Microbial translocation

In pathogenic HIV infections, the translocation of microbial products like LPS from the gastrointestinal tract to the circulation has been suggested as a major driver of chronic immune activation that is associated with disease progression. Increasing number of clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy and non-AIDS co morbidities.

Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls and an agonist of Toll-like receptor 4 (TLR-4) (1), is considered a major marker of microbial translocation (2-4). In addition to local defense against microbial translocation at the level of the GI mucosa and within the liver, several lines of protection are active in the systemic circulation to neutralize translocating LPS. These protective factors include IgM, IgG, and IgA specific for the LPS core antigen and endotoxin core antibodies (EndoCAb), and indeed, clinical conditions featuring an acute excess of circulating endotoxin result in the consumption of EndoCAb (e.g., sepsis) as they bind and neutralize LPS (5). In other clinical settings (e.g., inflammatory bowel disease [IBD]), chronic microbial translocation results in elevated LPS levels that are associated with high EndoCAb titers. Importantly, LPS induce several responses in the innate immune system, with the interaction of LPS with LPS binding protein (LBP), which catalytically transfers LPS onto membrane or soluble CD14 (sCD14), leading to NF-B activation and cytokine production (6).

Acute HIV infection is associated with relatively normal LPS levels, with increased LBP, sCD14, and EndoCAb levels compared to levels in uninfected individuals, thus suggesting that the ongoing translocation of LPS is rapidly counteracted by the host Ig response. However, EndoCAb titers decrease progressively as HIV infection enters its chronic phase, which becomes characterized by higher plasma levels of LPS. The extent of microbial translocation can be assessed either directly through the measurement of bacterial by-products in plasma, such as LPS and bacterial DNA or RNA fragments, or indirectly by sCD14, LBP, EndoCAb, and antiflagellin antibodies. Recently, plasma levels of intestinal fatty acid binding protein (IFABP), a marker of enterocyte damage (7), have also been used to correlate intestinal impairment and microbial translocation (8, 9)

In addition, the Limulus amebocyte lysate (LAL) assay allows for the quantitative determination of LPS in reference to known endotoxin concentrations and is therefore a direct measure of endotoxemia. However, the assay presents technical difficulties due to possible reagent contamination and the inhibitory nature of some plasma components which have rendered the assay difficult to reproduce. The pretreatment of samples by heating has been shown to provide more reliable results and is thus mandatory for plasma LPS measurements using the LAL technique.


Marchetti et al. Clinical Microbiology Reviews 2013, 26 (1): 2-18

Other references:

  1. Beutler B. 2000. Tlr4: central component of the sole mammalian LPS sensor. Curr. Opin. Immunol. 12:20 –26. 
  2. Caradonna L, Amati L, Magrone T, Pellegrino NM, Jirillo E, Caccavo D. 2000. Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. J. Endotoxin Res. 6:205–214. 
  3. Cooke KR, Gerbitz A, Crawford JM, Teshima T, Hill GR, Tesolin A, Rossignol DP, Ferrara JL. 2001. LPS antagonism reduces graft-versushost disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J. Clin. Invest. 107:1581–1589.
  4. Schietroma M, Carlei F, Cappelli S, Amicucci G. 2006. Intestinal permeability and systemic endotoxemia after laparotomic or laparoscopic cholecystectomy. Ann. Surg. 243:359 –363.
  5. Barclay GR, Scott BB, Wright IH, Rogers PN, Smith DG, Poxton IR. 1989. Changes in anti-endotoxin-IgG antibody and endotoxaemia in three cases of gram-negative septic shock. Circ. Shock 29:93–106.
  6. Anderson KV. 2000. Toll signaling pathways in the innate immune response. Curr. Opin. Immunol. 12:13–19.
  7. Pelsers MM, Namiot Z, Kisielewski W, Namiot A, Januszkiewicz M, Hermens WT, Glatz JF. 2003. Intestinal-type and liver-type fatty acidbinding protein in the intestine. Tissue distribution and clinical utility. Clin. Biochem. 36:529 –535.
  8. Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, Pedersen C, Ruxrungtham K, Lewin SR, Emery S, Neaton JD, Brenchley JM, Deeks SG, Sereti I, Douek DC, INSIGHT SMART Study Group. 2011. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J. Infect. Dis. 203:780 –790.
  9. Mavigner M, Cazabat M, Dubois M, L’Faqihi FE, Requena M, Pasquier C, Klopp P, Amar J, Alric L, Barange K, Vinel JP, Marchou B, Massip P, Izopet J, Delobel P. 2012. Altered CD4_ T cell homing to the gut impairs  mucosal immune reconstitution in treated HIV-infected individuals. J. Clin. Invest. 122:62– 69.

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