Abstract: Objective To investigate the effect of the gut microbial metabolite deaminotyrosine (DAT) on the production of interleukin-6 (IL-6) in macrophages and the underlying molecular mechanism. Methods Bone marrow-derived macrophages (BMDMs) were stimulated with lipopolysaccharide (LPS). The effect of DAT on the mRNA and protein expression of IL-6, Krüppel-like factor 4 (KLF4), and P300/CBP-associated factor (PCAF) in BMDMs was detected by real-time quantitative PCR (q-PCR) and enzyme-linked immunosorbent assay (ELISA). The expression of KLF4 in BMDMs was knocked down by siRNA, and the efficiency of KLF4 knockdown by siRNA was detected by Western blot. The mRNA and protein expression of IL-6 and KLF4 were detected by q-PCR and ELISA. Results DAT significantly reduced IL-6 expression in the supernatant of LPS-stimulated BMDMs (P<0.05) and promoted the transcription of KLF4 and PCAF genes. In BMDMs with KLF4 knockdown, the inhibitory effect of DAT on IL-6 production was abolished. Conclusions In LPS-stimulated BMDMs, DAT reduces IL-6 production by upregulating KLF4 expression.