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Dott. Maurizio Salamone
Biologo
Human
Gut
Mycobiota
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Pubmed search for Mycobiota 24 Settembre 2018
370 results
Filter «Humans» «In the last 5 Years
49 results
16 Reviews
PROBIOTICI
Bacterial Yeast
Prokaryotic (DNA loose in cytoplasm) Eukaryotic (nucleus)
Small Large size
AB-resistant genes + transfer between ≠ spp No antibiotic-resistant genes
Affected by AB Not affected by AB
Resistant to proteolysis
S. boulardii: more persistent, optimum growth at
37°C, resistant to low pH (survival gastric acidiy),
tolerant to bile salts
Dth: 1-2 x 1010 /day  concstool: 2 x 108 / g stool
Steady state: three days Telim: 3-5 days
Elmer et al. found that some types of fiber
(psyllium) increased SB levels by 22 %
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Figure 1. The archaeal and fungal components of the human gut microbiome.
Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with
Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
UPDATE CLASSIFICATION
Mycobank
http://www.mycobank.org/
Index Fungorum
http://www.indexfungorum.org/
names/names.asp
Figure 2. Analysis of co-occurrence among microbial lineages scored using the Dice index.
Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with
Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
Nat Rev Immunol. 2017 Oct;17(10):635-646.
«1 miliardo di anni fa
funghi e animali si sono
staccati dal ramo evolutivo
delle piante trovando nelle
nuove vie evolutive molti
modi di interazione
mutualmente reciproca»
Figure 3. Inter-generic relationships.
Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with
Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
Gut Mycobiota
13% of total microbiota
(wheight)
140 genus
mainly Basidiomycota
and Ascomycota
- Schei et al. Microbiome (2017) 5:107
- Hamad et al. Repertory of eukaryotes (eukaryome) in the human gastrointestinal
tract: taxonomy and detection methods. Parasite Immunol. 2016;38:12–36
Gut Mycobiota
RESIDENTI IN TRANSITO
- Temperature 37°
- Low oxigen atmosphere
- Wide pH variations
- Biliar salts
- Gastric acid
- Digestive enzimes
FEMS Microbiol Rev. 2017 Jul 1;41(4):479-511. doi: 10.1093/femsre/fuw047.
Forgotten fungi-the gut mycobiome in
human health and disease.
Gut Mycobiota
Hamad et al.
Repertory of
eukaryotes
(eukaryome) in the
human
gastrointestinal
tract: taxonomy
and detection
methods. Parasite
Immunol.
2016;38:12–36
FEMS Microbiol Rev. 2017 Jul 1;41(4):479-511. doi: 10.1093/femsre/fuw047.
Forgotten fungi-the gut mycobiome in
human health and disease.
Vaginal Mycobiota L. L. BRADFORD AND J. RAVEL Virulence 2017
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Int. J. Mol. Sci. 2017, 18, 330;
doi:10.3390/ijms18020330
Figure 6. Possible syntrophic relationships in the human gut consistent with data reported in this
study.
Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with
Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
adherent-invasive
Escherichia coli
and Candida spp.
Ward et al. BMC Medicine (2017) 15:30
Infant Mycobiota
Ward et al. BMC Medicine (2017) 15:30
Infant Mycobiota
Nat Rev Immunol. 2017 Oct;17(10):635-646.
Mycobiota & Dysbiosis
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Timeline of studies published on the gut
mycobiome and colour coded as follows: major
developments (grey), GI disease (blue),
immunocompromised hosts (red), healthy
populations (yellow), infants (purple), diet
(green) and other (teal).
FEMS Microbiol Rev. 2017 Jul 1;41(4):479-511. doi: 10.1093/femsre/fuw047.
Forgotten fungi-the gut mycobiome in
human health and disease.
- 26 % (24/94) and 25.3 % (38/150) of a series of
patients with unexplained GI symptoms had SIFO
- symptoms observed in these patients were belching,
bloating, indigestion, nausea, diarrhea, and gas
- small intestinal dysmotility and use of proton pump
inhibitors are possible underlying mechanism(s)
- a 2–3-week course of antifungal therapy is
recommended and may be effective in improving
symptoms, but evidence for eradication is lacking
Current Opinion in Microbiology 2017, 40:58-64
IFI
Invasive
Fungal
Infections
Algoritmo diagnostico
-2016
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Mycobiota and th Human Exposome
The chemical spectra of molecules in the organism is believed to
account for :
- about 40 nutrients
- 2,000 intermediary metabolites
- 200,000 peptides
- 500.000 lipids
- 400,000 sostanze chimiche
- Circa 300 micotossine principalmente da Fusarium, Claviceps,
Alternaria, Aspergillus, Candida e Penicillium (Marin et al., 2013).
Molte di queste sono di origine batterica o fungina…
Ricerca di Anticorpi anti- funghi e lieviti
Ricerca di metaboliti batterici
Ricerca di metaboliti fungini nelle urine per lo
studio delle disbiosi
Ricerca di metaboliti fungini nelle urine per lo
studio delle disbiosi
Disease Markers Volume 2018, Article ID 7451946, 16 pages
https://doi.org/10.1155/2018/7451946
ASCA, I2, and
OmpC altogether
can be found in
80% of patients
with CD
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Nature reviews Fungal Dysbiosis – 2017
Iliev, I. D., & Leonardi, I. (2017). Fungal dysbiosis: immunity and
interactions at mucosal barriers. Nature Reviews Immunology,
17(10), 635–646. doi:10.1038/nri.2017.55
Leonardi et al., Science 359, 232–236 (Gen. 2018)
SIFO
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Fungi are presents in most of the food we eat
Zuo, T., Kamm, M. A., Colombel, J.-F., & Ng, S. C. (2018).
Urbanization and the gut microbiota in
health and inflammatory bowel disease.
Nature Reviews Gastroenterology &
Hepatology, 15(7), 440–452.
doi:10.1038/s41575-018-0003-z
Zuo, T., Kamm, M. A., Colombel, J.-F., & Ng, S. C. (2018). Urbanization and the gut microbiota in health
and inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology,
15(7), 440–452. doi:10.1038/s41575-018-0003-z
Zuo, T., Kamm, M. A., Colombel, J.-F., & Ng, S. C. (2018). Urbanization and the gut microbiota in health
and inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology,
15(7), 440–452. doi:10.1038/s41575-018-0003-z
High-Fat Diet Changes Fungal Microbiomes and Interkingdom
Relationships in the Murine Gut
mSphere 2017 Oct 11;2(5). pii: e00351-17. doi: 10.1128/mSphere.00351-17.
eCollection 2017 Sep-Oct.
Decreased ethanol-induced liver
disease in mice treated with
antifungals..
jci.org Volume 127 Number 7 July 2017
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
the Basidiomycota:Ascomycota ratio and the
Candida albicans count were found to be
increased, while Saccharomyces cerevisiae
abundance decreased.
Other species’ numbers found elevated in CD
included Gibberella moniliformis,
Alternaria brassicicola and Cryptococcus
neoformans.
It is of interest that fungal microbiota correlated
with the CD activity index and the degree of
inflammation expressed by C-reactive protein
(CRP) concentration.
Mycobiota e Dieta
Hallen-Adams HE, Kachman SD, Kim J, Legge RM, Martınez I. Fungi inhabiting the healthy human gastrointestinal tract: a diverse and
dynamic community. Fungal Ecol 2015; 15:9-17; http://dx.doi.org/10.1016/j.funeco. 2015.01.006
Suhr MJ, Banjara N, Hallen-Adams HE. Sequence-based methods for detecting and evaluating the human gut mycobiome. Lett Appl Microbiol
2016; 62:209-15; PMID:26669281; http://dx.doi.org/10.1111/lam.12539
_________
Figure 5. Fungi-Diet relationships.
Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with Diet and
Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
McFarland LV, (2010). Systematic review and meta-analysis of Saccharomyces boulardii in adult
patients,
world J Gastroenterol, 16 (18), 2202-2222.
Probiotics: live microorganisms that confer a health benefit on the host
Saccharomyces boulardii (S.B.)
•SB was found to be sign. efficacious and safe in 84% of all treatment arms (26/31), 27 ≠trials.
•SB sign. effective in preventing antibiotic-associated diarrhea (AAD (p <0.001)
•In adults, recommended for prevention of AAD and traveler’s diarrhea
•Prevention of enteral nutrition related diarrhea and reduction of Heliobacter pylori treatment-
related symptoms
•Promise for prevention of C. difficile disease recurrences, irritable bowel syndrome, acute adult
diarrhea, Chron’s disease, giardiasis, human immunodeficiency virus-related diarrhea
McFarland LV, (2010). Systematic review and meta-analysis of Saccharomyces boulardii in adult patients, world J Gastroenterol, 16 (18), 2202-2222
Potentially, probiotics maintain or restore gut microecology 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
Date of download: 1/14/2014
Copyright © 2014 American Medical
Association. All rights reserved.
JAMA. 2012;307(18):1959-1969.
doi:10.1001/jama.2012.3507
Szajewska_2009
Szajewska H, Skórka A. Saccharomyces boulardii for treating acute
gastroenteritis in children: updated meta-analysis of randomized
controlled trials. Alimentary Pharmacology & Therapeutics 2009;30:
960–1.
In conclusion, this update of our meta-analysis of data from RCTs
confirms that in otherwise healthy infants and children, the use of
S. boulardii is associated with clinical benefits in the treatment of
AGE, specifically a reduction in the duration of diarrhoea by
approximately 1 day.
Saccharomyces boulardii: Meta-analysis using data from 7 RCTs: 944
healthy children with acute gastroenteritis.
The duration of diarrhea was reduced with 1.08 days (95% CI: 0.53-
1.64) in children who received the yeast compared with placebo.
Szajewska_2001: http://www.ncbi.nlm.nih.gov/pubmed/11698781
Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhoea in infants and
children; a systematic review of published randomized, double-blind, placebo-controlled trials. Journal of
Pediatric Gastroenterology and Nutrition 2001;33 Suppl 2:17–25.
BACKGROUND: This review was designed to assess the evidence from randomized controlled trials on effects of
probiotics in the treatment and prevention of acute infectious diarrhea in infants and children.
