Dingjiacheng Jia

in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.

Imbalance of gut microbiota homeostasis is related to the occurrence of ulcerative colitis (UC), and probiotics are thought to modulate immune microenvironment and repair barrier function. Here, in order to reveal the interaction between UC and gut microbiota, we screened a new probiotic strain by 16S rRNA sequencing from Dextran Sulfate Sodium (DSS)-induced colitis mice, and explored the mechanism and clinical relevance. Lactobacillus johnsonii (L. johnsonii), as a potential anti-inflammatory bacterium was decreased colonization in colitis mice. Gavage L. johnsonii could alleviate colitis by specifically increasing the proportion of intestinal macrophages and the secretion of Il-10 with macrophages depleted model and in Il10−/− mice. We identified this subset of immune cells activated by L. johnsonii as CD206+ macrophagesIL−10. Mechanistically, L. johnsonii supplementation enhanced the mobilization of CD206+ macrophagesIL−10 through the activation of STAT3 in vivo and in vitro. In addition, we revealed that TLR1/2 was essential for the activation of STAT3 and the recognition of L. johnsonii by macrophages. Clinically, there was positive correlation between the abundance of L. johnsonii and the expression level of MRC1, IL10 and TLR1/2 in UC tissues. L. johnsonii could activate native macrophages into CD206+ macrophages and release IL-10 through TLR1/2-STAT3 pathway to relieve experimental colitis. L. johnsonii may serve as an immunomodulator and anti-inflammatory therapeutic target for UC.

Abstract Background The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is not well explored. Here, we elucidated the functional role of Bifidobacterium adolescentis ( B.a ) on CRC and investigated its possible mechanism on the manipulation of cancer‐associated fibroblasts (CAFs) in CRC. Methods Different CRC animal models and various cell line models were established to explore the function of B.a on CRC. The single‐cell RNA sequencing (scRNA‐seq) or flow cytometry was used to detect the cell subsets in the TME of CRC. Western blot, quantitative real‐time polymerase chain reaction (qRT‐PCR), or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1 (GAS1) on CD143 + CAFs. Chromatin immunoprecipitation quantitative real‐time PCR (CHIP‐qPCR) was performed to investigate the regulation of transcription factor 4 (TCF4) on GAS1. Multi‐immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray. Results We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo. Supplementation with B.a suppressed Apc Min/+ spontaneous or AOM/DSS‐induced tumorigenesis in mice. scRNA‐seq revealed that B.a facilitated a subset of CD143 + CAFs by inhibiting the infiltration of Th2 cells, while promoting the TNF‐alpha + B cells in TME. CD143 + CAFs highly expressed GAS1 and exhibited tumor suppressive effect. Mechanistically, GAS1 was activated by the Wnt/β‐catenin signaling in CD143 + CAFs. B.a abundance was correlated with the expression level of CD143 and GAS1. The level of CD143 + CAFs predicted the better survival outcome in CRC patients. Conclusions These results highlighted that B.a induced a new subset of CD143 + CAFs by Wnt signaling‐regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic‐based modulation of TME in CRC.

The gut microbiota can produce a variety of microbial-derived metabolites to influence tumor development. Tryptophan, an essential amino acid in the human body, can be converted by microorganisms via the indole pathway to indole metabolites such as Indole-3-Lactic Acid (ILA), Indole-3-Propionic Acid (IPA), Indole Acetic Acid (IAA) and Indole-3-Aldehyde (IAld). Recent studies have shown that indole metabolites play key roles in tumor progression, and they can be used as adjuvant regimens for tumor immunotherapy or chemotherapy. Here, we summarize recent findings on the common microbial indole metabolites and provide a review of the mechanisms of different indole metabolites in the tumor microenvironment. We further discuss the limitations of current indole metabolite research and future possibilities. It is expected that microbial indole metabolites will provide new strategies for clinical therapy.