Effect of 3,3′-Diindolylmethane on Gut Microbiome in Colorectal Cancer

Abstract

Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world, and currently there is no cure for CRC. In the current study we investigated the effects of 3,3′-diindolylmethane (DIM) on the murine azoxymethane-dextran sodium sulfate (AOM-DSS) CRC model. Our data shows that administration of DIM alleviates symptoms associated with CRC. Endoscopy and histopathology showed DIM decreased colonic tissue damage and tumor growth. In addition, DIM was able to decrease myeloid-derived suppressor cells (MDSCs) in the blood and spleen in the AOM-DSS model. DIM treatment also significantly altered T cells populations which included decreases in Tregs and IL-10 producing T cells while increasing in Th1 and Th17 cells. We performed 16S rRNA sequencing of cecal flushes and validation with PCR revealed that AOM-DSS administration led to significant decreases in bacterial species Ruminococcus gnavus, Akkermansia muciniphila, Bifidobacterium pseudolongum, Haemophilus parainfluenza, and Acineobacter lwoffi, while increasing species such as Bacteroides acidifaciens, Bacteriodes ovalus, and Parabacteroides distasonis. However, mice that were treated with DIM showed a reversal in these gut microbial alterations caused by AOM-DSS CRC induction. We quantified short chain fatty acids (SCFA). AOM-DSS administration led to a significant decrease in i-butyric and n-butyric acids, however, mice that were treated with DIM increased these levels significantly. Finally we performed fecal transfer experiments to confirm that the alterations in gut microbiome by DIM mediated the anti-cancer effects. Collectively, these data show that DIM can ameliorate CRC by preventing cancer-associated gut microbial dysbiosis