METHODS: A systematic review of published, randomized, double-blind, placebo-controlled trials on probiotics in the
treatment or prevention of acute diarrhea defined as >3 loose or watery stools per 24 hours in infants and
children.
RESULTS: The use of probiotics as compared with placebo was associated with a significantly reduced risk of diarrhea
lasting >3 days. The pooled estimate risk was 0.43 (95% CI, 0.34-0.53) with a fixed-effect model, and remained
significant in a random-effect model (0.40; 95% CI, 0.28-0.57). Only Lactobacillus GG showed a consistent effect.
Probiotics significantly reduced the duration of diarrhea when compared with placebo, particularly in rotaviral
gastroenteritis-the pooled, weighted, mean difference (WMD) assuming the random-effect model was -20.1 hours
(95% CI, -26.1 to -14.2) and -24.8 (95% CI, -31.8 to -17.9) respectively. A meta-analysis of the prevention studies
was not feasible because of significant clinical and statistical heterogeneity.
CONCLUSIONS: There is evidence of a clinically significant benefit of probiotics in the treatment of acute infectious
diarrhea in infants and children, particularly in rotaviral gastroenteritis. Lactobacillus GG showed the most
consistent effect, although other probiotic strains may also be effective. Further research is needed. Clinical and
statistical heterogeneity of the prophylactic interventions preclude drawing firm conclusions about the efficacy of
probiotics in preventing acute gastroenteritis.
The risk of diarrhea lasting three or more days was reduced by 0.40 in the probiotic compared with the placebo group
(8 studies included; 731 children), and probiotics reduced the duration of diarrhea by 18.2 hours (n=8, 773
children).
Van Niel_2002: http://pediatrics.aappublications.org/content/109/4/678
Van Niel CW, Feudtner C, Garrison MM, Christakis DA. Lactobacillus therapy for acute infectious diarrhoea in children: a
meta-analysis. Pediatrics 2002;109(4):678–84.
Objective. Childhood diarrhea accounts for substantial morbidity and mortality worldwide. Multiple studies in children
have shown that Lactobacillus, administered orally, may have antidiarrheal properties. We conducted a meta-
analysis of randomized, controlled studies to assess whether treatment with Lactobacillus improves clinical
outcomes in children with acute infectious diarrhea.
Methods. Studies were sought in bibliographic databases of traditional biomedical as well as complementary and
alternative medicine literature published from 1966 to 2000. Search terms were “competitive inhibition,”
“diarrhea,” “gastroenteritis,” “Lactobacillus,” “probiotic,” “rotavirus,” and “yog(h)urt.” We included studies that
were adequately randomized, blinded, controlled trials in which the treatment group received Lactobacillus and
the control group received an adequate placebo and that reported clinical outcome measures of diarrhea
intensity. These inclusion criteria were applied by blind review and consensus. The original search yielded 26
studies, 9 of which met the criteria. Multiple observers independently extracted study characteristics and clinical
outcomes. Data sufficient to perform meta-analysis of the effect of Lactobacillus on diarrhea duration and
diarrhea frequency on day 2 were contained in 7 and 3 of the included studies, respectively.
Results. Summary point estimates indicate a reduction in diarrhea duration of 0.7 days (95% confidence interval: 0.3–
1.2 days) and a reduction in diarrhea frequency of 1.6 stools on day 2 of treatment (95% confidence interval: 0.7–
2.6 fewer stools) in the participants who received Lactobacillus compared with those who received placebo.
Details of treatment protocols varied among the studies. A preplanned subanalysis suggests a dose-effect
relationship.
Conclusion. The results of this meta-analysis suggest that Lactobacillus is safe and effective as a treatment for children
with acute infectious diarrhea.
Different lactobacilli strains. Probiotics reduced the duration of diarrhea with 0.7 days, and diarrhea frequency on day 2
by 1.6 (3 studies, 122 children).
Szajewska_2007a
Szajewska 2007b Szajewska H, Skórka A, Dylag M. Meta-analysis: Saccharomyces boulardii for treating acute diarrhoea
in children. Alimentary Pharmacology & Therapeutics 2007;25: 257–64.
AIM: To review evidence for the effectiveness of Lactobacillus casei GG (LGG) in treating acute infectious diarrhoea in
children.
METHODS: The following electronic databases were searched through August 2006 for studies relevant to acute
infectious diarrhoea and LGG: MEDLINE, EMBASE, CINAHL and The Cochrane Library; additional references were
obtained from reviewed articles. Only randomized-controlled trials (RCTs) were included.
RESULTS: Eight RCTs (988 participants) met the inclusion criteria. Compared with controls, LGG had no effect on the
total stool volume (two RCTs, n = 303). However, LGG was associated with a significant reduction in diarrhoea
duration (seven RCTs, 876 infants, weighted mean difference, WMD -1.1 days (95% confidence interval, CI -1.9 to -
0.3), particularly of rotavirus etiology (WMD -2.1 days, 95% CI -3.6 to -0.6), risk of diarrhoea >7 days (one RCT, n =
287, relative risk 0.25, 95% CI 0.09-0.75) and duration of hospitalization (three RCTs, n = 535, WMD -0.58, 95% CI -
0.8 to -0.4; significance was lost in the random effect model). There was no reduction in the number of stools at
any time interval.
CONCLUSIONS: The use of LGG is associated with moderate clinical benefits in the treatment of acute diarrhoea in
children. These findings should be interpreted with caution due to the important methodological limitations and
heterogeneity of most of the studies.
Studies involving Lactobacillus casei GG, L casei GG reduced the duration of diarrhea by 1.1 days (7 trials, 876 infants)
and was particularly effective in rotavirus diarrhea (duration reduced by 2.1 days).
Chmielewska 2008
Chmielewska A, RuszczyńskiM, Szajewska H. Lactobacillus reuteri strain ATCC 55730 for the treatment of acute
infectious diarrhea in children: a meta-analysis of randomized controlled trials. Metaanalysis 2008;10:32–6.
Background Probiotics may be of help for the management of acute diarrhoea, however, the effect is strain specific and
efficacy needs to be proven.
Aim To test the efficacy and safety of Lactobacillus reuteri DSM 17938 derived from L. reuteri ATCC 55730 in
children with acute diarrhoea. Primary outcomes were the rate of unresolved diarrhoea after 3 days of treatment
and duration of diarrhoea.
Methods Children (6–36 months), hospitalised in three paediatric hospitals in Southern Italy for acute diarrhoea
with clinical signs of dehydration were randomised to receive in a double-blind fashion either L. reuteri (dose of 4
× 108 colony-forming units/die) or placebo.
Results Out of 96 eligible children, 74 were enrolled, five patients were withdrawn; 35 in the L. reuteri group and
34 in the placebo group. Lactobacillus reuteri significantly reduced the duration of watery diarrhoea as compared
with placebo (2.1 ± 1.7 days vs. 3.3 ± 2.1 days; P < 0.03); on day two and three of treatment watery diarrhoea
persisted in 82% and 74% of the placebo and 55% and 45% of the L. reuteri recipients respectively (P < 0.01; P <
0.03). Finally, children receiving L. reuteri had a significantly lower relapse rate of diarrhoea (15% vs. 42%; P <
0.03). There was not a significant difference in hospital stay between the groups. No adverse events were
recorded.
Conclusion Our study shows that L. reuteri DSM 17938 as an adjunct to rehydration therapy is efficacious in the
treatment of acute diarrhoea reducing the frequency, duration and recrudescence rate of the disease.
Meta-analysis of 2 studies using Lactobacillus reuteri DSM 17938. This probiotic reduced the duration of diarrhea by 22
hours.
Wolvers_2010
Wolvers D, Antoine JM, Myllyluoma E, Schrezenmeir J, Szajewska H, Rijkers GT. Guidance for
substantiating the evidence for beneficial effects of probiotics: prevention and management
of infections by probiotics. Journal of Nutrition 2010;140(3): 698S–712S.
Sufficient consistent data exist for the management of infectious diarrhea in infants and traveler's
diarrhea, antibiotic-associated diarrhea, and necrotizing enterocolitis to conclude that certain
probiotics, under certain conditions, and in certain target populations, are beneficial in
reducing the risk of infection.
Different Bacterial strains and Saccharomyces boulardii. The beneficial effects
of probiotics in acute infectious diearrhea were dependent on the strain of
bacteria and the dose (a greater effect with doses >1010-1011 colony
forming units (CFU/day)
McFarland L.V, Meta-Analysis of Probiotics for the Prevention of Antibiotic Associated
Diarrhea and the Treatment of Clostridium difficile Disease.
American Journal of Gastroenterology 2006, 101: 812-822.
Evidenze scientifiche
dell’efficacia di Saccharomyces boulardii
In caso di diarrea associata all’uso di antibiotici (DAA):
Diarrea acuta
Disbiosi
- Clostridium Difficile Associated Diarrhea (CDAD**)
- riduzione delle difese immunitarie
- riduzione della sintesi di vitamine
- alterazione della funzione di barriera intestinale
(leaky gut)
Antibiotici
Riduzione della flora commensale
Oltre il 30% dei pazienti
Sviluppa una diarrea associata all’uso di antibiotici (DAA*)
Conseguenze:
Diarrea
- riduzione della qualità di vita
- doulori addominali
- gonfiore
- interruzione del trattamento con antibiotici
*AAD = Antibiotics Associated Diarrhea
*CDAD = Clostridium Difficile Associated Diarrhea
The use of antibiotics that disturb the gastrointestinal flora
is associated with clinical symptoms such as diarrhea,
which occurs in as many as 30% of patients.1,2 Symptoms
range from mild and self-limiting to severe, particularly in
Clostridium difficile infections, and antibiotic-associated
diarrhea (AAD) is an important reason for nonadherence
with antibiotic treatment.3
Probiotics for the Prevention and Treatment
of Antibiotic-Associated DiarrheaA Systematic
Review and Meta-analysis
JAMA. 2012;307(18):1959-1969. doi:10.1001/jama.2012.3507
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
La medicina tradizionale
si occupa principalmente
delle candidosi vulvo
vaginali e del cavo orale
Linee guida SIMAT per le
candidosi vulvo vaginali
Agente eziologico:
Candida albicans (80-92 %%), Candida glabrata,
Candida spp.
