Annamaria Staiano. Il terreno su cui si semina: Immunità e Microbiota

Transcription

1 Annamaria Staiano Il terreno su cui si semina: Immunità e Microbiota

2 Il terreno su cui si semina: Immunità e Microbiota Outline Sviluppo e composizione del microbiota intestinale Fattori che influenzano lo sviluppo del microbiota (dieta, etc) Influenza del microbiota sul sistema immune

3 Initial gut bacteria (founder species) depends upon delivery mode Vaginal delivery: -Lactobacillus, Prevotella spp -Vertical inheritance from mother C-section: Staphylococcus Corynebaterium Propionibacterium spp -Higher susceptibility to certain pathogens -Higher risk of atopic disease New strains (less certain in origin) outcompete old ones -Rapid increase in diversity -Early microbiota in development=high instability -Shifts in response to diet, illness -Highly distinct, differentiate microbiota -Microbial community may continue to change, but at a slower rate than in childhood Substantially different gut communities than in younger adults Dominguez-Bello MG et al. Gastroenterology 2011;140:

4 Vaginal versus caesarean-section delivery C. T. Peterson et al. Clinical and Experimental Immunolog,2013; 179:

5 Strains, in particular Actinobacteria and Bacteroidetes, were maintained over time within an individual and between family members but not between unrelated individuals. Thus, early gut colonizers, such as those acquired from our parents and siblings, have the potential to exert their physiologic, metabolic, and immunologic effects for most, and perhaps all, of our lives. Faith JJ, et al. Science Jul 5;341(6141):

6 Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. In germ-free (GF) mice, invariant natural killer T (inkt) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. Colonization of neonatal but not adult GF mice with a conventional microbiota protected the animals from mucosal inkt accumulation and related pathology. These results indicate that agesensitive contact with commensal microbes is critical for establishing mucosal inkt cell tolerance to later environmental exposures. Olszak T et al. Science Apr 27;336(6080):

7 Charbonneau MR et al. Cell Feb 25;164(5):

8 The concept that impaired postnatal gut microbiota development(maturation) is causally related to childhood undernutrition. Blanton LV et al. Science Jun 24;352(6293):1533.

9 M. Wang et al. / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8

10 By using high-throughput 16S rdna sequencing and biochemical analyses, we found significant differences in gut microbiota between the two groups. BF children showed a significant enrichment in Bacteroidetes and depletion in Firmicutes (P < 0.001), with a unique abundance of bacteria from the genus Prevotella and Xylanibacter, known to contain a set of bacterial genes for cellulose and xylan hydrolysis, completely lacking in the EU children. De Filippo C et al. Proc Natl Acad Sci U S A Aug 17;107(33):

11 Early life stress can have a lifelong impact on the microbial content of the intestine and permanently alter immune functioning. Early disruption of the host-microbe interplay can have lifelong consequences, not just in terms of intestinal function but in distal organs including the brain. The immune system and nervous system are in continuous communication in order to maintain a state of homeostasis. The challenge now is to fully decipher the molecular mechanisms that link the gut microbiota, immune, and central nervous system. There is evidence to pinpoint key sites of communication where gut microbial interventions either with drugs or diet or perhaps fecal microbiota transplantation may positively impact mental health. Dinan TG, Cryan JF. Neuropsychopharmacology Jul 13.

12 S. El Aidy et al. ClinTher. 2015;37: ClinTher. 2015;37:

13 L istituto di ricerca Fatebenefratelli di Brescia sta analizzando il rapporto tra i batteri presenti nel nostro apparato digerente e alcune malattie neurologiche come l Alzheimer.

14 The microbiota plays important roles in physiological functions such as the maturation of the immune system, the degradation of complex food macromolecules and also behaviour. As such, the immune system has developed tools to cohabit with the microbiota, but also to keep it under control. When this control is lost, dysbiosis, i.e. deregulation in bacterial communities, can occur and this can lead to inflammatory disorders, including inflammatory bowel disease, obesity, diabetes and autism. Rescigno M et al. Cell Microbiol Jul;16(7):

15 Interplay of the host immune system and gut microbiota The human immune system must establish an appropriate balance between tolerance to the gut commensal microbiota and vigilance to guard against infectious agents and opportunistic pathogens. Immune surveillance of the gut commensal community involves the recognition of a diversity of pathogenassociated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and bacterial peptidoglycan cell wall components through Toll-like receptors (TLRs) and nucleotide binding oligomerization domain proteins (NODs). Endogenous and exogenous signals in the gut are recognized by a repertoire of innate immune cell pattern recognition receptors (PRRs) mediating the interaction between bacterial ligands and the host C. T. Peterson et al. Clinical and Experimental Immunolog,2013; 179:

16 Interplay of the host immune system and gut microbiota In a healthy gut environment (left panel), goblet cells secrete mucin to establish a physical barrier excluding direct contact of the gut microbiota from the underlying epithelium. Paneth cells produce a number of anti-microbial defensins that are embedded in the mucin layer. Dendritic cells extend into the lumen to sample the commensal communities potentially as a means of determining self. During pathological conditions (right panel), mucin barrier is compromised which facilitates microbial invasion through the epithelium and leads to inflammation. C. T. Peterson et al. Clinical and Experimental Immunolog,2013; 179:

