Therapeutic role of ursodeoxycholic acid in colitis-associated cancer via gut microbiota modulation.

Inflammatory bowel disease (IBD) is a predisposing factor for colitis-associated cancer (CAC). The association between bile acids and the gut microbiota has been demonstrated in colon neoplasia; however, the effect of ursodeoxycholic acid (UDCA) on gut microbiota alteration in development of colitis and CAC is unknown. Our analysis of publicly available datasets demonstrated the association of UDCA treatment and accumulation of Akkermansia. UDCA-mediated alleviation of DSS-induced colitis was microbially dependent. UDCA treatment significantly upregulated Akkermansia colonization in a mouse model. Colonization of Akkermansia was associated with enhancement of the mucus layer upon UDCA treatment as well as activation of bile acid receptors in macrophages. UDCA played a role in CAC prevention and treatment in the AOM-DSS and ApcMin/+-DSS models through downregulation of inflammation and accumulation of Akkermansia. This study suggests that UDCA intervention could reshape intestinal gut homeostasis, facilitating colonization of Akkermansia and preventing and treating colitis and CAC.

A Review of the Research Applications of Centipeda minima.

Centipeda minima is a traditional Chinese medicine with wide applications and diverse pharmacological effects. Scholars have conducted extensive studies on its relevant clinical applications, especially its remarkable efficacy in cancer treatment. This paper thoroughly investigates the chemical composition and identification, pharmacological effects, and toxicity, along with the safety of Centipeda minima, so as to lay the foundation for corresponding clinical applications and product development. Furthermore, as global scholars have conducted extensive research on such clinical applications and made significant progress, the future development and utilization of Centipeda minima's active ingredients to create novel drugs are of great clinical significance.

Enteral nutrition promotes the remission of colitis by gut bacteria-mediated histidine biosynthesis.

BACKGROUND: Exclusive enteral nutrition (EEN) is an important alternative strategy for patients with Crohn's disease (CD), and during this process, microbiota alterations have been observed. However, the underlying mechanisms by which EEN reduces intestinal inflammation are currently unclear. METHODS: The therapeutic potential of enteral nutrition (EN) was assessed using various mouse models. Fecal full-length 16S rDNA sequencing analysis and several CD metagenome datasets were used to identify the candidate therapeutic bacteria Faecalibaculum rodentium (F. rodentium). Whole genome sequencing of F. rodentium and widely-targeted metabolome analysis of the supernatant showed that EN-induced F. rodentium accumulation protected against colitis via histidine biosynthesis. FINDINGS: The therapeutic potential of EN therapy was observed in both dextran sulfate sodium (DSS)-induced colitis and Il10-/- spontaneous colitis mouse models. Accumulation of F. rodentium after EN therapy was determined using full-length 16S rDNA sequencing and verified with several metagenome datasets from patients with CD. Colonization of an isolated F. rodentium could reduce colitis in Il10-/- mice. Significant histidine enrichment was observed in the F. rodentium culture supernatant, and a series of histidine biosynthesis genes were observed in the F. rodentium genome. Engineered Escherichia coli Nissle 1917 (EcN), encoding the heterologous hisG of F. rodentium (EcN-hisG), which was a key driver of histidine biosynthesis in F. rodentium, was found to protect against colitis. INTERPRETATION: This study suggests that EN-induced F. rodentium accumulation protects against colitis in mice via gut bacteria-mediated histidine biosynthesis. FUNDING: A full list of funding bodies can be found in the Acknowledgements section.

Dietary iron modulates gut microbiota and induces SLPI secretion to promote colorectal tumorigenesis.