Feequenza:
Il 75% delle donne ha avuto almeno 1 episodio di
candidosi vaginale durante la propria vita. Il 40 - 45%
due o più episodi.
Sintomi:
 prurito vulvare
 dolore vulvare
 secrezioni vaginali biancastre
 dispareunia Superficiale
Segni:
 eritema
 secrezioni
 lesioni satellite
 edema
TRATTAMENTO FARMACOLOGICO
PER I CASI SINTOMATICI
(Il 20% delle donne ha colonizzazione ma non sintomi)
Opzioni terapeutiche
 Fluconazolo CPR 150 mg, 1 CPR monosomm.
 Itraconazolo cpr 200 mg, 1/die per 3 giorni.
 Itraconazolo cpr 200 mg, 1 x 2/die per 1 giorno.
 Clotrimazolo crema 1% applicazione intravaginale
(5 g) per 7 - 14 giorni.
 Clotrimazolo candelette vaginali 100 mg per 7 ggi.
 Clotrimazolo candelette vaginali 100 mg, 1 x 2/die
per 3 giorni.
 Clotrimazolo candelette vaginali 500 mg, 1 singola
 Miconazolo crema 2% (5g) appl. Intravag. per 7gg.
 Miconazolo 200 mg ovuli, 1 ovulo per 3 giorni.
 Miconazolo 100 mg ovuli, 1 ovulo per 7 giorni.
 Nistatina candelette vaginale 100,000 U, per 14 gg
 Tioconazolo 6.5% (5 g) appl. intravaginale singola
 Terconazolo 0.4% (5 g) appl. intravaginale per 7 gg
La Candida, in quanto
fungo,
è indifferente ai
trattamenti con
antibiotici-
Semmai viene favorita da
questi perchè vengono
liberate nicchie
ecologiche e create le
premesse per una
disbiosi
Candidosi
Intestinale
SIFO
Candida albicans è un normale
abitante del nostro sistema digestivo.
E’ presente in proporzioni molto
piccole rispetto ad altri simbionti e non
causa sintomi specifici.
Un certo numero di fattori
predisponenti, molto spesso legati alla
dieta, possono causare lo sviluppo
selettivo di Candida albicans
nell'intestino.
Candidosi Intestinale
• CANDIDA ALBICANS (50 %)
• CANDIDA TROPICALIS
• CANDIDA PARAPSILOSIS
• CANDIDA KRUSEÏ
• CANDIDA PSEUDOTROPICALIS
• CANDIDA GLABRA (TORULOPSIS)
Candidosi Intestinale
Candidosi Intestinale
Le candidiasi croniche sono condizioni che
colpiscono milioni di persone in tutto il mondo,
ma sono paradossalmente poco considerate.
Questa patologia è insidiosa perché non si
accompagna a sintomi particolarmente evidenti,
ma può indebolire il sistema immunitario e
compromettere il potenziale di salute delle
persone affette, con conseguenti disturbi
funzionali.
Candidosi Intestinali: Fattori predisponenti
Lo squilibrio della flora intestinale, in
seguito a trattamento con antibiotici, è
uno dei principali fattori predisponenti la
proliferazione della Candida.
Tutti gli antibiotici sono implicati e alcuni
(Tetracicline) hanno anche un effetto
stimolante diretto sulla Candida.
Le cause principali sono legate al regime dietetico:
Un’alimentazione ricca di zuccheri raffinati; la Candida ama lo
zucchero. E’ in grado di produrre peptidi che attraversano la barriera
intestinale ed emato-encefalica che stimolano la voglia di zucchero.
Tutti i tipi di zucchero sono coinvolti; i frutti dolci, l’eccesso di prodotti
lattiero-caseari fermentati, di grassi saturi, possono alterare l’equilibrio
della microflora intestinale.
Numerosi farmaci, non solo gli antibiotici ma anche corisonici, la pillola
anticoncezionale, gli inibitori di pompa protonica di uso così frequente
per il trattamento di gastriti e Gerd
La sovralimentazione in generale e in particolare quando le capacità
digestine sono alterate
Cattiva digestione: gastrite atrofica, ipocloridria etc
Candidosi Intestinali: Fattori predisponenti
• Infezioni da funghi della pelle e delle unghie
• Stanchezza, affaticamento cronico o fibromialgia
• Disturbi funzionali intestinali come gonfiore, o alterazioni alvo
• Malattie autoimmuni quali la tiroidite di Hashimoto, l'artrite
reumatoide, la colite ulcerosa, il lupus, la psoriasi, la
scleroderma o la sclerosi multipla
• Difficoltà di concentrazione e di memorizzazione
• Eczemi, esacerbazione della psoriasi, orticaria e rash
• Irritabilità, alterazioni dell'umore, ansia o depressione
• Infezioni vaginali, infezioni del tratto urinario, prurito rettale o
prurito vaginale
• Allergie stagionali, febbre da fieno, riniti allergiche
• Desiderio smodato di zuccheri e carboidrati
Candidosi Intestinale: 10 sintomi più comuni
La Candida produce almento 35 tossine
conosciute: la più conosciuta è la candidina
(la più neurotossica)
- Le tossine alterano la funzione cerebrale.
- Alterano la funzione immunitaria
Nel medio termine provocano alterazioni
sistemiche che coinvolgono diversi sistemi.
Candidosi : Patogenesi e tossicità
Le candida produce acetaldeide.
L’ acetaldeide reagisce con un neurotrasmettitore del cervello, la
dopamina, causando sintomi a carico del SNC e disturbi dell’umore e
del comportamento come:
depressione,
ansia e attacchi di panico,
irritabilità,
sbalzi d’umore,
difficoltà di concentrazine e di memorizzazione
Candidosi Intestinale: Patogenesi
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654610/pdf/viru-4-119.pdf
Candidosi Intestinale: Patogenesi
Le candida produce acido tartarico:
Immediato senso di gonfiore
intestinale subito dopo il
pasto.
La colite intestinale è
probabilmente il sintomo più
comune e probabilmente il
più banale, della candidosi
cronica.
Disturbi funzionali intestinali cronicizzanti
Candidosi Intestinale: Patogenesi
• Gonfiore
• Produzione di gas
• Flatulenza
• Tensione della parete
addominale
• Alterazioni del transito
• Pirosi
• Gerd
Candidosi Intestinale:
disturbi funzionali intestinali
La candida aumenta la
permeabilità intestinale.
Una alterazione della
permeabilità facilita il transito
di molecole allergizzanti che
provocano effetti sistemici
dismetabolici
Candidosi Intestinale: Patogenesi
Disturbi neurofuzionali per carenza di minerali
Ipereccitabilità neuromuscolare
Disturbi del SNC da tossine
Depressione
Emicrania
Allergie per alterazione della risposta immunitaria umorale
Orticaria
Eczemi
Asma e ipersensibilità chimica multipla
Candidosi Intestinale:
disturbi extra-digestivi
La candida può migrare dal tubo digestivo e
aggredire l’apparato genitale e la pelle
• Mughetto
• Eczema micotico del cuoio capelluto,
ascelle, torace.
•Eczema micotico perianale
•Candidosi dell’apparato uro-genitale
Vaginite da Candida albicans
Le infezioni fungine dei piedi e
delle unghie dei piedi sono di
solito secondarie all’eccessivo
sviluppo del fungo nel tratto
digestivo.
Incredibile adattabilità metabolica e resilienza
La Candida è molto sensibile al pH intestinale
Una dieta alcalina non è GRADITA.....
Micosi intestinale: circolo vizioso
Candidosi: diagnostica di laboratorio
Analisi delle feci
Candidosi: diagnostica di laboratorio
-Coprocultura (esame delle feci, spesso negativo)
- IgG, IgA and IgM anticorpi specifici per Candida
Molti falsi negativi per la capacità immunosoppressive del lievito
- Ematocrito completo
Si può riscontrare aumento dei leucociti o un pattern di riduzione
nei leucociti e aumento dei neutrofili Il calo dei linfociti T4 (CD4) associato ad un
calo del rapporto tra linfociti T4/ linfociti t( (CD4/CD8) attesta la ridotta efficacia dell’immunità cellulare.
-Test dei metaboliti disbiotici nelle urine
La presenza di metaboliti fungini in eccesso (Es. D-Arabinitolo) è
indice di disbiosi e di sovracrescita fungina
-Reattività alla Candidina (principale tossina prodotta dal
lievito)
Il trattamento della candidiasi cronica deve essere
protratto meticolosamente per diversi mesi per
ottenere risultati sostenibili.
Il ritorno alle vecchie abitudini alimentari
frequentemente causa ricadute.
Candidosi Intestinale-Trattamento
 RIDURRE DRASTICAMENTE GLI ZUCCHERI
Evitare cibi ad alto contenuto di carboidrati, zucchero
raffinato (saccarosio, fruttosio), succhi di agrumi, miele,
sciroppo d'acero, frutta in genere, ad eccezione di mele,
ciliegie, frutti di bosco, pere.
Il riso ok perchè viene digerito rapidamente
Limitare il consumo eccessivo di verdure ricche di carboidrati
come patate, mais
 AIUTARE LA DIGESTIONE in generale e in particolare
quella DEI CARBOIDRATI se necessario integrando con
enzimi digestivi
Candidosi Intestinale-Trattamento
Qualche alimento vietato
Zucchero di canna o raffinato
Miele
Siroppo d’acero
Melasse
Marmellate e gelatine di frutta
Gelati, creme e budini
Bevande zuccherate (gassate e non)
Farine raffinate (pane, pasta biscotti)
Pizza, brioches
Riso bianco raffinato
Fecola di patate
Carote
Mais
Semolino cous cous
Cereali in fiocchi per la colazione
Riso soffiato
Cioccolato non fondente >70%
Candidosi
Intestinale
Trattamento
DIETETICO
DIETA PALEO
AUTOIMMUNE
Alimenti accettati
Cereali integrali senza glutine
Pane di miglio
Riso integrale
Fave e farina di fave
Ceci e farina di ceci
Lenticchie
Quore di palma
Pomodoro
Radicchio
Funghi
Carciofi
Insalate verdi
Spinaci
Piselli feschi o secchi
Candidosi
Intestinale
Trattamento
Igiene Intestinale
I probiotici sono indispensabili per contrastare lo sviluppo di
Candida, che è inibita da batteri lattici e bifidobatteri della
flora intestinale.
