Gut Microbiome and Colonization Resistance Against C. difficile by 4aq1sB6W

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									Gut Microbiome and Colonization
 Resistance Against C. difficile

            ANDY HONG
       Overview


      Introduction
      Pathogenesis
    Gut Microbiome
 Colonization Resistance
       Treatment
       Summary
Introduction – C. difficile


         Gram +’ve
          Anaerobe
   Vegetative & Endospore
   Opportunistic Pathogen
    C. difficile-Associated
       Disease (CDAD)
                Pathogenesis of CDAD


 Exposure
   Vegetative & Endospores

 Colonization
   Flagellar Cap (FliD)

   Proteases

   Adhesins (Cwp66, S-layer protein)

 Damage/Dissemination
   Toxins A & B
              Pathogenesis – Colonization

                                                        FliD


                                                        Flagella & Protease


                                                        Adhesins



                                                        Interactions between C.
                                                        difficile, Host Immune
                                                        Sytem, and Gut
                                                        Microbiota


Source: Hooper, L. V. (2009). Do symbiotic bacteria subvert host
immunity? Nature Reviews Microbiology, 7, 367-374.
Role of Gut Microflora



                    Source: Britton, R. A.
                    & Young, V. B. (2012).
                    Interaction between
                    the intestinal
                    microbiota and host in
                    Clostridium difficile
                    colonization
                    resistance. Trends in
                    Microbiology, 20(7),
                    313-319
                 Human Gut Microbiome

• Bacteriodetes:                         5%          8%            25%
  Cytophaga-
  Flavobacterium-            2%
  Bacteroides (CFB)
• Firmicutes: Low G+C
  Gram positive bacteria
  (Clostridial cluster IV,
  cluster IX, cluster XIV,
  Eubacterium)                                         60%
• Proteobacteria:
  eg E.coli,                      Bacteroidetes   Firmicutes
  Enterobacteriaceae
                                  Actinomycetes   Proteobacteria
• Actinomycetes:: high            Other
  G+C Gram positives, eg
  Bifidobacteria
           Alteration in Gut Microbiome

a) Antibiotics (AMB & Cefoperazone) – ICD




Source: Antonopoulosm, D. A., Huse, S. M., Morrison, H. G., Schmidt, T. M., Sogin,
M. L., and Young, V. B. (2009). Infection and Immunity, 77(6), 2367-2375
           Alteration in Gut Microbiome

a) C. difficile Colonization




Source: Chang et al. (2007). Infection and Immunity, 77(6), 2367-2375
             Colonization Resistance


 Definition


 Innate
 Immunity

 2 Types:
 Direct vs
 Indirect
            Colonization Resistance - Direct



 3 Mechanisms
  a.    Niche
        Exclusion
  b.    Production of
        antimicrobial
        products



 Source: Britton, R. A. &
 Young, V. B. (2012).
    Colonization Resistance - Direct




 3 Mechanisms
   c. Conversion
      of host
      metabolites
      (Bile Acid)

  Source: Britton, R. A. &
  Young, V. B. (2012).
          Colonization Resistance - Indirect



 Interacting
 with the host
 to stimulate
 immune
 response

 Source: Britton, R. A. &
 Young, V. B. (2012).
                              Treatment

 Synbiotics:
  Prebiotic +
  Probiotic
  Application
   Challenges


 Fecal
  Transplant
     Efficacy
     Effects

  Source: Borody & Khoruts (2012).
  Nature Reviews
  Gastroenterology & Hepatology,
  9, 88-96
            Saccharomyces Boulardii


 Probiotic
 Prophylactic
 4 Effects
   a.  Alteration/
       Restoration
       of Gut
       Microbiome




 Source: Barc et al. (2008).
 Anaerobe,14, 229–233
              Saccharomyces Boulardii

• 4 Effects
  b. Anti-toxin activity (Protease Production)




  Source: Castagliuolo, I., Riegler, M. F., Valenick, L., LaMont, J. T.,
  & Pothoulakis, C. (1998). Infection and Immunity, 67(1), 302-307
            Saccharomyces Boulardii

• 4 Effects
   c.   Intestinal barrier protection (Prevent C. difficile
        Adherence)




   Source: Tasteyre, A., Barc, M, Karjalainen, T., Bourlioux, P., &
   Collignon, A. (2001). Microbial Pathogenesis, 32, 219-225
          Saccharomyces Boulardii

• 4 Effects
   d. immunomodulation




 Source: Qamar et al., (2001). Infection and Immunity, 69(4),
 2762-2765.
                            Summary

 Indigenous gut microbiota provide colonization resistance
    = Innate Immunity
   Antibiotic or colonization of C. difficile can lead to acute or
    chronic alterations in gut microbiota.
   Colonization resistance occur via direct and/or indirect
    mechanisms.
   Treatments, such as synbiotics and fecal transplant,
    targeting the gut microbiota may prevent CDAD.
   S. boulardii may restore and alter the gut microbiome to
    promote colonization resistance again C. difficile
             Conclusion/Limitation

 Lack of data regarding the composition of gut
  microbiota makes it difficult to identify specific
  microorganisms that contribute to colonization
  resistance.
 It is unclear which of the potential mechanisms of
  colonization resistance are the most important in
  vivo.
 The role of host immune system in mediating
  colonization resistance is not fully understood.
Thank You

								
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