosenescence Microbs-gut link alterations leads to dysbiosis Junk foods ++ Added sugar Lack of fibers
  24. 24. Microbs-gut link alteration Leaky Gut Dysbiosis
  25. 25. Gastro-intestinal diseases associated to an unbalanced gut microbiota 1.Gastrointestinal infections 2.Irritable Bowel Syndrome 3.Chronical Inflammatory Gut Diseases (M.I.C.I.) 4.Small Bowel Bacterial Overgrowth (S.I.B.O) 5.Food Intolerances 6.Obesity and Metabolic Syndrome 7.Liver diseases 8.…Colon Cancer 9.…Autoimmune diseases??
  26. 26. ANTI-FUNGINE PLANT EXTRANTS - Berberina (Hcl o rstratti come Coptis (Coptis chinensis) Noce (Juglans regia); Artiglio del gatto (Uncaria tomentosa); Acido caprilico Oli essenziali (Melaleuca,TeeTree, Lavender, Rosmary, Sage, Oregano) Aglio estratti (Allium sativum); Semi di pompelmo estratti Melissa officinalis estratti; FUNGICIDE ROTATION RESTORE INTESTINAL BARRIER REINOCULATION OF GOOD BACTERIA IMMUNE SYSTEM REPAIR Vit D, - Pantotenic Acid, Molibdenum, Zinc, Selenium LIVER DETOX PROGRAM N acetylcisteine (NAC), - Glutatione DONT FORGETYOUR MOUTH AND ANUS
  27. 27. Gastro-intestinal diseases associated to an unbalanced gut microbiota 1.Gastrointestinal infections
  28. 28. • Campylobacter • Shigella • Salmonella • … 1.4 episodes/yr Post-Infectious IBS Acute Symptoms Recovery Spiller et al., Gastroenterology 2009;136:1979-88 Post-Infectious IBS (6-17%) Gastrointestinal infection
  29. 29. Potentially, probiotics maintain or restore gut micro-ecology during or after antibiotic treatment through: - receptor competition, - competition for nutrients, - inhibition of epithelial and mucosal adherence of pathogens, - introduction of lower colonic pH favoring the growth of nonpathogenic species, - stimulation of immunity, or production of antimicrobial substances.4,5 1.Gastrointestinal infections
  30. 30. GUT MICROBIOTA IN IBS Rajilic-Stojanovic - Gastroenterology 2011 Human intestinal tract chip (HITChip) is a comprehensive and highly reproducible phylogenetic microarray that enables the parallel profiling and semi-quantitative analysis of >1000 representative intestinal phylotypes Microbiota of IBS and healthy subjects are significantly different (P =0.0005) HC IBS
  31. 31. GUT MICROBIOTA IN IBS  2-fold decreased level of Bacteroidetes (P <0.0001)  10% decreased level of Actinobacteria (P =0.0340)  1.5-fold reduction of Bifidobacteria (P <0.05)  >5% increased level of  Firmicutes (P <0.0001) Firmicutes/Bacteroides ratio 2-fold larger in IBS patients (P=0.0002) Rajilic-Stojanovic - Gastroenterology 2011
  32. 32. Gut Bacteria in Health and Disease Gastroenterol Hepatol (N Y). 2013 September;9(9):560-569. Gastro-intestinal diseases associated to an unbalanced gut microbiota
  33. 33. Mast Cell-Nerve Vicinity Correlates with Abdominal Pain in IBS • Mucosal supernatants evoke increased activation of sensory nerve pathways in rodents • MC-nerve vicinity correlated with severity of abdominal pain (r = 0.75; p = 0.001) Mast Cells Nerves Mast cell Nerve Barbara et al., Gastroenterology 2004;126:693-702 Barbara et al., Gastroenterology 2007;132:26-37 Cenac et al., J Clin Invest 2007;117:636-47
  34. 34. Gut Bacteria in Health and Disease Gastroenterol Hepatol (N Y). 2013 September;9(9):560-569. 2. IBD and MICI Gastro-intestinal diseases associated to an unbalanced gut microbiota
  35. 35. Daniel N. Frank et al, PNAS 2007 Bacterial variety in IBD human mucosa
  36. 36. Metabolic syndrome to Tipe II diabetes  overwheight, diabetes, dislipidemies, obesity  > zonulina  LPS  Metabolic changes
  37. 37. From microbiota to obesity and fat storage 2 key factors: - Gut microflora - Barrier permeability
  38. 38. Microbiota, Leaky gut and fat storage Dysbiosys and Leaky gut: - disregulate the « ponderostate » - Increase fat storage
  39. 39. Immunitary diseases • Tollerance to food antigens • Filtered antigens presentation  Physiologically there is Selective filtration
  40. 40. Chronic fatigue and fibromyalgia
  41. 41. Depression and psychiatric disorders Neuropsychiatric disorders (tymic / cognitive) Low grade inflammation Immune hyperactivation Cortitrope hyperactivity DA 5HT Dysbiosis and Leaky gut