Soprattutto dopo trattamenti ripetuti con antibiotici ripetuti,
la flora è danneggiata e non può esercitare il suo ruolo di
modulazione e di controllo della crescita di agenti patogeni che
possono colonizzare l'intestino.
Diversi ceppi probiotici come il Lactobacillus acidophilus NCFM
e il Saccharomices boulardi hanno dimostrato efficacia
nell'inibire la crescita di Candida.
Il trattamento con probiotici deve essere continuato per mesi.
Candidosi
Intestinale
Trattamento
Disturbi funzionali intestinali cronici:
origine fungina o parassitaria
• Approccio?
- Combattere ed eliminare le cause
- Riequilibrare l’ecosistema intestinale
- Agire direttamente sul microbiota con probiotici
- Modifiche dietetiche e dello stile di vita  (disbiosi di origine
fungina)
Estratti Vegetali ad Azione Antifungina
• Acidi grassi a media catena
l'acido undecenico
l'acido laurico o monolaurina (prodotti come Lauricidin)
• acido caprilico
• Uncaria tomentosa
• Pau d'arco
• Oli essenziali di timo, origano o bergamotto
• Coptide (ranunculacea)
• Tea tre oil
• Semi di pompelmo
• Berberina (da Berberis aristata o Hydrastis)
• Estratti d’aglio (Allicina)
Acido caprilico
• L'acido caprilico (nome IUPAC, acido ottanoico) è un acido
carbossilico.
• A temperatura ambiente si presenta come un liquido incolore
dall'odore tenue, corrosivo, oleoso poco solubile in acqua
dall’odore sgradevole (rancido).
• Si trova in natura nella noce di cocco e nel latte materno.
 Caprilato di calcio: da acidi grassi a media catena del cocco
- azione antimicotica1
- disturba la produzione della parete cellulare della Candida
- inibisce la proliferazione eccessiva della Candida
 Acido caprilico e caprico inibiscono la formazione micellare di
candida a bassa concentrazione e sono utilizzabili anche per
uso locale nelle infezioni del cavo orale
 Il Saccharomices boulardii contrasta la Candida secernendo
acido caprilico e inibisce la sua diffusione
Berberis aristata DC
La berberina, utilizzata da secoli nelle medicine tradizionali per
numerose finalità.
La sua azione più conosciuta e di contribuire alla regolazione del
metabolismo del colesterolo. Azione supportata da numerosi
studi clinici.
• La berberina può inoltre supportare lo sviluppo di
microrganismi non patogeni simbionti nel nostro intestino e
contribuire ad una normale funzione dell’apparato GI **
Berberis aristata DC Estratto secco di corteccia
Titolato in berberina (>95%)
- supporta lo sviluppo di microrganismi non patogeni simbionti nel nostro
intestino
- contribuisce ad una normale funzione dell’apparato gastrointestinale
- inibisce la acil-CoA: sterol aciltrasferasi di Candida albicans3
La berberina è un alcaloide presente in numerose specie vegetali e in particolar modo nel
genere Berberis.
Nuove evidenze mostrano un’attività della berberina su Candida albicans.
La berberina:
- -provoca aumento della permeabilità di membrana e depolarizzazione della membrana
cellulare in colture di Candida
- Inibisce la trasformazione di Candida in forma di ife (che invadono altri tessuti)
- Azione sinergica con anfotericina, miconazolo e fluconazolo
- Lo studio ha confermato un’azione anti candida e stabilito MIC 17.75 μg/mL
- La berberina può indurre apoptosi nella Candida per aumento dei ROS
- La berberina induce un cambiamento nel metabolismo degli steroli in Candida inibendo la
produzione di ergosterolo
Attività della berberina da sola e in combinazione con ampicillina contro Stafilococco
aureus resistente alla meticillina
Attività antimicrobiche (verso i batteri) della berberina
- Inibizione della produzione di biofilm batterici in fase di ADESIONE E DI
STABILIZZAZIONE (legame con proteine beta amiloidi del biofilm)
Semi di pompelmo
• L’estratto di semi di Pompelmo è ricavato dai semi e dalle
membrane del frutto disidratato.
• I flavanoni presenti in elevata concentrazione influenzano la
funzionalità di membrana di numerosi batteri. In questo modo
l’estratto ha un’azione sull’equilibrio microbiotico inibendo la
proliferazione di alcuni ceppi patogeni. Interessante anche
l’attività di sostegno al microcircolo***
* Citrus grandis L. (pompelmo) Estratto secco di semi
- titolato in bioflavonoidi (flavanoni) 50%
- Azione antimicrobica e regolatrice del microbiota intestinale
Attività antimicrobica dei semi di
pompelmo
Aglio
• L’allicina è un composto solforato che la pianta di aglio
produce per difendersi dai parassiti come funghi e batteri.
• Il suo caratteristico odore pungente può essere fastidioso
dopo assuzione orale. Per questo motivo la formulazione del
Candex contiene un estratto dearomatizzato.
• L’estratto di aglio ha una funzione digestiva e antiossidante*
Allium sativum L. (aglio) Estratto secco di bulbi
titolato in allicina (1%)
- azione antibatterico, antielmintica, antimicotica e
antisaccaromiceti4
Scanning electron
microscopy pictures of
growing UPEC CFT073
biofilm. Biofilm
architecture was
investigated via SEM in the
presence or absence of
allicin. The images were
untreated control (A) or
treated with 12 µg/mL (B);
25 µg/mL (C); and 50
µg/mL (D) of allicin
Origano
• L’estratto secco di Origanum contiene sostanze volatili
aromatiche prodotte dalla pianta per difendersi da parassiti
come batteri e funghi. Contribuisce alla normale regolarità
intestinale e all’eliminazione di gas ****
Origano (estratto secco di foglia)
ricco in carvacrolo e timololo
 Inibisce la proliferazione eccessiva della Candida
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Commensal Fungi in Health and Disease
FUNGAL COMMUNITIES IN HEALTHY CONDITIONS
ARE DIFFERENT THAN IN DISEASE CONDITIONS
Mucor spp. were specifically noted as more prevalent in
non-obese controls compared to obese subjects, and the
decreased relative abundance of Mucor in obese
subjects was reversed when patients lost weight.
It is uncertain whether these mycobiota changes are
simply a marker for obesity or whether fungal dysbiosis
can actually contribute to the pathogenesis of obesity.
If the latter is true, this could suggest that the mycobiota
may be a potential therapeutic target to combat obesity
and related metabolic disorders.
yeasts (Cryptococcus neoformans, Candida spp., Trichosporon spp.)
moniliaceous moulds (Aspergillus spp., Fusarium spp.)
Mucoromycetes (Mucor spp., Rhizopus spp.)
dimorphic fungi (Blastomyces dermatitidis, Coccidioides spp., Histoplasma capsulatum),
dematiaceous fungi (Cladophialophora bantiana, Exophiala dermatitidis).
Pazienti immunocompromessi
Infezione per inalazione o procedure mediche
Trattamento con triazoli in grado
di passare barriera
ematoencefalica
ISAVUCONAZOLO
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Aspergillus
fumigatus
is the most
important FFHP,
involving 85–90% of
invasive aspergillosis
Dott. Maurizio Salamone Sett-2018
Human Gut Mycobiota
• Human Gut Mycobiota
• Classification of the most important genera (resident and transient)
• Interactions with host, bacterial community
• From mutualism to fulminant pathogenicity
• Fungal metabolites of clinical and diagnostic interest
• Mycobiota and immune system
• Mycobiota and the diet
• Equilibrium of the intestinal ecosystem FGID's and MICI
• Probiotic action of Saccharomices boulardii
• Candida albicans and candidiasis
• Mucor sp., how little we know about you..
• Saccharomyces cerevisiae, other yeasts and molds
• Overview of drug therapy in fungal overgrowths
Science 18 May 2018: Vol. 360, Issue 6390, pp. 739-742
La grande famiglia
dei disinfettanti intestinali
• Antibiotici sistemici
- metronidazolo, macrolidi, fluorchinolonici, ciclosporine
• Antibiotici ad azione locale
- Rifaximina, vancomicina
• Batteriostatici
– Bacitracina, neomicina
• Antimicotici
– Nistatina, fluconazolo, metroimidazolo
• Ecomodulatori intestinali
– Miscele di sostanze naturali in grado di
modularela presenza relativa di gruppi di
simbionti (con azione antimicrobica leggera)
Evidenze cliniche per un approccio sinergico con
estratti vegetali
104 Pazienti trattati con rifaximina o estratti di piante per 4 settimane
Gli estratti vegetali di Metagenics erano efficaci e meglio tollerati di rifaximina 1,2g/die in
pazienti con SIBO (positivi al breath test con lattulosio)
Successo terapeutico in 17 su 37 (46%) rispetto ai 23/67 di rifaximina (34%)
Minori effetti indesiderati nel gruppo con estratti vegetali (meno diarrea).
La presa in carico del paziente in medicina
funzionale con la strategia delle 4R
Rimuovere Le cause di squilibrio
dell’ecosistema intestinale
1. Parassiti (elminti)
2. Microbi patogeni
3. Allergeni alimentari
4. Nutrienti in eccesso
5. Alcool e tossici xenobionti
Rimpiazzare Quello che manca per una
corretta digestione
1. Enzimi digestivi
2. Sali biliari
3. Modulazione acidità
gastrica
Reinoculare Simbionti probiotici
preparando loro il terreno
Probiotici
Lactobacillus acidophilus NCFM,
Bifidobacterium lactis Bl-07 NH019 Saccharomices
boulardii
Prebiotici (fos e inuline)
Riparare Mantenere la salute degli
enterociti e la funzione di
barriera intestinale
Glutammina, vitamine,
minerali, antiossidanti
curcumina, quercetina
Science 18 May 2018: Vol. 360, Issue 6390, pp. 739-742
Contatti: msal37@gmail.com +39 3663461468
https://www.linkedin.com/in/mauriziosalamone
http://www.slideshare.net/Maurizio37
https://www.facebook.com/maurizio.salamone
Maurizio Salamone, biologist
Science Manager - Metagenics Italia srl.
