Microbiota and Immune System PDF

Microbiota and Immune Response Microbiota & Immune System Co-evolved - 100 million years Associated not only with the local immune response but also with the systemic immune responses à signaling and regulation Role in response to cancer immunotherapies-precision therapies...

Microbiota and Immune Response Microbiota & Immune System Co-evolved - 100 million years Associated not only with the local immune response but also with the systemic immune responses à signaling and regulation Role in response to cancer immunotherapies-precision therapies Figure : Human-based approaches for studying microbiota-immune interactions Top panel: Longitudinal intervention studies in humans. A suggested model for microbiota-immune studies: starting with a cohort of participants that undergo a lifestyle intervention that perturbs the microbiota (diet, weight loss, antibiotic use, etc.). Participants are monitored over time, donating samples for both microbiota and immune system profiling. Candidate interactions between microbiota and immune features are identified using machine learning or other means. These interactions can then be studied in a mouse model and in vitro to elucidate their mechanistic underpinnings. Bottom panel: Traditional v. industrialized population studies. A suggested model for identifying microbes/microbial functionality relevant to lifestyle-related immune disorders: comparing the microbiome of individuals along a gradient of industrialized lifestyles. Focus should be placed on microbial elements that are shared across geographically distinct populations of similar lifestyles, but vary along a gradient of industrialization rather than geography. Once identified, those microbes along with their microbial genetic elements (Yellow markers in figure) or metabolites can be studied mechanistically in murine and in vitro models for their role in immune health or dysregulation.  Microbiota-accessible carbohydrates Ecological concepts applied to microbiota states (Costello et al., 2012). A suggested model for understanding microbial communities: Ancestral microbiomes represent stable communities different from those found in industrialized settings, with changes seen in overall diversity and in carbohydrate utilization capacity. Proposed drivers for this change over time are: dietary changes, more widespread use of antibiotics, increased sanitation contribute to microbiome configuration seen in industrialized settings. To restore beneficial aspects of our microbiota absent in western guts, we propose dietary changes, strain re-introduction, or possibly even Fecal Microbiota Transplant (FMT). The complexity of the microbial landscape An array of bacterial taxa (different colors represent different species) colonize the length of the GIT, the majority of which reside in the large intestine. Bacteria also may preferentially colonize the intestinal lumen, the mucus, or intestinal crypts in the epithelium. Bacteria of the same species may contain different genetic components as well as differential expression of genes (zoomed in box) allowing it to differentially process substrates and produce distinct metabolites, denoted by X and Y below box. Bacteria produce a variety of metabolites (pink hexagons) that modulate other bacteria as well as traffic across the intestinal barrier to influence the host. These diverse metabolites, including short-chain fatty acids (SCFA), indolepropionic acid (IPA), tryptamine and secondary bile acids modulate host cells both locally and systemically to influence host physiology as well as immune activation. Vice-versa Host immunity also plays a central role in diversity!!! Segmented Filamentous Bacteria 1. Some bacteria interact with host immunity because they produce metabolites that affect the immune system and/or proximity to host tissue. àAffecting Th17 ve IgA response SFB 2. It has not only intestinal barrier function-colonization resistance, but also systemic anti-fungal and antibacterial effects in general.  3. Clostridium sppà SCFA increaseà T regulatory cells 4. Bacteria in the colon mucosaàAnti infectious and anti tumour immune response—CD 8 T lymphocyte (CTL) etkileşimi üstünden CD 4 Thelper: Th1, Th2, Treg, Th17 CD 8 CTL Adaptive Cellular Immune Response Antibody mediated Adaptive Humoral Immune Response – B cells Bile acids Microorganism-derived secondary bile acids—they have anti-inflammatory properties, generally: they act through cytokines IL-10** increase IL-12 ve TNF-alpha adecrease--tolerance  Preventive and/or curative Diseasesàinfectionsà chronic conditions: Type 1-2 D, obesity, cancer etc Problems in immune regulation and chronic inflammation  VANISH (Volatile and/or Associated Negatively with Industrialized Societies of Humans) taxa Civilization/industrilization— predisposition to inflammatory diseases Therapeutic approaches related to microbiota-immune response interactions Change Diet—Change microbiota—regulate immune systemàdefeat disease Colonization resistance Prevention of pathogenic bacteria from invasion Inhibition of endogenous bacteria overgrowth which are present in a certain amount Protection against enteric pathogens Discovered mainly by detecting increased susceptibility to various enteric pathogens under the influence of atb Colonization resistance Fecal microbiota transplantation attempts to reshape a healthy microbiota in the sick person— re-establishing colonization resistance. Colonization resistance Commensal anaerobic bacteria-obligate anaerobes: various forms of barrier formation against enteric pathogens (facultative anaerobic bacteria) C.difficile** Gram negatif enterik bakteriler-patojen grup (fakültatifler)** Vankomisine dirençli Enterokoklar (VRE): Gram pozitif Listeria monocytogenes Metisiline dirençli Staphylokoklar (MRSA) Koagülaz negatif Staphylokoklar*biyofilm mg Colonization Resistance: Indirect vs Direct Epithelial barrier at the portals of entry The major interfaces between the body and the external The major interfaces between the body and the external environment—the skin, environmentà gastrointestinal tract, the skin, gastrointestinal tract, respiratory tract, and respiratory tract, and genitourinary tract—are genitourinary tract protected àare protected by layers of by layers of epithelial cells that epithelial cells that provide provide physical physical and chemical barriers and chemical barriers against against infection infection ingestion, inhalation, and sexual activity* Defensin, cathelicidin Gamma delta T cells Result Application of protective taxa as selective probiotics Use of certain microflora members in replacement therapy in nosocomial diseases C.difficile related colitis Damage related to enteric bacteria Vancomycine resistant Enterococci Colonocytes** Ecologically, the immune system co-evolved with the microbiota, enabling the microbiota to evolve in a beneficial way. Colonocytes—the epithelial cells in the colon maintain physiological homeostasis by shaping the microbiota Antibiotic pressure** Fermentation product à reduction in microflora SCFA reduction Failure to preserve epithelial hypoxia Decreased Treg triggering Increase in inflammation