Gastroenterology. 2007 Nov;133(5):1487-98. Epub 2007 Aug 3.

Microbial mannan inhibits bacterial killing by macrophages: a possible
pathogenic mechanism for Crohn's disease.

Mpofu CM, Campbell BJ, Subramanian S, Marshall-Clarke S, Hart CA, Cross A,
Roberts CL, McGoldrick A, Edwards SW, Rhodes JM.

Division of Gastroenterology, School of Clinical Science, University of
Liverpool, Liverpool, United Kingdom.

BACKGROUND & AIMS: Crohn's disease (CD) is mimicked by inherited phagocyte
disorders and is associated with circulating antibodies against yeast
mannan (anti-Saccharomyces cerevisiae antibody; ASCA). We speculated that
mannans might impair phagocyte function. METHODS: S cerevisiae mannan was
assessed for its effects on human peripheral blood neutrophils, adherent
monocytes, and monocyte-derived macrophages (MDM). RESULTS: Mannan caused
dose-related increased survival of CD Escherichia coli HM605 within
adherent monocytes from 24% +/- 10.5% (control) to 114% +/- 22.7% with
mannan 1 mg/mL at 2 hours (mean +/- SEM, n = 9; P = .0002). Electron
microscopy showed E coli HM605 surviving and probably replicating within
macrophage vesicles. Mannan (1 mg/mL) inhibited the respiratory burst in
neutrophils and monocytes (both P = .002) and bacterial killing within MDM
(P < .001). E coli survival was increased within macrophages from
TLR4(-/-) (126% +/- 3.5% survival at 2 hours) and MyD88(-/-) (134.8% +/-
6.5%) mice compared with wild-type mice (both P < .0001). Mannan had no
additional effect, showing that TLR4 and MyD88 are involved in bacterial
killing by macrophages and its inhibition by mannan. Putative
CD-associated micro-organisms were screened for the ASCA mannan epitope by
Galanthus nivalis lectin (GNA) blotting. ASCA epitope was expressed by
Candida albicans and Mycobacterium paratuberculosis but not by
Mycobacterium tuberculosis or E coli. Supernatants from M paratuberculosis
culture inhibited killing of E coli HM605 by adherent human monocytes and
murine macrophages. The inhibitory activity was removed by GNA-affinity
chromatography. CONCLUSIONS: Suppression of mucosal phagocyte function by
microbial mannans, possibly of Mycobacterial origin, may contribute to CD
pathogenesis.