Dietary iron intake is closely related to the incidence of colorectal cancer. However, the interactions among dietary iron, gut microbiota, and epithelial cells in promoting tumorigenesis have rarely been discussed. Here, we report that gut microbiota plays a crucial role in promoting colorectal tumorigenesis in multiple mice models under excessive dietary iron intake. Gut microbiota modulated by excessive dietary iron are pathogenic, irritating the permeability of the gut barrier and causing leakage of lumen bacteria. Mechanistically, epithelial cells released more secretory leukocyte protease inhibitor (SLPI) to combat the leaked bacteria and limit inflammation. The upregulated SLPI acted as a pro-tumorigenic factor and promoted colorectal tumorigenesis by activating the MAPK signaling pathway. Moreover, excessive dietary iron significantly depleted Akkermansiaceae in the gut microbiota; while supplementation with Akkermansia muciniphila could successfully attenuate the tumorigenic effect from excessive dietary iron. Overall, excessive dietary iron perturbs diet - microbiome-epithelium interactions, which contributes to intestinal tumor initiation.

Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes ß-catenin palmitoylation to drive colorectal cancer progression.

Metabolic reprogramming is a hallmark of cancer. However, it is not well known how metabolism affects cancer progression. We identified that metabolic enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes ß-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of ß-catenin and subsequent ß-Trcp-mediated proteasomal degradation. In return, stabilized ß-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of ß-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-ß-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated ß-catenin palmitoylation and stabilization and hyperactivates ß-catenin signaling thus promoting CRC progression. Particularly, targeting ß-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit ß-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-ß-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating ß-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or ß-catenin palmitoylation as a viable option for CRC treatment.

Mesenteric Adipose Tissue-Derived Klebsiella variicola Disrupts Intestinal Barrier and Promotes Colitis by Type VI Secretion System.

Mesenteric adipose tissue (MAT) in Crohn's disease (CD) is associated with transmural inflammation. Extended mesenteric excision can reduce surgical recurrence and improve long-term outcomes, indicating that MAT plays an important role in the pathogenesis of CD. Bacterial translocation has been reported to occur in the MAT of patients with CD (CD-MAT), but the mechanisms by which translocated bacteria lead to intestinal colitis remain unclear. Here it is shown that members of Enterobacteriaceae are highly enriched in CD-MAT compared with non-CD controls. Viable Klebsiella variicola in Enterobacteriaceae is isolated exclusively in CD-MAT and can induce a pro-inflammatory response in vitro and exacerbates colitis both in dextran sulfate sodium (DSS)-induced colitis mice model and IL-10-/- spontaneous colitis mice model. Mechanistically, active type VI secretion system (T6SS) is identified in the genome of K. variicola, which can impair the intestinal barrier by inhibiting the zonula occludens (ZO-1) expression. Dysfunction of T6SS by CRISPR interference system alleviates the inhibitory effect of K. variicola on ZO-1 expression and attenuated colitis in mice. Overall, these findings demonstrate that a novel colitis-promoting bacteria exist in the mesenteric adipose tissue of CD, opening a new therapeutic avenue for colitis management.

c-Myc-IMPDH1/2 axis promotes tumourigenesis by regulating GTP metabolic reprogramming.

BACKGROUND: Metabolic reprogramming is a hallmark of cancer. Metabolic rate-limiting enzymes and oncogenic c-Myc (Myc) play critical roles in metabolic reprogramming to affect tumourigenesis. However, a systematic assessment of metabolic rate-limiting enzymes and their relationship with Myc in human cancers is lacking. METHODS: Multiple Pan-cancer datasets were used to develop the transcriptome, genomic alterations, clinical outcomes and Myc correlation landscapes of 168 metabolic rate-limiting enzymes across 20 cancers. Real-time quantitative PCR and immunoblotting were, respectively, used to examine the mRNA and protein of inosine monophosphate dehydrogenase 1 (IMPDH1) in human colorectal cancer (CRC), azoxymethane/dextran sulphate sodium-induced mouse CRC and spontaneous intestinal tumours from APCMin/+ mice. Clone formation, CCK-8 and subcutaneous xenograft model were applied to investigate the possible mechanisms connecting IMPDH1 to CRC growth. Co-immunoprecipitation and protein half-life assay were used to explore the mechanisms underlying the regulation of IMPDH1. RESULTS: We explored the global expression patterns, dysregulation profiles, genomic alterations and clinical relevance of 168 metabolic rate-limiting enzymes across human cancers. Importantly, a series of enzymes were associated with Myc, especially top three upregulated enzymes (TK1, RRM2 and IMPDH1) were positively correlated with Myc in multiple cancers. As a proof-of-concept exemplification, we demonstrated that IMPDH1, a rate-limiting enzyme in GTP biosynthesis, is highly upregulated in CRC and promotes CRC growth in vitro and in vivo. Mechanistically, IMPDH2 stabilizes IMPDH1 by decreasing the polyubiquitination levels of IMPDH1, and Myc promotes the de novo GTP biosynthesis by the transcriptional activation of IMPDH1/2. Finally, we confirmed that the Myc-IMPDH1/2 axis is dysregulated across human cancers. CONCLUSIONS: Our study highlights the essential roles of metabolic rate-limiting enzymes in tumourigenesis and their crosstalk with Myc, and the Myc-IMPDH1/2 axis promotes tumourigenesis by altering GTP metabolic reprogramming. Our results propose the inhibition of IMPDH1 as a viable option for cancer treatment.

