Severe Defects in the Macrophage Barrier to Gut Microflora in Inflammatory Bowel Disease and Colon Cancer

Abstract

The continuity of the subepithelial band of lamina propria-indigenous macrophages (SBLP-M) discourages commensal gut bacteria from invading the host. In this Review we analyzed the impact of a disintegrating SBLP-M in inflammatory bowel disease (IBD), which results in microbiota inflow, inadequate immune responses and IBD-associated colon cancer. In previous work, we analyzed endoscopic biopsies taken from normal-looking descending colon in 247 patients with IBD, and 167 from control patients without IBD. Sections immunostained for cluster of differentiation 68 (CD68) protein showed no inflammatory changes. In IBD, the band of CD68+ SBLP-M was fragmented or minute in 59% (47/80) and absent in 9% (7/80). In contrast, only 31% (51/167) of the biopsies from control patients had a fragmented/minute band of CD68+ SBLP-M and this band was not absent in any (p<0.05). The finding that the band of CD68+ SBLP-M was fragmented to totally lost in IBD suggests a long-lasting defect in the barrier against the gut microbiome in IBD. The lack of ongoing inflammation in colonic biopsies should rule-out the participation of bone marrow-derived inflammation-elicited macrophages in loss of the barrier. Today, it is widely accepted that dysbiosis and inappropriate immune response to microbial flora play a pivotal role in the pathogenesis and development of IBD-associated colon cancer. Based on present knowledge, it is submitted that defects in the SBLP-M barrier in IBD encourage the trespassing of the gut microflora into the host, thereby destabilizing host immunity. These events in concert may play the ultimate pivotal role in the evolution of colon cancer in patients with IBD.