17 Houghteling PD, Walker WA..J Pediatr Gastroenterol Nutr Mar;60(3):

18 The mammalian gut microbiota is involved in the intestinal homeostasis and shapes the adaptive immune system. The interaction between TLRs and different ligands induces CD8+ T activation and na ıve CD4+ T polarization towards Th17, Th1, and Treg subsets. The Th17 cells act against pathogens and promote autoimmune disease. The Th1 cells upregulate the production of proinflammatory cytokines, whereas Treg cells produce IL-10 and are involved in the maintenance of homeostasis and in a downregulation of inflammation. CD8+ T cells induce the IFN- and other cytotoxic mediators production. Valentini M et al. J Immunol Res. 2014;2014:586939

19 Bacterial components that affect innate and adaptive immunity in the intestine. Tomkovich S, Jobin C. Immunology Jan;147(1):1-10.

20 Microbiome innate-immune-system interactions are involved in multifactorial diseases Thaiss C. et al. Nature Jul 6;535(7610):65-74

21 Role of Intestinal Bacteria in the Pathogenesis of the Inflammatory Bowel Disease Animals kept under specific germ free conditions do not develop inflammation until bacteria are introduced Inflammation and lesions generally occur in intestinal regions with the highest number of bacteria Antibiotic treatment is a viable treatment option for some IBD patients Luminal and mucosa-associated microflora of IBD patients differs from healthy controls Diversion of the fecal stream induces clinical improvement in Crohn s patients Inflamm Bowel Dis 2009;15:

22 Sartor RB. Gastroenterology ;126:

23 T300A variant of autophagy ATG16L1 gene is associated with decreased antigen sampling and processing by dendritic cells in pediatric Crohn's disease. The main risk alleles gene NOD2 / CARD15, ATG16L1 and IRGM1, correlate with susceptibility to Crohn's disease (CD) through a reduction of 'autophagy BACT MFI% / DRCD11c+ * Wild Type Risk Het DC Bact DC+ Bact Wild Type=7 Risk=13 Het=13 ATG16L1 T300A is associated with reduced function of dendritic cells of pediatric patients with Crohn's disease Strisciuglio C. et al, Inflamm Bowel Dis. 2013;19:

24 Bifidobacteria enhance antigen sampling and processing by dendritic cells in pediatric IBD EVALUATION OF E.COLI PARTICLES UPTAKE BEFORE AND AFTER INCUBATION OF DENDRITIC CELLS WITH BIFIDOBACTERIA Bacteria particles (MFI) p=0.01* p=0.04* CD11c Bacteria Particles Before treatment with bifidobacteria *Wilcoxon test CD11c Bacteria Particles *Man-Withney test CD= CROHN UC= ULCERATIVE COLITIS HC= HEALTHY CONTROLS After treatment with bifidobacteria Strisciuglio C. et al, Inflam Bowel Dis 2015,

25 Disorders associated with alterations to the intestinal microbiota that could be treated by FMT. Smits LP et al.gastroenterology 2013;145:

26 Nutrients can have short- and long-term effects in shaping the composition of the microbiota. The microbiota and its metabolic machinery produce a myriad of metabolites that serve as important messengers between the diet, microbiota, and host. Short-chain fatty acids affect immune responses and epithelial integrity via Gprotein coupled receptors and epigenetic mechanisms. By increasing our understanding of interactions between diet, immunity, and the microbiota, we might develop food-based approaches to prevent or treat many diseases. There now is scientific evidence to support the adage we are what we eat, and this process begins in early life. Tilg and Moschen. Gastroenterology 2015;148:

27 A distributed network of brain regions showing decreases in the FMPP group during the emotional faces attention task is shown in the shaded regions. Three regions of interest selected from the network for study in the resting state are highlighted in pink (insula), green (periaqueductal gray), and blue (somatosensory regions). The change in network strength with intervention is depicted graphically. Tillisch K et al. GASTROENTEROLOGY 2013;144:

28 In children with IBS a mixture of Bifidobacterium infantis M-63, breve M-16V, and longum BB536 is associated with improvement in AP and QoL. These findings were not confirmed in FD subjects. Giannetti E. et al. J Clin Gastroenterol In press

29 The immune system and microbiota develop and mature together, beginning at birth, or even potentially in the womb. This early coexistence is likely essential in shaping the immune system response to avoid unwanted immune reactions to intestinal microbial components. An inappropriate response to indigenous bacteria could have deleterious consequences for the host as seen with inflammatory bowel diseases (IBD). Tomkovich S, Jobin C. Immunology Jan;147(1):1-10. Probiotics are important means to produce specific host benefits through different mechanisms, among which modification of the intestinal microbiota is noteworthy. Mol Nutr Food Res Aug 8. [Epub ahead of print]