Società Internazionale di Neuropsicocardiologia
Disclaimer:
Maurizio Salamone is a Metagenics Italia srl employe

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Human Gut Mycobiota

  • 2. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 3. Pubmed search for Mycobiota 24 Settembre 2018 370 results Filter «Humans» «In the last 5 Years 49 results 16 Reviews
  • 4. PROBIOTICI Bacterial Yeast Prokaryotic (DNA loose in cytoplasm) Eukaryotic (nucleus) Small Large size AB-resistant genes + transfer between ≠ spp No antibiotic-resistant genes Affected by AB Not affected by AB Resistant to proteolysis S. boulardii: more persistent, optimum growth at 37°C, resistant to low pH (survival gastric acidiy), tolerant to bile salts Dth: 1-2 x 1010 /day  concstool: 2 x 108 / g stool Steady state: three days Telim: 3-5 days Elmer et al. found that some types of fiber (psyllium) increased SB levels by 22 %
  • 5. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 6. Figure 1. The archaeal and fungal components of the human gut microbiome. Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019 UPDATE CLASSIFICATION Mycobank http://www.mycobank.org/ Index Fungorum http://www.indexfungorum.org/ names/names.asp
  • 7. Figure 2. Analysis of co-occurrence among microbial lineages scored using the Dice index. Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
  • 8. Nat Rev Immunol. 2017 Oct;17(10):635-646. «1 miliardo di anni fa funghi e animali si sono staccati dal ramo evolutivo delle piante trovando nelle nuove vie evolutive molti modi di interazione mutualmente reciproca»
  • 9. Figure 3. Inter-generic relationships. Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
  • 10. Gut Mycobiota 13% of total microbiota (wheight) 140 genus mainly Basidiomycota and Ascomycota - Schei et al. Microbiome (2017) 5:107 - Hamad et al. Repertory of eukaryotes (eukaryome) in the human gastrointestinal tract: taxonomy and detection methods. Parasite Immunol. 2016;38:12–36
  • 11. Gut Mycobiota RESIDENTI IN TRANSITO - Temperature 37° - Low oxigen atmosphere - Wide pH variations - Biliar salts - Gastric acid - Digestive enzimes
  • 12. FEMS Microbiol Rev. 2017 Jul 1;41(4):479-511. doi: 10.1093/femsre/fuw047. Forgotten fungi-the gut mycobiome in human health and disease.
  • 13. Gut Mycobiota Hamad et al. Repertory of eukaryotes (eukaryome) in the human gastrointestinal tract: taxonomy and detection methods. Parasite Immunol. 2016;38:12–36
  • 14. FEMS Microbiol Rev. 2017 Jul 1;41(4):479-511. doi: 10.1093/femsre/fuw047. Forgotten fungi-the gut mycobiome in human health and disease.
  • 15. Vaginal Mycobiota L. L. BRADFORD AND J. RAVEL Virulence 2017
  • 16. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 17. Int. J. Mol. Sci. 2017, 18, 330; doi:10.3390/ijms18020330
  • 18. Figure 6. Possible syntrophic relationships in the human gut consistent with data reported in this study. Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
  • 19.
  • 20.
  • 22.
  • 23. Ward et al. BMC Medicine (2017) 15:30 Infant Mycobiota
  • 24. Ward et al. BMC Medicine (2017) 15:30 Infant Mycobiota
  • 25. Nat Rev Immunol. 2017 Oct;17(10):635-646. Mycobiota & Dysbiosis
  • 26. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 27. Timeline of studies published on the gut mycobiome and colour coded as follows: major developments (grey), GI disease (blue), immunocompromised hosts (red), healthy populations (yellow), infants (purple), diet (green) and other (teal). FEMS Microbiol Rev. 2017 Jul 1;41(4):479-511. doi: 10.1093/femsre/fuw047. Forgotten fungi-the gut mycobiome in human health and disease.
  • 28.
  • 29. - 26 % (24/94) and 25.3 % (38/150) of a series of patients with unexplained GI symptoms had SIFO - symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas - small intestinal dysmotility and use of proton pump inhibitors are possible underlying mechanism(s) - a 2–3-week course of antifungal therapy is recommended and may be effective in improving symptoms, but evidence for eradication is lacking
  • 30. Current Opinion in Microbiology 2017, 40:58-64
  • 31.
  • 33. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 34. Mycobiota and th Human Exposome The chemical spectra of molecules in the organism is believed to account for : - about 40 nutrients - 2,000 intermediary metabolites - 200,000 peptides - 500.000 lipids - 400,000 sostanze chimiche - Circa 300 micotossine principalmente da Fusarium, Claviceps, Alternaria, Aspergillus, Candida e Penicillium (Marin et al., 2013). Molte di queste sono di origine batterica o fungina…
  • 35.
  • 36. Ricerca di Anticorpi anti- funghi e lieviti
  • 38. Ricerca di metaboliti fungini nelle urine per lo studio delle disbiosi
  • 39. Ricerca di metaboliti fungini nelle urine per lo studio delle disbiosi
  • 40. Disease Markers Volume 2018, Article ID 7451946, 16 pages https://doi.org/10.1155/2018/7451946 ASCA, I2, and OmpC altogether can be found in 80% of patients with CD
  • 41. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 42.
  • 43. Nature reviews Fungal Dysbiosis – 2017 Iliev, I. D., & Leonardi, I. (2017). Fungal dysbiosis: immunity and interactions at mucosal barriers. Nature Reviews Immunology, 17(10), 635–646. doi:10.1038/nri.2017.55
  • 44.
  • 45. Leonardi et al., Science 359, 232–236 (Gen. 2018)
  • 46. SIFO
  • 47. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 48. Fungi are presents in most of the food we eat
  • 49. Zuo, T., Kamm, M. A., Colombel, J.-F., & Ng, S. C. (2018). Urbanization and the gut microbiota in health and inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology, 15(7), 440–452. doi:10.1038/s41575-018-0003-z
  • 50. Zuo, T., Kamm, M. A., Colombel, J.-F., & Ng, S. C. (2018). Urbanization and the gut microbiota in health and inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology, 15(7), 440–452. doi:10.1038/s41575-018-0003-z
  • 51. Zuo, T., Kamm, M. A., Colombel, J.-F., & Ng, S. C. (2018). Urbanization and the gut microbiota in health and inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology, 15(7), 440–452. doi:10.1038/s41575-018-0003-z
  • 52. High-Fat Diet Changes Fungal Microbiomes and Interkingdom Relationships in the Murine Gut mSphere 2017 Oct 11;2(5). pii: e00351-17. doi: 10.1128/mSphere.00351-17. eCollection 2017 Sep-Oct.
  • 53.
  • 54. Decreased ethanol-induced liver disease in mice treated with antifungals.. jci.org Volume 127 Number 7 July 2017
  • 55. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 56.
  • 57.
  • 58. the Basidiomycota:Ascomycota ratio and the Candida albicans count were found to be increased, while Saccharomyces cerevisiae abundance decreased. Other species’ numbers found elevated in CD included Gibberella moniliformis, Alternaria brassicicola and Cryptococcus neoformans. It is of interest that fungal microbiota correlated with the CD activity index and the degree of inflammation expressed by C-reactive protein (CRP) concentration.
  • 59.
  • 60. Mycobiota e Dieta Hallen-Adams HE, Kachman SD, Kim J, Legge RM, Martınez I. Fungi inhabiting the healthy human gastrointestinal tract: a diverse and dynamic community. Fungal Ecol 2015; 15:9-17; http://dx.doi.org/10.1016/j.funeco. 2015.01.006 Suhr MJ, Banjara N, Hallen-Adams HE. Sequence-based methods for detecting and evaluating the human gut mycobiome. Lett Appl Microbiol 2016; 62:209-15; PMID:26669281; http://dx.doi.org/10.1111/lam.12539 _________
  • 61. Figure 5. Fungi-Diet relationships. Hoffmann C, Dollive S, Grunberg S, Chen J, Li H, et al. (2013) Archaea and Fungi of the Human Gut Microbiome: Correlations with Diet and Bacterial Residents. PLOS ONE 8(6): e66019. https://doi.org/10.1371/journal.pone.0066019 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066019
  • 62. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 63. McFarland LV, (2010). Systematic review and meta-analysis of Saccharomyces boulardii in adult patients, world J Gastroenterol, 16 (18), 2202-2222. Probiotics: live microorganisms that confer a health benefit on the host Saccharomyces boulardii (S.B.) •SB was found to be sign. efficacious and safe in 84% of all treatment arms (26/31), 27 ≠trials. •SB sign. effective in preventing antibiotic-associated diarrhea (AAD (p <0.001) •In adults, recommended for prevention of AAD and traveler’s diarrhea •Prevention of enteral nutrition related diarrhea and reduction of Heliobacter pylori treatment- related symptoms •Promise for prevention of C. difficile disease recurrences, irritable bowel syndrome, acute adult diarrhea, Chron’s disease, giardiasis, human immunodeficiency virus-related diarrhea McFarland LV, (2010). Systematic review and meta-analysis of Saccharomyces boulardii in adult patients, world J Gastroenterol, 16 (18), 2202-2222
  • 64. Potentially, probiotics maintain or restore gut microecology 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
  • 65.
  • 66.
  • 67.
  • 68.
  • 69.
  • 70. Date of download: 1/14/2014 Copyright © 2014 American Medical Association. All rights reserved. JAMA. 2012;307(18):1959-1969. doi:10.1001/jama.2012.3507
  • 71. Szajewska_2009 Szajewska H, Skórka A. Saccharomyces boulardii for treating acute gastroenteritis in children: updated meta-analysis of randomized controlled trials. Alimentary Pharmacology & Therapeutics 2009;30: 960–1. In conclusion, this update of our meta-analysis of data from RCTs confirms that in otherwise healthy infants and children, the use of S. boulardii is associated with clinical benefits in the treatment of AGE, specifically a reduction in the duration of diarrhoea by approximately 1 day. Saccharomyces boulardii: Meta-analysis using data from 7 RCTs: 944 healthy children with acute gastroenteritis. The duration of diarrhea was reduced with 1.08 days (95% CI: 0.53- 1.64) in children who received the yeast compared with placebo.
