Intervention withα-Ketoglutarate Ameliorates Colitis-Related Colorectal Carcinoma via Modulation of the Gut Microbiome

Abstract

The intestinal microbiome plays a crucial role in promoting intestinal health, and perturbations to its constitution may result in chronic intestinal inflammation and lead to colorectal cancer (CRC).α-Ketoglutarate is an important intermediary in the NF-κB-mediated inflammatory pathway that maintains intestinal homeostasis and prevents initiation of intestinal inflammation, a known precursor to carcinoma development. The objective of this study was to assess the potential protective effects ofα-ketoglutarate intervention against CRC development, which may arise due to its known anti-inflammatory and antitumour effects. CRC was induced in C57BL/6 mice using azoxymethane (AOM) and dextran sulfate sodium (DSS). Tumour frequency, histological rating, and colonic microbiota were assessed in colonic samples. The findings demonstrated thatα-ketoglutarate offered significant protection against CRC development in mice. Furthermore,α-ketoglutarate also exhibited immunomodulatory effects mediated via downregulation of interleukin (IL)-6, IL-22, tumour necrosis factor (TNF)-α, and IL-1βcytokines. Finally, intervention withα-ketoglutarate tended to minimise the frequency of opportunistic pathogens (EscherichiaandEnterococcus) while increasing the populations ofAkkermansia, Butyricicoccus,Clostridium,andRuminococcus. Taken together, our findings show that dietaryα-ketoglutarate intervention may protect against inflammation-related CRC.