IPA and its precursors differently modulate the proliferation, differentiation, and integrity of intestinal epithelial cells

Abstract

BACKGROUND/OBJECTIVES: Indole-3-propionic acid (IPA) is a tryptophan-derived microbial metabolite that has been associated with protective effects against inflammatory and metabolic diseases.However, there is a lack of knowledge regarding the effects of IPA under physiological conditions and at the intestinal level.MATERIALS/METHODS: Human intestinal epithelial Caco-2 cells were treated for 2, 24, and/ or 72 h with IPA or its precursors -indole, tryptophan, and propionate -at 1, 10, 100, 250, or 500 M to assess cell viability, integrity, differentiation, and proliferation.RESULTS: IPA induced cell proliferation and this effect was associated with a higher expression of extracellular signal-regulated kinase 2 (ERK2) and a lower expression of c-Jun.Although indole and propionate also induced cell proliferation, this involved ERK2 and c-Jun independent mechanisms.On the other hand, both tryptophan and propionate increased cell integrity and reduced the expression of claudin-1, whereas propionate decreased cell differentiation.CONCLUSIONS: In conclusion, these findings suggested that IPA and its precursors distinctly contribute to the proliferation, differentiation, and barrier function properties of human intestinal epithelial cells.Moreover, the pro-proliferative effect of IPA in intestinal epithelial cells was not explained by its precursors and is rather related to its whole chemical structure.Maintaining IPA at physiological levels, e.g., through IPA-producing commensal bacteria, may be important to preserve the integrity of the intestinal barrier and play an integral role in maintaining metabolic homeostasis.