  • 72. Szajewska_2001: http://www.ncbi.nlm.nih.gov/pubmed/11698781 Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhoea in infants and children; a systematic review of published randomized, double-blind, placebo-controlled trials. Journal of Pediatric Gastroenterology and Nutrition 2001;33 Suppl 2:17–25. BACKGROUND: This review was designed to assess the evidence from randomized controlled trials on effects of probiotics in the treatment and prevention of acute infectious diarrhea in infants and children. METHODS: A systematic review of published, randomized, double-blind, placebo-controlled trials on probiotics in the treatment or prevention of acute diarrhea defined as >3 loose or watery stools per 24 hours in infants and children. RESULTS: The use of probiotics as compared with placebo was associated with a significantly reduced risk of diarrhea lasting >3 days. The pooled estimate risk was 0.43 (95% CI, 0.34-0.53) with a fixed-effect model, and remained significant in a random-effect model (0.40; 95% CI, 0.28-0.57). Only Lactobacillus GG showed a consistent effect. Probiotics significantly reduced the duration of diarrhea when compared with placebo, particularly in rotaviral gastroenteritis-the pooled, weighted, mean difference (WMD) assuming the random-effect model was -20.1 hours (95% CI, -26.1 to -14.2) and -24.8 (95% CI, -31.8 to -17.9) respectively. A meta-analysis of the prevention studies was not feasible because of significant clinical and statistical heterogeneity. CONCLUSIONS: There is evidence of a clinically significant benefit of probiotics in the treatment of acute infectious diarrhea in infants and children, particularly in rotaviral gastroenteritis. Lactobacillus GG showed the most consistent effect, although other probiotic strains may also be effective. Further research is needed. Clinical and statistical heterogeneity of the prophylactic interventions preclude drawing firm conclusions about the efficacy of probiotics in preventing acute gastroenteritis. The risk of diarrhea lasting three or more days was reduced by 0.40 in the probiotic compared with the placebo group (8 studies included; 731 children), and probiotics reduced the duration of diarrhea by 18.2 hours (n=8, 773 children).
  • 73. Van Niel_2002: http://pediatrics.aappublications.org/content/109/4/678 Van Niel CW, Feudtner C, Garrison MM, Christakis DA. Lactobacillus therapy for acute infectious diarrhoea in children: a meta-analysis. Pediatrics 2002;109(4):678–84. Objective. Childhood diarrhea accounts for substantial morbidity and mortality worldwide. Multiple studies in children have shown that Lactobacillus, administered orally, may have antidiarrheal properties. We conducted a meta- analysis of randomized, controlled studies to assess whether treatment with Lactobacillus improves clinical outcomes in children with acute infectious diarrhea. Methods. Studies were sought in bibliographic databases of traditional biomedical as well as complementary and alternative medicine literature published from 1966 to 2000. Search terms were “competitive inhibition,” “diarrhea,” “gastroenteritis,” “Lactobacillus,” “probiotic,” “rotavirus,” and “yog(h)urt.” We included studies that were adequately randomized, blinded, controlled trials in which the treatment group received Lactobacillus and the control group received an adequate placebo and that reported clinical outcome measures of diarrhea intensity. These inclusion criteria were applied by blind review and consensus. The original search yielded 26 studies, 9 of which met the criteria. Multiple observers independently extracted study characteristics and clinical outcomes. Data sufficient to perform meta-analysis of the effect of Lactobacillus on diarrhea duration and diarrhea frequency on day 2 were contained in 7 and 3 of the included studies, respectively. Results. Summary point estimates indicate a reduction in diarrhea duration of 0.7 days (95% confidence interval: 0.3– 1.2 days) and a reduction in diarrhea frequency of 1.6 stools on day 2 of treatment (95% confidence interval: 0.7– 2.6 fewer stools) in the participants who received Lactobacillus compared with those who received placebo. Details of treatment protocols varied among the studies. A preplanned subanalysis suggests a dose-effect relationship. Conclusion. The results of this meta-analysis suggest that Lactobacillus is safe and effective as a treatment for children with acute infectious diarrhea. Different lactobacilli strains. Probiotics reduced the duration of diarrhea with 0.7 days, and diarrhea frequency on day 2 by 1.6 (3 studies, 122 children).
  • 74. Szajewska_2007a Szajewska 2007b Szajewska H, Skórka A, Dylag M. Meta-analysis: Saccharomyces boulardii for treating acute diarrhoea in children. Alimentary Pharmacology & Therapeutics 2007;25: 257–64. AIM: To review evidence for the effectiveness of Lactobacillus casei GG (LGG) in treating acute infectious diarrhoea in children. METHODS: The following electronic databases were searched through August 2006 for studies relevant to acute infectious diarrhoea and LGG: MEDLINE, EMBASE, CINAHL and The Cochrane Library; additional references were obtained from reviewed articles. Only randomized-controlled trials (RCTs) were included. RESULTS: Eight RCTs (988 participants) met the inclusion criteria. Compared with controls, LGG had no effect on the total stool volume (two RCTs, n = 303). However, LGG was associated with a significant reduction in diarrhoea duration (seven RCTs, 876 infants, weighted mean difference, WMD -1.1 days (95% confidence interval, CI -1.9 to - 0.3), particularly of rotavirus etiology (WMD -2.1 days, 95% CI -3.6 to -0.6), risk of diarrhoea >7 days (one RCT, n = 287, relative risk 0.25, 95% CI 0.09-0.75) and duration of hospitalization (three RCTs, n = 535, WMD -0.58, 95% CI - 0.8 to -0.4; significance was lost in the random effect model). There was no reduction in the number of stools at any time interval. CONCLUSIONS: The use of LGG is associated with moderate clinical benefits in the treatment of acute diarrhoea in children. These findings should be interpreted with caution due to the important methodological limitations and heterogeneity of most of the studies. Studies involving Lactobacillus casei GG, L casei GG reduced the duration of diarrhea by 1.1 days (7 trials, 876 infants) and was particularly effective in rotavirus diarrhea (duration reduced by 2.1 days).
  • 75. Chmielewska 2008 Chmielewska A, RuszczyÅ„skiM, Szajewska H. Lactobacillus reuteri strain ATCC 55730 for the treatment of acute infectious diarrhea in children: a meta-analysis of randomized controlled trials. Metaanalysis 2008;10:32–6. Background Probiotics may be of help for the management of acute diarrhoea, however, the effect is strain specific and efficacy needs to be proven. Aim To test the efficacy and safety of Lactobacillus reuteri DSM 17938 derived from L. reuteri ATCC 55730 in children with acute diarrhoea. Primary outcomes were the rate of unresolved diarrhoea after 3 days of treatment and duration of diarrhoea. Methods Children (6–36 months), hospitalised in three paediatric hospitals in Southern Italy for acute diarrhoea with clinical signs of dehydration were randomised to receive in a double-blind fashion either L. reuteri (dose of 4 × 108 colony-forming units/die) or placebo. Results Out of 96 eligible children, 74 were enrolled, five patients were withdrawn; 35 in the L. reuteri group and 34 in the placebo group. Lactobacillus reuteri significantly reduced the duration of watery diarrhoea as compared with placebo (2.1 ± 1.7 days vs. 3.3 ± 2.1 days; P < 0.03); on day two and three of treatment watery diarrhoea persisted in 82% and 74% of the placebo and 55% and 45% of the L. reuteri recipients respectively (P < 0.01; P < 0.03). Finally, children receiving L. reuteri had a significantly lower relapse rate of diarrhoea (15% vs. 42%; P < 0.03). There was not a significant difference in hospital stay between the groups. No adverse events were recorded. Conclusion Our study shows that L. reuteri DSM 17938 as an adjunct to rehydration therapy is efficacious in the treatment of acute diarrhoea reducing the frequency, duration and recrudescence rate of the disease. Meta-analysis of 2 studies using Lactobacillus reuteri DSM 17938. This probiotic reduced the duration of diarrhea by 22 hours.
  • 76. Wolvers_2010 Wolvers D, Antoine JM, Myllyluoma E, Schrezenmeir J, Szajewska H, Rijkers GT. Guidance for substantiating the evidence for beneficial effects of probiotics: prevention and management of infections by probiotics. Journal of Nutrition 2010;140(3): 698S–712S. Sufficient consistent data exist for the management of infectious diarrhea in infants and traveler's diarrhea, antibiotic-associated diarrhea, and necrotizing enterocolitis to conclude that certain probiotics, under certain conditions, and in certain target populations, are beneficial in reducing the risk of infection. Different Bacterial strains and Saccharomyces boulardii. The beneficial effects of probiotics in acute infectious diearrhea were dependent on the strain of bacteria and the dose (a greater effect with doses >1010-1011 colony forming units (CFU/day)
  • 77. McFarland L.V, Meta-Analysis of Probiotics for the Prevention of Antibiotic Associated Diarrhea and the Treatment of Clostridium difficile Disease. American Journal of Gastroenterology 2006, 101: 812-822. Evidenze scientifiche dell’efficacia di Saccharomyces boulardii In caso di diarrea associata all’uso di antibiotici (DAA): Diarrea acuta
  • 78.
  • 79. Disbiosi - Clostridium Difficile Associated Diarrhea (CDAD**) - riduzione delle difese immunitarie - riduzione della sintesi di vitamine - alterazione della funzione di barriera intestinale (leaky gut) Antibiotici Riduzione della flora commensale Oltre il 30% dei pazienti Sviluppa una diarrea associata all’uso di antibiotici (DAA*) Conseguenze: Diarrea - riduzione della qualità di vita - doulori addominali - gonfiore - interruzione del trattamento con antibiotici *AAD = Antibiotics Associated Diarrhea *CDAD = Clostridium Difficile Associated Diarrhea
  • 80. The use of antibiotics that disturb the gastrointestinal flora is associated with clinical symptoms such as diarrhea, which occurs in as many as 30% of patients.1,2 Symptoms range from mild and self-limiting to severe, particularly in Clostridium difficile infections, and antibiotic-associated diarrhea (AAD) is an important reason for nonadherence with antibiotic treatment.3 Probiotics for the Prevention and Treatment of Antibiotic-Associated DiarrheaA Systematic Review and Meta-analysis JAMA. 2012;307(18):1959-1969. doi:10.1001/jama.2012.3507
  • 81. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 82.
  • 83.
  • 84.
  • 85.
  • 86.