  42. 42. Gut Bacteria in Health and Disease Gastroenterol Hepatol (N Y). 2013 September;9(9):560-569. Liver is the first target of altered gut permeability
  43. 43. Unselected population NAFLD (20-30% of total) NASH (2-3%) Cirrhosis ?% HCC ?% 1-2% may progress over 15-20 years Gut microbiota and liver diseases Gut Microbiota
  44. 44. Gut Iperpermeability • Reduced nutrients absorption • Augmented transit of pathogens and antigens Mucosal then systemic immunitary response activation • Immune response activation(1) • Auto-immnune disorders (2) Food intoleerances and allergies(1) • Gluten sensitivity or celiac disease • Intollerance to lactose or ipereattivity to nichel Low grade local then systemic inflammation • expression of pro-infflammatory cytochines • rheumatic diseases Lipidic and glucidig metabolic disregualtion (3) (5) • Increase of fat mass • Overwheight and obesity • Type II diabetes • Liver steatosis Neuro encocrin disregulation • Mood alterations • Hungry and satiety signalizzation are altered (1) Le Scienze Ottobre 2009 n. 494 “Le sorprese della celiachia” (2 ) Ann N Y Acad Sci. 2009 May;1165:195-205 (3) Curr Opin Gastroenterol. 2008 Nov;24(6):701-6 (5) Genes Nutr (2011) 6:241–260 DOI 10.1007/s12263-011-0230-1 Functional gut disorders Transit alteration Chronic fatigue (6) and lack of energy Cephalalgia Joints pain Consequences of Leaky Gut (4) J Allergy Clin Immunol. 2009 Jul;124(1):3-20; quiz 21-2 (5) Genes Nutr (2011) 6:241–260 DOI 10.1007/s12263-011-0230-1 (6) Neuro Endocrinol Lett. 2008 Feb;29(1):117-24. Atopies
  45. 45. Mucus layer Intestinal Lumen Endotelium (enterocites) Enteric immunitary and nervous system 4 functional levels of intestinal ecosystem Nutrients can influence:  mucus production  endotelial integrity  Junction stability  microbial balance
  46. 46. Mucus layer Intestinal Lumen Endotelium (enterocites) Enteric immunitary and nervous system 4 functional levels of intestinal ecosystem How?  ATP production  tight junctions protein production  Membrane fluidity  Microbic trophysm
  47. 47. 48 Basic Supplementation Leaky Gut Syndrome and functional problems Integrative nutritional approach to digestive tract disorders More symtoms •Children >6 years and healthy adults • Athlets •Elderly • Unbalanced diets • Gut habits disorders • Bloating • Dysbiosis • Chronic use of FANS • Post-antibiotic therapy •Post surgery • Bariatric surgery • Integrative nutritional approach to digestive tract disorders
  48. 48. 49 Clinical Trial - Policlinico Gemelli
  49. 49. 28 patients completed 2° mesurement. 51CrEDTA average score 7,43 (SD: ±2,75) at baseline 5,93 (SD: ± 2,7333) after treatment (P=0.089). Average value EQ-5D VAS was 40.0 (SD: ±14,86) at baseline 64.6 (SD: ± 9) after treatment (P<0.0001). +61.5% Trend diminuzione “A multimodal approach, with a combination of different healing agents, seems to be effective both in improving intestinal permeability and in ameliorating symptoms” PERMEABILITA’ INTESTINALE Cr-EDTA SINTOMI- EQ-5D VAS
  50. 50. Epigenetic role of nutrients: Vitamine D Pleiotropic effects Acts on > 2.100 genes scheletric and extra-scheletric activity (1) Vitamin D for Health:A Global Perspective Arash Hossein-nezhad, Michael F. Holick Mayo Clinic proceedings
  51. 51. New frontiers: Faecal Microbiota Transplantation
  52. 52. New frontiers: Faecal Microbiota Transplantation: regulatory aspects
  53. 53. Bio-therapy • Probiotics • Prebiotics • Symbiotics and Post-biotics • Specific formulas of nutrients and bioactive substances (mainly botanicals)
  54. 54. SUMMARY Microbiota and gut-related diseases • GUT Microbiota is a complex organ enrolled in crucial tropho- metabolic, barrier and immunological functions • Balance between different bacterial species and between bacteria and host strongly influences human health • An unbalanced gut microbiota (Dysbiosis) is involved in the pathogenesis of most GI disorders • Microbiota assessment and remodulation are key strategies for restablishment of a correct host-bacteria cross talk
  55. 55. Thanks for your attention