“Objective. to investigate the effects of 5-hydroxytryptamine (5-ht) and intestinal flora on depression-like behavior induced by lead exposure in rats. methods. 30 healthy spf adult male sd rats were randomly divided into control group and lead exposure group. the depression-like behavior of rats was detected. the blood, striatum, and intestinal tissue were collected. the lead content was detected by icp-ms. the mrna expressions of chga, tph1, 5-ht, and 5-ht3r were tested by qrt-pcr. the content of 5ht was checked by hplc-ecd. the content of 5-ht3r was detected by elisa. the protein expressions of 5-ht, 5-ht3r, chga, and tph were gauged by immunohistochemistry. fecal samples were collected, and the composition of intestinal flora in experimental rats was analyzed by 16 s rna metagene sequencing. results. lead exposure can greatly cause depression. the content of 5-ht in blood and striatum in the lead exposure group decreased, and the expression levels of 5-ht, 5-ht3 r, chga, and tph in the intestine decreased distinctly. compared with the control group, the distribution of a-polymorphism related indexes simpson, chao1, shannon, and ace in rats with depressive-like behavior after lead exposure was significantly increased; in the lead exposure group, there were 61 different operational taxonomic units (outs) in intestinal flora at the family level. based on linear discriminant analysis, it was found that the key bacteria were lactobacillaceae and bifidobacteriaceae, and their abundance decreased evidently in the lead exposure group. conclusion. lead exposure improves depressive-like behavior by affecting intestinal flora and regulating neurotransmitter 5-ht through the intestinal-brain axis.”