Il microbiota come mediatore dell interazione tra l uomo e le sostanze che ingerisce

Transcription

1 Cosmofarma(BO), Il microbiota come mediatore dell interazione tra l uomo e le sostanze che ingerisce Marina Elli, PhD

2 Multifactorial determinants shaping human microbiome (Blandino et al. 2016)

3 Resilience Resistence of the ecosystem If the gut microbiota normally exists in a stable state, how resistant is this state to change in response to different perturbations? Resilience is the amount of stress or perturbation that can be tolerated before a system s trajectory changes towards a different equilibrium state (Greenhalgh et al. 2016)

4 Healthy functional core microbiota 2016 core microbiota come un pool di funzioni genetiche e metaboliche realizzate dal microbiota in un particolare habitat (non necessariamente dagli stessi micoorganismi) (Lloyd-Price et al. 2016)

5 Healthy core microbiota HMP Nature 486 (2012)

6 Healthy functional core microbiome HMP Nature 486 (2012)

7 Biunivocal relationship between host& microbiota Pharmacological interventions Nutritional status Circadian rhythm Phatology Environmental influences

8 Drugs& Bugs.the ultimate fate of drugs has been substantially neglected especially with reference to the role of gut microbiota in drugs degradation low solubility new drug candidates as well as slow-release formulations represent a large reservoir of substrate for colon bacteria raising the need for the early assessment of drug stability in the presence of gut bacteria. Not all individuals respond to drug treatment in the same way, with lack of efficacy and adverse drug reactions (particularly idiosyncratic toxicity) representing a major cause of concern for both clinicians and the pharmaceutical industry

9 Degradative activity on drugs by gut microbial enzymes AZOREDUCTASES: sulfonamides used for MICI degraded in the small intestine NITROREDUCTASES: benzodiazepine che generano composti teratogeni HYDROLASES: degradazione del lattulosio SUCCINATE GROUPS REMOVAL: sulfathiazolo DEHYDROXYLATION: decarbossilazione di L-dopa ACETYLATION: mesalazina DEACETYLATION: phenacetin CUTTING N-OXIDE BONDS: Taglio di legami N-oxide (ranitidina) PROTEOLYSIS: insulina e calcitonina

10 Mechanisms of interaction drugs / microbes with impact on bioavailability, efficacy and adverse effects «..microbiome-encoded enzymes, now represent plausible intermediate targets to alter drug pharmacokinetics (absorption, distribution, metabolism and elimination) to consequently enhance clinical response (Enright et al. 2016)

11 Example of transient inactivation of bacterial enzymatic activity The selective inhibition of bacterial β-glucuronidases was recently shown to alleviate drug-induced gastrointestinal toxicity in mice, including the damage caused by the widely used anticancer drug irinotecan (Wallace et al. 2015)

12 Mechanisms of interaction drugs / microbes with impact on bioavailability, efficacy and adverse effects Microbe-mediated bioactivation of pro-drug formulations Microbial biotransformation and generation of bioinactive and toxic metabolites Microbe-mediated alteration of drug absorption Microbe-mediated deconjugation Microbe-mediated drug inactivation Microbe-mediated alteration of host drug metabolism Intervention by transient inactivation of the microbiome (ehnancing microbe-to-microbe competition, antibiotics, bacterial enzyme inactivation) Intervention by probiotics New therapeutic opportunities Microbiota-oriented drug discovery Personalized medicine

13 MODE approach

14 Studying the approach of an antibiotic on GIT microbiota Antibiotic Evaluation of the impact of the antibiotic on the GI microbiotaof IBS adult 15 adult patients(18-75 years) assuming 550 mg of antibiotic3 timesper dayfor15 days Fecal sampling T0, T14 days, T56 days(wash-out) Plate count of 5 bacterial groups antibiotic-resistant Identification of colonies Ab-resistant DGGE analysis of major bacterial profiles quantitative RT-PCR Microbial ecology by NGS

15 bac01_001_t0 bac04_002_t0 bac07_003_t0 bac10_004_t0 bac13_005_t0 bac16_006_t0 bac19_007_t0 bac22_008_t0 bac25_009_t0 bac28_010_t0 bac31_011_t0 bac34_012_t0 bac37_013_t0 bac40_014_t0 bac43_015_t0 bac02_001_t14 bac05_002_t14 bac08_003_t14 bac11_004_t14 bac14_005_t14 bac17_006_t14 bac20_007_t14 bac23_008_t14 bac26_009_t14 bac29_010_t14 bac32_011_t14 bac35_012_t14 bac38_013_t14 bac41_014_t14 bac44_015_t14 bac03_001_t56 bac06_002_t56 bac09_003_t56 bac12_004_t56 bac15_005_t56 bac18_006_t56 bac21_007_t56 bac24_008_t56 bac27_009_t56 bac30_010_t56 bac33_011_t56 bac36_012_t56 bac39_013_t56 bac42_014_t56 bac45_015_t56 (Soldi et al. 2015) Bifidobacterium Coprococcus Subdoligranulum Bifidobacterium Bacteroides Parabacteroides Prevotella Alistipes Streptococcus Clostridium Anaerostipes Blautia Coprococcus Lachnospiraceae_IS Lachnospira Roseburia Peptostreptococcaceae_IS Faecalibacterium Ruminococcaceae_IS Oscillibacter Ruminococcus Subdoligranulum unc_ruminococcaceae Dialister Phascolarctobacterium Veillonella Escherichia other Figure 1d Genus clusters: Barplots of taxonomical classification of sequences for times 0 (left), 14 (middle) and 56 (right).

16 Rapporto biunivoco tra microbiota e ospite Pharmacological interventions Nutritional status Circadian rhythm Phatology Environmental influences

17 Microbe-to-Human relationships (De Vos WM, 2012) (De Vos WM, 2012)

18 Mechanisms of interaction food / microbes with impact on bioavailability, efficacy and adverse effects Human gut microbiota responds rapidly to diet change Long-term dietary habits are one of the driving forces of the hgm Personalized nutrition Change in diet variably alters hgm on different people

19 Human gut microbiota responds rapidly to diet change * (Tagliabue et al Clinical Nutrition)

20 High-plant polysaccharide diet & human microbiota (De Filippo et al. 2010)

21 Change in diet variably alters human gut microbiota on different people Faecal bifidobacteria (log 10 CFUs) 11,00 10,00 9,00 8,00 7,00 Subgroup 1 Subgroup 2 6,00 Day 0 Day 15 Day 30 Day 60 FIGURE 1 Comparison of the mean bifidobacteria faecal counts (in log10 CFUs) of the two subgroups of psyllium seed husk-treated volunteers at 4 different time points (Day 0, Day 15, Day 30 and Day 60). Grey bars refer to women presenting less thank 10 log10 CFUs at Day 0 (Subgroup 2). Dot bars show average faecal bifidobacteria counts of subjects presenting equal or more than 10 log10 CFUs per g of wet faeces at Day 0(Subgroup 1). (Elli et al. 2008)

22 Modulation of human microbiome (Sonnenburg & Backed 2016)

23 Mechanisms of interaction food / microbes with impact on bioavailability, efficacy and adverse effects Human gut microbiota responds rapidly to diet change Intervention by transient suppression / modulation of dietary components New dietary opportunities Long-term dietary habits are one of the driving forces of the hgm Personalized nutrition Change in diet variably alters hgm on different people Intervention by probiotics Microbiota-oriented diet management

24 Grazie per l attenzione!!