Colonic epithelial atrophy induced by a fibre-free diet in rats is reversed by minimal amounts of luminal butyrate,but only in the short term

Background: Luminal butyrate may be trophic to the colonic epithelium, but this effect is poorly characterized. The aim of the present study was to define the dose?response, time‐course, site‐specificity and the dependence on background diet of the effects of butyrate on epithelial proliferation in normal distal colon, using an in vivo rat model of colonic substrate delivery. Methods: Male Sprague‐Dawley rats, maintained on a fibre‐free diet, had butyrate infused twice daily into the colonic lumen via polyethylene tubes placed at laparotomy. Varying dose levels (0?80 µmol/d; 4 d), site (caecal vs distal colonic), duration of infusions (1?5 weeks; 80 µmol/d), or dietary fibre intake were investigated. Epithelial proliferative indices were assessed stathmokinetically. Results: Four‐day infusions of butyrate led to a progressive trophic effect (cells/crypt column increased from 37.9 ± 1.6 at 0 µmol/d to 44.7 ± 1.2 at 80 µmol/d) on fibre‐deprived colonic mucosa, related linearly to the daily butyrate dose (P < 0.001, linear regression). This effect was mediated by increases in the number and proportion of mitoses, related to the square of the butyrate dose (P < 0.001 in each case, polynomial regression). Butyrate (80 µmol/d) was associated with significantly higher cellularity (59.9 ± 1.4) and mitotic activity (4.9 ± 0.6) per crypt column compared to vehicle controls (50.3 ± 1.6 and 0.9 ± 0.2, respectively; P < 0.05, t‐tests), at 1 and 3 weeks, but not at 5 weeks. Butyrate had similar effects on distal colonic crypt cellularity (62.0 ± 1.5) when delivered caecally, but in rats fed a fibre‐containing diet, colonic crypt cellularity (55.3 ± 3.2) was similar to baseline (59.6 ± 1.9). Conclusions: Trophic effects of butyrate are concentration‐dependent and occur at low doses in the short term, but are not sustained over longer periods. They are seen only in a fibre‐deprived state and appear to be independent of the site of administration.