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PTU-032 Differential bacterial clearance and cytokine secretion by macrophages explains localisation of Crohn's disease to the gut
  1. B Hayee1,
  2. G Sewell1,
  3. F Z Rahman1,
  4. S L Bloom2,
  5. A M Smith1,
  6. A W Segal1
  1. 1Department of Molecular Medicine, University College London, London, UK
  2. 2Department of Gastroenterology, UCLH NHS Foundation Trust, London, UK

Abstract

Introduction The clearance of Escherichia coli (EC) from the tissues in Crohn's disease (CD) is grossly impaired,1 particularly at high inoculating doses of bacteria. It has not been determined whether this is specific to Gram-negative bacteria. These studies were conducted to determine whether the inflammatory response to the Gram-positive bacterium S. aureus (SA) in vivo and clearance of these bacteria is abnormal in CD. Macrophage cytokine secretion, which in CD is markedly deficient in response to stimulation with EC1, was also studied in response to SA.

Methods The acute inflammatory response to SA, and clearance of 32P-labelled, UV-killed SA (NCTC 6571) from a forearm injection site1 was compared over 72 h in five healthy controls (HC) and 5 patients with CD. Results were compared with historical data for EC (in the same subjects). TNF-α secretion by peripheral blood monocyte (PBMC)-derived macrophages after stimulation with SA and EC were compared in all participants, and up to n=50 for HCs and CD (using Bioassay and ELISA techniques).

Results Local blood flow after inoculation of 3×107 SA was significantly lower than that observed after inoculation of 3×107 EC (p<0.0001). Neither the magnitude of the inflammatory response, nor clearance of SA was different in CD compared to HCs (p=0.66). Clearance of SA in CD was more rapid than that of EC (p<0.05), while in HCs, clearance of SA was slower than that of EC, but not significantly different (p=0.11). TNF-α secretion by CD macrophages was significantly reduced after stimulation with EC (p<0.001). No significant differences were found in CD compared to HC after stimulation with SA.

Conclusion EC is a more potent activator of acute inflammation than SA. Macrophage cytokine secretion and subsequent clearance of SA was normal in CD – a significantly different response to that seen with EC. This is likely to reflect the different composition of these organisms (particularly the presence of LPS in Gram-negative species) and could explain the restriction of CD predominantly to areas of the gastrointestinal tract containing high concentrations of Gram-negative bacteria.

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