Sandbox: spontaneous bacterial peritonitis

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Overview

Spontaneous bacterial peritonitis(SBP) is an advanced clinical expression of a pathological bacterial translocation as it develops from normal inhabitant gut bacteria through breakage of immune barriers.[1]

Pathogenesis

Bacterial Translocation

It is defined as the translocation of either bacteria or bacterial products such as lipopolysacharides (LPS), bacterial DNA, peptidoglycans, muramyl-dipeptides from gut into mesenteric lymph nodes.[2]

Physiological: It is the normal bacterial translocation in healthy individuals due to lack of pro-inflammatory responses against commensal bacteria. Physiological translocation is crucial for the development of host immunity response.

Pathological: It is developed due to abnormal increase in physiological translocation in both rate and degree by breaking the normal immunological barriers.

Barriers that limit pathological transmission:

  1. Interstinal lumen and it's secretory components such as inner and outer mucus layer, antimicrobial peptides: This is the primary barrier that limit direct contact between the intestinal bacteria and the epithelial cell surface
  2. Epithelial barrier with the gut-associated lymphatic tissue (GALT) and autonomic nervous system: This is a mechanical barrier with local immunological response elements (e.g., TNF and other pro-inflammatory cytokines) that rapidly detects and kill the pathogen that manage to penetrate
  3. Systemic immune system: This includes hematogenous (portal venous) and lymphatic (ductus thoracicus) route of delivery that acts as a third immune barrier to prevent or minimize the pathogen to disseminate systemically from local immune system such as lymph nodes.

Mechanism of pathological bacterial translocation

Breaking these immune barriers can progress physiological BT into pathological BT.

Bacterial Translocation
I. Immune response by

gut associated lymphoid tissue

A. Innate immunity Innate immunity is the first line of defense mechanism against invading pathogen that detects common bacterial motifs such as microbial-associated molecular patterns (MAMPs) through germline-coded pattern-recognition receptors (PRR) on intestinal cells.[3]

Mechanism of breaking of innate immunity

  1. Dendritic cells below the epithelial layer allows pathogen via dendritic processes with out affecting tight junction function.
  2. Disruption of epithelial barrier by antigenic properties of the pathogen with the underlying epithelial layer and compromises its epithelial integrity.
  3. Access provided by M- cells overlying payers patches with in the villous epithelium through antigen presenting cells.[4]
B. Adaptive immunity Bacterial translocation through epithelial cells

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Release of chemokines form epithelial cells

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Recruitment of dendritic cells towards mucosa

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Dendritic cells induces adaptive immunity through mucosal B and T lymphocytes[5]

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a. Bacterial antigen present to Matured T- lymphocytes, followed by activation B-lymphocytes through T- helper cells

b. Antigen presenting cells present microbial antigen to matured B- lymphocytes, eventually B-cell releases Ig-A mucosal immunoglobulins against pathogen and it's product

Mechanism of breaking adaptive immunity: Due to the underlying immunocompromised states such as cirrhosis, there is a depletion of both T and B cells and hypogamaglobilinemia, results in weak development of adaptive immunity with insufficient bacterial killing that leads to lethal dissemination of commensal bacteria.[6][7][8][9]

II. Mesenteric lymph nodes (MLN) In a healthy gut, dendritic cells transport pathological bacteria to mesenteric lymph nodes which induces local immune response and are killed without inducing systemic immunity.

In immunocompromised state, lack of local immune response by MLN is reduced, eventually permits the translocation of intestinal bacteria systemically, which eventually may lead to sepsis and death.

Mechanism involving in spreading bacteria beyond MLN:[10][11]

  • Deficient innate and adaptive immunity
  • Impaired chemotactic, opsonic, phagocytic activity of macropharges
  • Impaired RES activity
III. Systemic immune response Translocation beyond MLN through hematogenous or lymphatic path is specific and depends on the microbial-specific systemic immune response.[12] Lymphatic and portalvenous route in parallel are disrupt in liver cirrhosis which results in dissemination of bacterial pathogen.

References

  1. ↑ Benten D, Wiest R (2012) Gut microbiome and intestinal barrier failure--the "Achilles heel" in hepatology? J Hepatol 56 (6):1221-3. DOI:10.1016/j.jhep.2012.03.003 PMID: 22406521
  2. ↑ Berg RD, Garlington AW (1979) Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun 23 (2):403-11. PMID: 154474
  3. ↑ Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2 (8):675-80. DOI:10.1038/90609 PMID: 11477402
  4. ↑ Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M et al. (2009) Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 462 (7270):226-30. DOI:10.1038/nature08529 PMID: 19907495
  5. ↑ Muñoz L, José Borrero M, Ubeda M, Lario M, Díaz D, Francés R et al. (2012) Interaction between intestinal dendritic cells and bacteria translocated from the gut in rats with cirrhosis. Hepatology 56 (5):1861-9. DOI:10.1002/hep.25854 PMID: 22611024
  6. ↑ Kirkland D, Benson A, Mirpuri J, Pifer R, Hou B, DeFranco AL et al. (2012) B cell-intrinsic MyD88 signaling prevents the lethal dissemination of commensal bacteria during colonic damage. Immunity 36 (2):228-38. DOI:10.1016/j.immuni.2011.11.019 PMID: 22306056
  7. ↑ Doi H, Iyer TK, Carpenter E, Li H, Chang KM, Vonderheide RH et al. (2012) Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population. Hepatology 55 (3):709-19. DOI:10.1002/hep.24689 PMID: 21932384
  8. ↑ Gautreaux MD, Deitch EA, Berg RD (1994) T lymphocytes in host defense against bacterial translocation from the gastrointestinal tract. Infect Immun 62 (7):2874-84. PMID: 7911786
  9. ↑ Owens WE, Berg RD (1980) Bacterial translocation from the gastrointestinal tract of athymic (nu/nu) mice. Infect Immun 27 (2):461-7. PMID: 6966611
  10. ↑ Rimola A, Soto R, Bory F, Arroyo V, Piera C, Rodes J (1984). "Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis". Hepatology. 4 (1): 53–8. PMID 6693068.
  11. ↑ Trevisani F, Castelli E, Foschi FG, Parazza M, Loggi E, Bertelli M; et al. (2002). "Impaired tuftsin activity in cirrhosis: relationship with splenic function and clinical outcome". Gut. 50 (5): 707–12. PMC 1773217. PMID 11950821.
  12. ↑ Macpherson AJ, Gatto D, Sainsbury E, Harriman GR, Hengartner H, Zinkernagel RM (2000). "A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria". Science. 288 (5474): 2222–6. PMID 10864873.
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