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Crypt fission is now established as an important mechanism of intestinal growth and regeneration. It has been proposed that increased crypt size is the stimulus for crypt fission, because crypts preparing for fission are generally larger. Consequently, we investigated the effects of epidermal growth factor (EGF) and dimethylhydrazine, which are both known to stimulate crypt cell proliferation, on crypt fission in the rat intestine. We also examined whether the effects of EGF on both proliferation and crypt fission are modified by the pretreatment with dimethylhydrazine for 16 weeks, dimethylhydrazine was then discontinued for 8 weeks, followed by intravenous infusion of EGF for 1 week. There were four groups: vehicle alone, EGF alone, dimethylhydrazine alone, and dimethylhydrazine followed by EGF infusion. The rats were killed at 25 weeks and rates of intestinal crypt cell production, crypt size, and crypt fission were determined. Intravenously infused EGF significantly increased crypt cell production rate, but the magnitude of the effect decreased from the proximal to the distal colon. EGF caused an increase in crypt area, possibly reflecting an increase in crypt size. Importantly dimethylhydrazine had no significant effect on crypt cell production rate nor on crypt area in the distal colon, but it did cause an increase in crypt area in the mid-colon. The crypt fission index was significantly decreased by EGF and increased by dimethylhydrazine. There was no qualitative interaction between EGF and dimethylhydrazine. These results demonstrate the marked proliferative effect of intravenously infused EGF in the colon of orally fed rats, with significant site effects (P = 0.0007); the effect was greatest in the proximal colon and disappeared in the distal colon. The observation that EGF reduced crypt fission indicates that increased cell proliferation, per se, is not a stimulus for crypt fission. This is further supported by the observation that dimethylhydrazine increases crypt fission in crypts of normal size in the distal colon without significantly increasing cell proliferation. These results suggest that increasing crypt cellularity by proliferation is not sufficient to induce crypt fission, and factors other than increased crypt size by proliferation can control crypt fission. It is also probable that cell proliferation and crypt fission are independently regulated. Crypt fission appears to play a considerable role in the intestinal response to carcinogens.

In the small intestine and colon, administration of mutagens leads to the emergence of crypts populated by cells with a different, mutated phenotype. This is preceded by a transient rise in the frequency of crypts with a partially mutated phenotype, and the disappearance of these partially mutated crypts occurs contemporaneously with the attainment of a plateau value of the wholly mutated crypts. Here, using the mutagen ethyl nitrosourea and loss of glucose-6-phosphate dehydrogenase staining as a marker, we show that the plateau is reached at between 4.6 and 7 weeks in the colon and at 12 weeks in the small intestine of the same mice. Explanations for this difference have included differences in the stem cell cycle time of a single "master" stem cell or multiple stem cells occupying a stem cell "niche" with random loss after stem cell division. However, we demonstrate that the crypt fission index, or the incidence of crypts in fission, is some four times higher in the colon than in the small intestine at the time of ethyl nitrosourea injection, and propose an alternative hypothesis based on crypt fission as the mechanism for the more rapid evolution of wholly mutated crypts in the colon. The hypothesis should enable us to predict the results of future experiments, namely that the emergence of wholly mutated crypts is proportional to the crypt fission index.

The present study was conducted to compare the effect of soy polysaccharide (SP)-supplemented and fibre-free enteral diets and a normal chow diet on intestinal and colonic adaptation of rat gastrointestinal morphometrics and cytokinetics. Results showed that the fibre-free diet caused a significant decrease in various gut parameters, such as cell proliferation, tissue wet weight, and intestinal brush border enzymes, when compared to the normal gut of chow-fed rats. However the SP-supplemented enteral diet resulted in a significant improvement in several parameters in most regions along the gastrointestinal tract, when compared to orally-fed animals. These studies demonstrate that significant changes occur in the intestine as a result of enteral diets, with regional variation. Furthermore, the results demonstrate that SP stimulates crypt cell proliferation which could, in part, hasten recovery from intestinal mucosal damage. The addition of SP to enteral diets seems potentially advantageous.

The mechanism by which lack of gastric acid causes hypergastrinaemia was investigated in seven patients with pernicious anaemia. Perfusion of gastric juice from the fasting patients (adjusted to pH 7.0) into the stomachs of conscious rats caused a significant rise in plasma gastrin (median 14 [range 2-20] pmol/l to 27 [12-65] pmol/l; p less than 0.01), whereas perfusion of bicarbonate buffer (18 [13-23] pmol/l to 20 [9-25] pmol/l) or gastric juice from a duodenal ulcer patient (also pH 7.0; 13 [3-30] pmol/l to 17 [9-27] pmol/l) had no significant effect. During gastric lavage at pH 7.0 the median plasma gastrin concentration of the pernicious anaemia patients fell from 320 (63-1760) pmol/l to 125 (46-760) pmol/l (p less than 0.03).

To find out whether non-steroidial anti-inflammatory drugs (NSAIDs) inhibit the proliferation of mucosal cells that normally leads to healing of gastric ulcers a microdissection technique was used to quantify mitosis in gastric glands at the ulcer edge in relation to that in the adjacent mucosa. The regeneration index thus obtained of the ulcer edge was greater in the 9 subjects with gastric ulcers not taking NSAIDs (mean index 3.1 [SEM 0.61]) than that in the 8 patients taking NSAIDs (index 1.49 [0.16]). In rats in which gastric ulcers were produced with a cryoprobe, the ulcers were larger and slower to heal in those receiving indomethacin than in controls; also, immunohistochemical staining indicated significantly fewer mitotic cells in glands adjacent to the ulcer in indomethacin-treated rats (8 mitoses [SEM 3]) than in control animals (25 [5]). The prostaglandin E1 analogue misoprostol reversed the inhibition of healing and substantially restored the proliferative rate in the animals. Inhibition of epithelial cell division normally involved in gastric ulcer healing would contribute to the high prevalence of gastric ulcer during NSAID therapy.