  • 87. La medicina tradizionale si occupa principalmente delle candidosi vulvo vaginali e del cavo orale
  • 88. Linee guida SIMAT per le candidosi vulvo vaginali Agente eziologico: Candida albicans (80-92 %%), Candida glabrata, Candida spp. Feequenza: Il 75% delle donne ha avuto almeno 1 episodio di candidosi vaginale durante la propria vita. Il 40 - 45% due o più episodi. Sintomi:  prurito vulvare  dolore vulvare  secrezioni vaginali biancastre  dispareunia Superficiale Segni:  eritema  secrezioni  lesioni satellite  edema TRATTAMENTO FARMACOLOGICO PER I CASI SINTOMATICI (Il 20% delle donne ha colonizzazione ma non sintomi) Opzioni terapeutiche  Fluconazolo CPR 150 mg, 1 CPR monosomm.  Itraconazolo cpr 200 mg, 1/die per 3 giorni.  Itraconazolo cpr 200 mg, 1 x 2/die per 1 giorno.  Clotrimazolo crema 1% applicazione intravaginale (5 g) per 7 - 14 giorni.  Clotrimazolo candelette vaginali 100 mg per 7 ggi.  Clotrimazolo candelette vaginali 100 mg, 1 x 2/die per 3 giorni.  Clotrimazolo candelette vaginali 500 mg, 1 singola  Miconazolo crema 2% (5g) appl. Intravag. per 7gg.  Miconazolo 200 mg ovuli, 1 ovulo per 3 giorni.  Miconazolo 100 mg ovuli, 1 ovulo per 7 giorni.  Nistatina candelette vaginale 100,000 U, per 14 gg  Tioconazolo 6.5% (5 g) appl. intravaginale singola  Terconazolo 0.4% (5 g) appl. intravaginale per 7 gg
  • 89. La Candida, in quanto fungo, è indifferente ai trattamenti con antibiotici- Semmai viene favorita da questi perchè vengono liberate nicchie ecologiche e create le premesse per una disbiosi
  • 91. SIFO
  • 92. Candida albicans è un normale abitante del nostro sistema digestivo. E’ presente in proporzioni molto piccole rispetto ad altri simbionti e non causa sintomi specifici. Un certo numero di fattori predisponenti, molto spesso legati alla dieta, possono causare lo sviluppo selettivo di Candida albicans nell'intestino. Candidosi Intestinale
  • 93. • CANDIDA ALBICANS (50 %) • CANDIDA TROPICALIS • CANDIDA PARAPSILOSIS • CANDIDA KRUSEÏ • CANDIDA PSEUDOTROPICALIS • CANDIDA GLABRA (TORULOPSIS) Candidosi Intestinale
  • 94. Candidosi Intestinale Le candidiasi croniche sono condizioni che colpiscono milioni di persone in tutto il mondo, ma sono paradossalmente poco considerate. Questa patologia è insidiosa perché non si accompagna a sintomi particolarmente evidenti, ma può indebolire il sistema immunitario e compromettere il potenziale di salute delle persone affette, con conseguenti disturbi funzionali.
  • 95. Candidosi Intestinali: Fattori predisponenti Lo squilibrio della flora intestinale, in seguito a trattamento con antibiotici, è uno dei principali fattori predisponenti la proliferazione della Candida. Tutti gli antibiotici sono implicati e alcuni (Tetracicline) hanno anche un effetto stimolante diretto sulla Candida.
  • 96. Le cause principali sono legate al regime dietetico: Un’alimentazione ricca di zuccheri raffinati; la Candida ama lo zucchero. E’ in grado di produrre peptidi che attraversano la barriera intestinale ed emato-encefalica che stimolano la voglia di zucchero. Tutti i tipi di zucchero sono coinvolti; i frutti dolci, l’eccesso di prodotti lattiero-caseari fermentati, di grassi saturi, possono alterare l’equilibrio della microflora intestinale. Numerosi farmaci, non solo gli antibiotici ma anche corisonici, la pillola anticoncezionale, gli inibitori di pompa protonica di uso così frequente per il trattamento di gastriti e Gerd La sovralimentazione in generale e in particolare quando le capacità digestine sono alterate Cattiva digestione: gastrite atrofica, ipocloridria etc Candidosi Intestinali: Fattori predisponenti
  • 97. • Infezioni da funghi della pelle e delle unghie • Stanchezza, affaticamento cronico o fibromialgia • Disturbi funzionali intestinali come gonfiore, o alterazioni alvo • Malattie autoimmuni quali la tiroidite di Hashimoto, l'artrite reumatoide, la colite ulcerosa, il lupus, la psoriasi, la scleroderma o la sclerosi multipla • Difficoltà di concentrazione e di memorizzazione • Eczemi, esacerbazione della psoriasi, orticaria e rash • Irritabilità, alterazioni dell'umore, ansia o depressione • Infezioni vaginali, infezioni del tratto urinario, prurito rettale o prurito vaginale • Allergie stagionali, febbre da fieno, riniti allergiche • Desiderio smodato di zuccheri e carboidrati Candidosi Intestinale: 10 sintomi più comuni
  • 98. La Candida produce almento 35 tossine conosciute: la più conosciuta è la candidina (la più neurotossica) - Le tossine alterano la funzione cerebrale. - Alterano la funzione immunitaria Nel medio termine provocano alterazioni sistemiche che coinvolgono diversi sistemi. Candidosi : Patogenesi e tossicità
  • 99. Le candida produce acetaldeide. L’ acetaldeide reagisce con un neurotrasmettitore del cervello, la dopamina, causando sintomi a carico del SNC e disturbi dell’umore e del comportamento come: depressione, ansia e attacchi di panico, irritabilità, sbalzi d’umore, difficoltà di concentrazine e di memorizzazione Candidosi Intestinale: Patogenesi
  • 101. Candidosi Intestinale: Patogenesi Le candida produce acido tartarico:
  • 102.
  • 103. Immediato senso di gonfiore intestinale subito dopo il pasto. La colite intestinale è probabilmente il sintomo più comune e probabilmente il più banale, della candidosi cronica. Disturbi funzionali intestinali cronicizzanti Candidosi Intestinale: Patogenesi
  • 104. • Gonfiore • Produzione di gas • Flatulenza • Tensione della parete addominale • Alterazioni del transito • Pirosi • Gerd Candidosi Intestinale: disturbi funzionali intestinali
  • 105. La candida aumenta la permeabilità intestinale. Una alterazione della permeabilità facilita il transito di molecole allergizzanti che provocano effetti sistemici dismetabolici Candidosi Intestinale: Patogenesi
  • 106. Disturbi neurofuzionali per carenza di minerali Ipereccitabilità neuromuscolare Disturbi del SNC da tossine Depressione Emicrania Allergie per alterazione della risposta immunitaria umorale Orticaria Eczemi Asma e ipersensibilità chimica multipla Candidosi Intestinale: disturbi extra-digestivi
  • 107. La candida può migrare dal tubo digestivo e aggredire l’apparato genitale e la pelle • Mughetto • Eczema micotico del cuoio capelluto, ascelle, torace. •Eczema micotico perianale •Candidosi dell’apparato uro-genitale
  • 108. Vaginite da Candida albicans Le infezioni fungine dei piedi e delle unghie dei piedi sono di solito secondarie all’eccessivo sviluppo del fungo nel tratto digestivo.
  • 110. La Candida è molto sensibile al pH intestinale Una dieta alcalina non è GRADITA.....
  • 112. Candidosi: diagnostica di laboratorio Analisi delle feci
  • 113. Candidosi: diagnostica di laboratorio -Coprocultura (esame delle feci, spesso negativo) - IgG, IgA and IgM anticorpi specifici per Candida Molti falsi negativi per la capacità immunosoppressive del lievito - Ematocrito completo Si può riscontrare aumento dei leucociti o un pattern di riduzione nei leucociti e aumento dei neutrofili Il calo dei linfociti T4 (CD4) associato ad un calo del rapporto tra linfociti T4/ linfociti t( (CD4/CD8) attesta la ridotta efficacia dell’immunità cellulare. -Test dei metaboliti disbiotici nelle urine La presenza di metaboliti fungini in eccesso (Es. D-Arabinitolo) è indice di disbiosi e di sovracrescita fungina -Reattività alla Candidina (principale tossina prodotta dal lievito)
  • 114. Il trattamento della candidiasi cronica deve essere protratto meticolosamente per diversi mesi per ottenere risultati sostenibili. Il ritorno alle vecchie abitudini alimentari frequentemente causa ricadute. Candidosi Intestinale-Trattamento
  • 115.  RIDURRE DRASTICAMENTE GLI ZUCCHERI Evitare cibi ad alto contenuto di carboidrati, zucchero raffinato (saccarosio, fruttosio), succhi di agrumi, miele, sciroppo d'acero, frutta in genere, ad eccezione di mele, ciliegie, frutti di bosco, pere. Il riso ok perchè viene digerito rapidamente Limitare il consumo eccessivo di verdure ricche di carboidrati come patate, mais  AIUTARE LA DIGESTIONE in generale e in particolare quella DEI CARBOIDRATI se necessario integrando con enzimi digestivi Candidosi Intestinale-Trattamento
  • 116. Qualche alimento vietato Zucchero di canna o raffinato Miele Siroppo d’acero Melasse Marmellate e gelatine di frutta Gelati, creme e budini Bevande zuccherate (gassate e non) Farine raffinate (pane, pasta biscotti) Pizza, brioches Riso bianco raffinato Fecola di patate Carote Mais Semolino cous cous Cereali in fiocchi per la colazione Riso soffiato Cioccolato non fondente >70% Candidosi Intestinale Trattamento DIETETICO DIETA PALEO AUTOIMMUNE
  • 117. Alimenti accettati Cereali integrali senza glutine Pane di miglio Riso integrale Fave e farina di fave Ceci e farina di ceci Lenticchie Quore di palma Pomodoro Radicchio Funghi Carciofi Insalate verdi Spinaci Piselli feschi o secchi Candidosi Intestinale Trattamento
  • 118. Igiene Intestinale I probiotici sono indispensabili per contrastare lo sviluppo di Candida, che è inibita da batteri lattici e bifidobatteri della flora intestinale. Soprattutto dopo trattamenti ripetuti con antibiotici ripetuti, la flora è danneggiata e non può esercitare il suo ruolo di modulazione e di controllo della crescita di agenti patogeni che possono colonizzare l'intestino. Diversi ceppi probiotici come il Lactobacillus acidophilus NCFM e il Saccharomices boulardi hanno dimostrato efficacia nell'inibire la crescita di Candida. Il trattamento con probiotici deve essere continuato per mesi. Candidosi Intestinale Trattamento
  • 119. Disturbi funzionali intestinali cronici: origine fungina o parassitaria • Approccio? - Combattere ed eliminare le cause - Riequilibrare l’ecosistema intestinale - Agire direttamente sul microbiota con probiotici - Modifiche dietetiche e dello stile di vita  (disbiosi di origine fungina)
  • 120. Estratti Vegetali ad Azione Antifungina • Acidi grassi a media catena l'acido undecenico l'acido laurico o monolaurina (prodotti come Lauricidin) • acido caprilico • Uncaria tomentosa • Pau d'arco • Oli essenziali di timo, origano o bergamotto • Coptide (ranunculacea) • Tea tre oil • Semi di pompelmo • Berberina (da Berberis aristata o Hydrastis) • Estratti d’aglio (Allicina)
  • 121. Acido caprilico • L'acido caprilico (nome IUPAC, acido ottanoico) è un acido carbossilico. • A temperatura ambiente si presenta come un liquido incolore dall'odore tenue, corrosivo, oleoso poco solubile in acqua dall’odore sgradevole (rancido). • Si trova in natura nella noce di cocco e nel latte materno.  Caprilato di calcio: da acidi grassi a media catena del cocco - azione antimicotica1 - disturba la produzione della parete cellulare della Candida - inibisce la proliferazione eccessiva della Candida
  • 122.  Acido caprilico e caprico inibiscono la formazione micellare di candida a bassa concentrazione e sono utilizzabili anche per uso locale nelle infezioni del cavo orale
  • 123.  Il Saccharomices boulardii contrasta la Candida secernendo acido caprilico e inibisce la sua diffusione
  • 124. Berberis aristata DC La berberina, utilizzata da secoli nelle medicine tradizionali per numerose finalità. La sua azione più conosciuta e di contribuire alla regolazione del metabolismo del colesterolo. Azione supportata da numerosi studi clinici. • La berberina può inoltre supportare lo sviluppo di microrganismi non patogeni simbionti nel nostro intestino e contribuire ad una normale funzione dell’apparato GI ** Berberis aristata DC Estratto secco di corteccia Titolato in berberina (>95%) - supporta lo sviluppo di microrganismi non patogeni simbionti nel nostro intestino - contribuisce ad una normale funzione dell’apparato gastrointestinale - inibisce la acil-CoA: sterol aciltrasferasi di Candida albicans3
  • 125.
