1. The gut microbiota plays an important role in metabolic, barrier, and immune functions that influence human health. An imbalance in gut bacteria (dysbiosis) is involved in many gastrointestinal disorders. 2. Maintaining balance between gut bacteria species and the host is crucial, as dysbiosis can lead to increased intestinal permeability ("leaky gut") and low-grade inflammation, contributing to conditions like IBS, IBD, obesity, and diabetes. 3. Modulating the gut microbiota through probiotics, prebiotics, dietary changes, and supplements can help restore balance and proper communication between bacteria and host, potentially improving gastrointestinal symptoms and health.

1. Microbiota, leaky gut syndrome
and gut-related diseases
Dott. Maurizio Salamone Metagenics Academy

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. 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. Gut microbioma contains more than:
- 1000 species
- 1014 bacteria + virus and fungi.
Are we only human?

5. A world inside a world
Lee YKL, Science 2010

6. A complex network of micro-ecosystems
ECOLOGICAL APPROACH:
- Energy balance
- Matter balance
- Living organism composition
- Limiting factors of each community
- Reproductive cycles

7. Human microbiota start from a sterile
environment guaranteed by the mother
placental barrier
Real colonization
of gut fetus starts
at birth

8. Human Microbiome projects: 3 main enterotypes
ENTEROTYPE 1:
Bacteroides
ENTEROTYPE 2:
Prevotella
ENTEROTYPE 3:
Ruminococcus
Arumugam – Nature 2011

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. Mucus layer
Intestinal Lumen
Endotelium (enterocites)
Enteric immunitary and
nervous system
4 functional levels of intestinal ecosystem

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. Zoom on Tight Junctions

13. Gut permeability is regulated
Mucus
Microbiota
Junctional complex
Enterocytes

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. 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. 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. Can Nutritional Modulation of Maternal Intestinal
Microbiota Influence the Development of the Infant
Gastrointestinal Tract?
J. Nutr. 142: 1921–1928, 2012.

18. Many cells participate in maintaining health at the intestinal-lumen
interface. ILCs: innate lymphoid cells, AMPs: anti-microbial peptides,
sIgA: secretory IgA

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. The gut-immune interface
Macdonald TT, Monteleone G. Science. 2005 Mar 25;307(5717):1920-5. Review.

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. 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.  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. Microbs-gut
link alteration
Leaky
Gut
Dysbiosis

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??

27. 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

28. Gastro-intestinal diseases associated to an unbalanced gut microbiota
1.Gastrointestinal infections

29. • 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. Daniel N. Frank et al, PNAS 2007
Bacterial variety in IBD human mucosa

37. Metabolic syndrome to Tipe II diabetes
 overwheight, diabetes, dislipidemies, obesity
 > zonulina
 LPS
 Metabolic changes

38. From microbiota to obesity and fat storage
2 key factors:
- Gut microflora
- Barrier permeability

39. Microbiota, Leaky gut and fat storage
Dysbiosys and Leaky gut:
- disregulate the « ponderostate »
- Increase fat storage

40. Immunitary diseases
• Tollerance to food antigens
• Filtered antigens presentation
 Physiologically there is
Selective filtration

41. Chronic fatigue and fibromyalgia

42. Depression and psychiatric disorders
Neuropsychiatric
disorders
(tymic / cognitive)
Low grade
inflammation
Immune hyperactivation
Cortitrope
hyperactivity
DA
5HT
Dysbiosis and Leaky gut

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 49
Clinical Trial - Policlinico Gemelli

50. 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

51. 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

52. New frontiers: Faecal Microbiota Transplantation

54. New frontiers: Faecal Microbiota
Transplantation:
regulatory aspects

55. Bio-therapy
• Probiotics
• Prebiotics
• Symbiotics and Post-biotics
• Specific formulas of nutrients and
bioactive substances (mainly botanicals)

56. 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

57. Thanks for your attention