We studied the correlation between fecal levels of short-chain fatty acids (SCFA), bile acids (BA), and colonic mucosal proliferation in humans on a free diet. Subjects [n = 43: 27 men and 16 women; 61 +/- 7 and 59 +/- 6 (SE) yr old, respectively] were outpatients who previously underwent resection of at least two sporadic colon polyps. Mucosal proliferation was determined by [3H]thymidine incorporation in vitro in three colorectal biopsies obtained without cathartics and was expressed as labeling index (LI). BA were analyzed in feces by mass spectrometry and SCFA by gas chromatography. We found that increasing levels of BA in feces did not correlate with higher LI. On the contrary, higher levels of SCFA were significantly associated with lower LI in the colonic mucosa (P for trend = 0.02). In conclusion, in humans on a free diet, intestinal proliferation seems to be regulated by the levels of SCFA in feces and not by BA. Because a lower intestinal proliferation is associated with a decreased colon cancer risk, treatments or diets that increase colonic levels of SCFA might be beneficial for colonic mucosa.