  • 126. La berberina è un alcaloide presente in numerose specie vegetali e in particolar modo nel genere Berberis. Nuove evidenze mostrano un’attività della berberina su Candida albicans. La berberina: - -provoca aumento della permeabilità di membrana e depolarizzazione della membrana cellulare in colture di Candida - Inibisce la trasformazione di Candida in forma di ife (che invadono altri tessuti) - Azione sinergica con anfotericina, miconazolo e fluconazolo - Lo studio ha confermato un’azione anti candida e stabilito MIC 17.75 μg/mL - La berberina può indurre apoptosi nella Candida per aumento dei ROS - La berberina induce un cambiamento nel metabolismo degli steroli in Candida inibendo la produzione di ergosterolo
  • 127. Attività della berberina da sola e in combinazione con ampicillina contro Stafilococco aureus resistente alla meticillina
  • 128. Attività antimicrobiche (verso i batteri) della berberina - Inibizione della produzione di biofilm batterici in fase di ADESIONE E DI STABILIZZAZIONE (legame con proteine beta amiloidi del biofilm)
  • 129.
  • 130.
  • 131. Semi di pompelmo • L’estratto di semi di Pompelmo è ricavato dai semi e dalle membrane del frutto disidratato. • I flavanoni presenti in elevata concentrazione influenzano la funzionalità di membrana di numerosi batteri. In questo modo l’estratto ha un’azione sull’equilibrio microbiotico inibendo la proliferazione di alcuni ceppi patogeni. Interessante anche l’attività di sostegno al microcircolo*** * Citrus grandis L. (pompelmo) Estratto secco di semi - titolato in bioflavonoidi (flavanoni) 50% - Azione antimicrobica e regolatrice del microbiota intestinale
  • 132. Attività antimicrobica dei semi di pompelmo
  • 133. Aglio • L’allicina è un composto solforato che la pianta di aglio produce per difendersi dai parassiti come funghi e batteri. • Il suo caratteristico odore pungente può essere fastidioso dopo assuzione orale. Per questo motivo la formulazione del Candex contiene un estratto dearomatizzato. • L’estratto di aglio ha una funzione digestiva e antiossidante* Allium sativum L. (aglio) Estratto secco di bulbi titolato in allicina (1%) - azione antibatterico, antielmintica, antimicotica e antisaccaromiceti4
  • 134.
  • 135.
  • 136. Scanning electron microscopy pictures of growing UPEC CFT073 biofilm. Biofilm architecture was investigated via SEM in the presence or absence of allicin. The images were untreated control (A) or treated with 12 µg/mL (B); 25 µg/mL (C); and 50 µg/mL (D) of allicin
  • 137.
  • 138.
  • 139. Origano • L’estratto secco di Origanum contiene sostanze volatili aromatiche prodotte dalla pianta per difendersi da parassiti come batteri e funghi. Contribuisce alla normale regolarità intestinale e all’eliminazione di gas **** Origano (estratto secco di foglia) ricco in carvacrolo e timololo  Inibisce la proliferazione eccessiva della Candida
  • 140.
  • 141.
  • 142. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 143. Commensal Fungi in Health and Disease FUNGAL COMMUNITIES IN HEALTHY CONDITIONS ARE DIFFERENT THAN IN DISEASE CONDITIONS Mucor spp. were specifically noted as more prevalent in non-obese controls compared to obese subjects, and the decreased relative abundance of Mucor in obese subjects was reversed when patients lost weight. It is uncertain whether these mycobiota changes are simply a marker for obesity or whether fungal dysbiosis can actually contribute to the pathogenesis of obesity. If the latter is true, this could suggest that the mycobiota may be a potential therapeutic target to combat obesity and related metabolic disorders.
  • 144.
  • 145. yeasts (Cryptococcus neoformans, Candida spp., Trichosporon spp.) moniliaceous moulds (Aspergillus spp., Fusarium spp.) Mucoromycetes (Mucor spp., Rhizopus spp.) dimorphic fungi (Blastomyces dermatitidis, Coccidioides spp., Histoplasma capsulatum), dematiaceous fungi (Cladophialophora bantiana, Exophiala dermatitidis). Pazienti immunocompromessi Infezione per inalazione o procedure mediche
  • 146. Trattamento con triazoli in grado di passare barriera ematoencefalica ISAVUCONAZOLO
  • 147. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 148. Aspergillus fumigatus is the most important FFHP, involving 85–90% of invasive aspergillosis
  • 149.
  • 150. Dott. Maurizio Salamone Sett-2018 Human Gut Mycobiota • Human Gut Mycobiota • Classification of the most important genera (resident and transient) • Interactions with host, bacterial community • From mutualism to fulminant pathogenicity • Fungal metabolites of clinical and diagnostic interest • Mycobiota and immune system • Mycobiota and the diet • Equilibrium of the intestinal ecosystem FGID's and MICI • Probiotic action of Saccharomices boulardii • Candida albicans and candidiasis • Mucor sp., how little we know about you.. • Saccharomyces cerevisiae, other yeasts and molds • Overview of drug therapy in fungal overgrowths
  • 151. Science 18 May 2018: Vol. 360, Issue 6390, pp. 739-742
  • 152.
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  • 156.
  • 157. La grande famiglia dei disinfettanti intestinali • Antibiotici sistemici - metronidazolo, macrolidi, fluorchinolonici, ciclosporine • Antibiotici ad azione locale - Rifaximina, vancomicina • Batteriostatici – Bacitracina, neomicina • Antimicotici – Nistatina, fluconazolo, metroimidazolo • Ecomodulatori intestinali – Miscele di sostanze naturali in grado di modularela presenza relativa di gruppi di simbionti (con azione antimicrobica leggera)
  • 158. Evidenze cliniche per un approccio sinergico con estratti vegetali 104 Pazienti trattati con rifaximina o estratti di piante per 4 settimane Gli estratti vegetali di Metagenics erano efficaci e meglio tollerati di rifaximina 1,2g/die in pazienti con SIBO (positivi al breath test con lattulosio) Successo terapeutico in 17 su 37 (46%) rispetto ai 23/67 di rifaximina (34%) Minori effetti indesiderati nel gruppo con estratti vegetali (meno diarrea).
  • 159. La presa in carico del paziente in medicina funzionale con la strategia delle 4R Rimuovere Le cause di squilibrio dell’ecosistema intestinale 1. Parassiti (elminti) 2. Microbi patogeni 3. Allergeni alimentari 4. Nutrienti in eccesso 5. Alcool e tossici xenobionti Rimpiazzare Quello che manca per una corretta digestione 1. Enzimi digestivi 2. Sali biliari 3. Modulazione acidità gastrica Reinoculare Simbionti probiotici preparando loro il terreno Probiotici Lactobacillus acidophilus NCFM, Bifidobacterium lactis Bl-07 NH019 Saccharomices boulardii Prebiotici (fos e inuline) Riparare Mantenere la salute degli enterociti e la funzione di barriera intestinale Glutammina, vitamine, minerali, antiossidanti curcumina, quercetina
  • 160. Science 18 May 2018: Vol. 360, Issue 6390, pp. 739-742
  • 161. Contatti: msal37@gmail.com +39 3663461468 https://www.linkedin.com/in/mauriziosalamone http://www.slideshare.net/Maurizio37 https://www.facebook.com/maurizio.salamone Maurizio Salamone, biologist Science Manager - Metagenics Italia srl. Società Internazionale di Neuropsicocardiologia Disclaimer: Maurizio Salamone is a Metagenics Italia srl employe