DOSE‐DEPENDENT EFFECT OF LUMINAL BUTYRATE ON EPITHELIAL PROLIFERATION IN THE DISTAL COLON OF RATS

Abstract

Butyrate, a major product of bacterial fermentation of dietary fibre, is trophic to the colonic epithelium, when deprived of dietary fibre or faecal stream. However, the dose–response relationship of butyrate to this trophic effect is not known. The mechanism of this effect is still debated and how it relates to the antitumorigenic action of butyrate is unclear.Aim To characterise the dose–response relationship of the effect of butyrate delivered topically to the distal colon on fibre‐deprived atrophic colonic epithelium in rats.Methods Sixty‐four male Sprague–Dawley rats were maintained on a fibre‐free AIN 93G diet for 3 weeks to induce mucosal atrophy in the colon. The rats then underwent laparotomy for colonic intubation, in which a polyethylene tube was positioned at the proximal end of the distal colon via a caecotomy. After recovering from surgery, they were randomly divided into five groups, which were given for 4 days twice daily infusions of 0.5 mL butyrate at doses of 0, 10, 20, 40 or 80 mm (at which complete reversal of atrophy has been previously observed). Prior to sacrifice, the rats were injected intraperitoneally with vincristine to induce mitotic arrest. Crypt column heights and mitotic arrests were quantified by light microscopy.Results All treatment groups were healthy and stress‐free. The mucosa of vehicle‐infused rats was atrophic (mean 38 cells/crypt). Effects of twice daily infusions of butyrate were first observed on cell proliferation (number of mitotic arrests per crypt column) at 10 mm, and increased linearly to 80 mm. Crypt column height increased linearly from 20 mm to 80 mm, at which a mean of 45 cells/crypt were observed (the number usually observed in chow‐fed healthy rats). The mitotic index (number of mitotic arrests per 100 crypt cells) also increased linearly from 10 mm.Conclusions Butyrate's trophic effect showed a linear dose–dependent relationship. Although a maximal effect was not convincingly demonstrated, the results indicate that very small amounts of butyrate are required to affect epithelial proliferation. Since much higher luminal delivery is required to suppress tumorigenesis in this model, the mechanism by which butyrate exerts its trophic and antitumorigenic effects are likely to be different.