Our review focuses on the colonic macrophage, a monocyte-derived, tissue-resident macrophage, and the role it plays in health and disease, specifically in inflammatory conditions such as inflammatory bowel disease and cancer of the colon and rectum. We give special emphasis to macrophage polarization, or phenotype, in these different states. We focus on macrophages because they are one of the most numerous leukocytes in the colon, and because they normally contribute to homeostasis through an anti-inflammatory phenotype. However, in conditions such as inflammatory bowel disease, proinflammatory macrophages are increased in the colon and have been linked to disease severity and progression. In colorectal cancer, tumor cells may employ anti-inflammatory macrophages to promote tumor growth and dissemination, whereas proinflammatory macrophages may antagonize tumor growth. Given the key roles that this cell type plays in homeostasis, inflammation, and cancer, the colonic macrophage is an intriguing therapeutic target. As such, potential macrophage-targeting strategies are discussed.

Administration of a hapten together with a barrier breaker, such as ethanol, into the colon of a rat results in extensive mucosal injury and inflammation that bears some similarity to the colonic inflammation characterizing inflammatory bowel disease in humans. This inflammation and injury gradually subsides over the weeks after its induction. We have attempted to determine whether this colitis can be "reactivated" by administration of the hapten systemically weeks after its initial intracolonic administration. Six weeks after intracolonic administration of trinitrobenzene sulfonic acid (the hapten) in a vehicle of 50% ethanol, most of the colonic injury and inflammation had subsided. Intravenous administration of the hapten at 24-h intervals over 3 days resulted in reactivation of the colitis, with significant increases in macroscopic and histological damage scores (mucosal injury and inflammation) and a significant increase in granulocyte infiltration, as measured by tissue myeloperoxidase (MPO) infiltration, as measured by tissue myeloperoxidase (MPO) activity. The increase in MPO activity occurred only in the region previously exposed to the hapten. Intravenous administration of saline did not reactivate the colitis, nor did intravenous administration of the hapten to rats previously treated intracolonically with saline or the ethanol vehicle. Reactivation of colitis by hapten administration was not accompanied by activation of mucosal mast cells. Treatment with dexamethasone prevented the increase in colonic damage score and MPO activity elicited by intravenous hapten administration. Cyclosporin A reduced MPO activity, and 5-aminosalicylic acid reduced the colonic damage score, whereas lidocaine and two inhibitors of leukotriene synthesis did not significantly affect either of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence supports involvement of microflora in the transition of chronic inflammation to neoplasia. We investigated the protective efficacy of the probiotic VSL#3 in a model of colitis-associated colorectal cancer. Chronic colitis was induced in Sprague-Dawley rats by administration of trinitrobenzene sulfonic acid (TNBS), followed 6 wk later by systemic reactivation. To induce colitis-associated dysplasia and cancer, the animals received TNBS (intravenously) twice a week for 10 wk. One group received VSL#3 in drinking water from 1 wk before colitis induction until death. The colons were examined for damage and presence of dysplasia or cancer. Samples were analyzed for cell proliferation and apoptosis, vitamin D receptor (VDR) expression, angiogenic factors, and presence of alkaline sphingomyelinase or phosphatase. Microbial community composition was evaluated by terminal restriction fragment-length polymorphism analysis of the bacterial 16S rRNA gene. None of the probiotic-treated animals developed carcinoma, and no high-grade dysplasia was found in either the proximal or mid colon. In contrast, 29% of the animals in the control group developed carcinoma in one or more regions of the colon. VSL#3-treated animals had significantly less damage than the vehicle treated-controls in all areas of the colon, and this correlated with decreased richness and diversity of the mucosally adherent microbiota. Treatment with the probiotic increased the antiangiogenic factor angiostatin, VDR expression, and alkaline sphingomyelinase. We concluded that pretreatment with the probiotic VSL#3 can attenuate various inflammatory-associated parameters, delaying transition to dysplasia and cancer, thus offering its potential therapeutic use in patients with long-standing colitis.

Background. Compositional changes within the normal intestinal microbiota have been associated with the development of various intestinal inflammatory disorders