Comprehensive Analysis of the Expression and Prognosis for MMPs in Human Colorectal Cancer.

BACKGROUND: Previous study implicated that genes of matrix metalloproteinase (MMP) family play an important role in tumor invasion, neoangiogenesis, and metastasis. However, the diverse expression patterns and prognostic values of 24 MMPs in colorectal cancer are yet to be analyzed. METHODS: In this study, by integrating public database and our data, we first investigated the expression levels and protein levels of MMPs in patients with colorectal cancer. Then, by using TCGA and GEO datasets, we evaluated the association of MMPs with clinicopathological parameters and prognosis of colorectal cancer. Finally, by using the cBioPortal online tool, we analyzed the alterations of MMPs and did the network and pathway analyses for MMPs and their nearby genes. RESULTS: We found that, MMP1, MMP3, MMP7, MMP9-MMP12, and MMP14 were consistently upregulated in public dataset and our samples. Whereas, MMP28 was consistently downregulated in public dataset and our samples. In the clinicopathological analyses, upregulated MMP11, MMP14, MMP16, MMP17, MMP19, and MMP23B were significantly associated with a higher tumor stage. In the survival analyses, upregulated MMP11, MMP14, MMP17, and MMP19 were significantly associated with a shorter progression-free survival (PFS) time and a shorter relapse-free (RFS) time. DISCUSSION: This study implied that MMP11, MMP14, MMP17, and MMP19 are potential targets of precision therapy for patients with colorectal cancer.

Microbiota in mesenteric adipose tissue from Crohn's disease promote colitis in mice.

BACKGROUND: Mesenteric adipose tissue (mAT) hyperplasia, known as creeping fat is a pathologic characteristic of Crohn's disease (CD). The reserve of creeping fat in surgery is associated with poor prognosis of CD patients, but the mechanism remains unknown. METHODS: Mesenteric microbiome, metabolome, and host transcriptome were characterized using a cohort of 48 patients with CD and 16 non-CD controls. Multidimensional data including 16S ribosomal RNA gene sequencing (16S rRNA), host RNA sequencing, and metabolome were integrated to reveal network interaction. Mesenteric resident bacteria were isolated from mAT and functionally investigated both in the dextran sulfate sodium (DSS) model and in the Il10 gene-deficient (Il10-/-) mouse colitis model to validate their pro-inflammatory roles. RESULTS: Mesenteric microbiota contributed to aberrant metabolites production and transcripts in mATs from patients with CD. The presence of mAT resident microbiota was associated with the development of CD. Achromobacter pulmonis (A. pulmonis) isolated from CD mAT could translocate to mAT and exacerbate both DSS-induced and Il10 gene-deficient (Il10-/-) spontaneous colitis in mice. The levels of A. pulmonis in both mAT and mucous layer from CD patients were higher compared to those from the non-CD group. CONCLUSIONS: This study suggests that the mesenteric microbiota from patients with CD sculpt a detrimental microenvironment and promote intestinal inflammation. Video abstract.