Bifidobacterium breve-derived indole-3-lactic acid ameliorates colitis-associated tumorigenesis by directing the differentiation of immature colonic macrophages

Abstract

Aim: To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by Bifidobacterium breve (B. breve) and its associated metabolites in the initiation of colitis-associated colorectal cancer (CAC). Methods: Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to create a CAC model. The tumor-suppressive effect of B. breve and variations of macrophage subsets were evaluated. Intestinal macrophages were ablated to determine their role in the protective effects of B. breve. Efficacious molecules produced by B. breve were identified by non-targeted and targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The molecular mechanism was further verified in murine bone marrow-derived macrophages (BMDMs), macrophages derived from human peripheral blood mononuclear cells (hPBMCs), and demonstrated in CAC mice. Results: B. breve alleviated colitis symptoms, delayed colonic tumorigenesis, and promoted phenotypic differentiation of immature inflammatory macrophages into mature homeostatic macrophages. On the contrary, the ablation of intestinal macrophages largely annulled the protective effects of B. breve. Microbial analysis of colonic contents revealed the enrichment of probiotics and the depletion of potential pathogens following B. breve supplementation. Moreover, indole-3-lactic acid (ILA) was positively correlated with B. breve in CAC mice and highly enriched in the culture supernatant of B. breve. Also, the addition of ILA directly promoted AKT phosphorylation and restricted the pro-inflammatory response of murine BMDMs and macrophages derived from hPBMCs in vitro. The effects of ILA in murine BMDMs and macrophages derived from hPBMCs were abolished by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or the AKT inhibitor MK-2206. Furthermore, ILA could protect against tumorigenesis by regulating macrophage differentiation in CAC mice; the AhR antagonist largely abrogated the effects of B. breve and ILA in relieving colitis and tumorigenesis. Conclusion: B. breve-mediated tryptophan metabolism ameliorates the precancerous inflammatory intestinal milieu to inhibit tumorigenesis by directing the differentiation of immature colonic macrophages.

Characterization of Eurotium cristatum Fermented Thinned Young Apple and Mechanisms Underlying Its Alleviating Impacts on Experimental Colitis

“…Wang et al , reported that Lactobacillus-derived indole lactic acid could promote the expression of key bacterial enzymes implicated in tryptophan metabolism, leading to the synthesis of other indole derivatives including indole-3-propionic acid and indole-3-acetic acid, possessing the ability to reduce colonic inflammation. Anticolitis effect of indole lactic acid was also shown in previous studies conducted by Li et al and Wang et al Moreover, anti-inflammation effect of indole-3-carboxaldehyde has been recently recognized. Indole-3-carboxaldehyde has been shown to alleviate inflammation in the colon, liver, and kidney. , Although mechanisms underlying the benefits of indole derivatives remain exclusive, they may act as key PXR-modulating activators, subsequently attenuating inflammation by inhibiting NF-κB signaling. − …”

Indole Lactic Acid in Plasma and Urine: A Potential Biomarker for Chronic Kidney Disease and Inflammatory

“…ILA has the potential to regulate intestinal homeostasis by reducing the accumulation of inflammatory macrophages. 9 By increasing H3K27ac binding at the enhancer regions of IL12a, ILA facilitated the augmentation of IL12a production in dendritic cells, thereby promoting the stimulation of CD8 T cell immunity against tumor growth. Additionally, ILA exhibited the ability to enhance the activity of CD8 T cells present within the tumor microenvironment by modulating chromatin accessibility.…”