The Interactions of Diet and Colonic Microflora in Regulating Colonic Mucosal Growth

Abstract

The colonic mucosa can adapt its growth to alterations in diet. Metabolites from colonic microflora are frequently implicated as the primary factor in mediating the colonic mucosal response to diet; however, there is also evidence indicating that diet may have a direct effect in mediating this response. The aim of this study was to determine the role of diet, microflora, and microflora metabolites in altering the growth of the colonic mucosa. Two 28-day feeding studies were conducted using Sprague-Dawley rats. The first study compared the growth of the colonic mucosa in germ-free and conventional rats fed 6 different diets. The second study compared the growth of the colonic mucosa to the concentration of bacterial-derived short-chain fatty acids (SCFAs), bile acids, and ammonia. The diets that were fed consisted of (1) AIN-76a diet without dietary fiber; (2) standard AIN-76a diet, which contained 5% cellulose; (3) AIN-76a diet with 5% guar gum; (4) a "Western" human diet with 20% fat and 10% cellulose; (5) AIN-76a diet formulated to mimic Diet 4 in fat content but with 2.5% cellulose; and (6) Purina Rodent Chow. Quantitative volumetric and stereologic analysis was used to assess changes in total colonic mucosal volume as a measure of mucosal growth. In germ-free rats, Diets 2-4 and 6 induced a significant increase (18-38%) in mucosal volume compared to Diet 1. In conventional animals, only Diets 4 and 6 induced a significant increase (up to 63%) in mucosal volume compared to Diet 1. Relative to the germ-free animals, only conventional animals on Diets 4 and 6 had an increase in mucosal volume. The increases in mucosal volume in Diets 4 and 6 were not consistently associated with increased SCFAs, ammonia, or bile acids. There was a wide range in the colonic concentrations of SCFAs (2-fold), ammonia (6-fold), and bile acids (10-fold). The presence of colonic microflora in and of itself does not lead to enhanced colonic mucosal growth. Rather, there are unique interactions between specific types of diet and microflora that lead to a growth-promoting effect. This effect could not be explained by alterations in the concentration of SCFAs, ammonia, or bile acids in colonic contents.

Only fibres promoting a stable butyrate producing colonic ecosystem decrease the rate of aberrant crypt foci in rats

“…The mucosa can also alter its growth characteristics by crypt duplication, increasing the number of crypts per unit length and total length in response to diet 1617 63 64 Such an increase in length was apparent in our study with high butyrate producing diets, as well as deeper crypts in the caecum where fermentation was the most intensive.…”

“…In other long term studies, no (or a very modest) increase in proliferation21 56-57 61 occurred with high fibre diets, and SCFAs did not correlate with various mucosal growth characteristics 2156 62 63 In rats fed a high fibre diet (guar gum), proliferation of distal colonic mucosa returned to the level of the control diet after a transient increase over a period of 9–21 days 52. The mucosa can also alter its growth characteristics by crypt duplication, increasing the number of crypts per unit length and total length in response to diet 16…”

Dietary lignan and proanthocyanidin consumption and colorectal adenoma recurrence in the Polyp Prevention Trial

“…Alternatively, the lignan to lipid ratio may influence cancer risk because lignans and lipids both alter the metabolism of steroid hormones,6, 21 which are involved in the etiology of colorectal tumorigenesis. Dietary lipids may modify the effect of dietary fibre, which is closely associated with lignan consumption,6, 20 on colorectal carcinogenesis, as has been demonstrated in animal models 42–44. The gender difference in risk of colorectal neoplasms observed in this and other studies,18, 19, 41 may be related to the ability of lignans to bind to estrogen receptors and thereby antagonizing endogenously synthesized estrogen6, 18, 21 but there is some evidence to suggest that this may also increase proliferation of colonic epithelial cells 2, 45…”

Digestive System

“…There may also be an interaction between dietary fiber content and colonic microflora that influences mucosal growth, although the mechanism is unclear. 669 It is generally argued that the increase in cecal size and mucosal hypertrophy appears related to the osmotic activity of the cecal contents in rodents treated with large doses of these agents and is therefore not relevant to humans exposed to low doses. Thus the changes represent a physiological adaptation to increased osmotic forces when high doses are given irrespective of the contributing compounds.…”

“…675 Pertinent to the assessment of drug safety is the fact that atypical hyperplasia and eventually neoplasia can be induced by non-genotoxic agents such as dextran sodium sulfate that produce prolonged chronic colonic inflammation. 669 Potential therapeutic agents designed to poorly absorb may produce similar alterations in the rodent colon when administered in very high doses.…”