Chemotherapy-induced microbiota exacerbates the toxicity of chemotherapy through the suppression of interleukin-10 from macrophages.

The gut microbiota has been shown to influence the efficacy and toxicity of chemotherapy, thereby affecting treatment outcomes. Understanding the mechanism by which microbiota affects chemotherapeutic toxicity would have a profound impact on cancer management. In this study, we report that fecal microbiota transplantation from oxaliplatin-exposed mice promotes toxicity in recipient mice. Splenic RNA sequencing and macrophage depletion experiment showed that the microbiota-induced toxicity of oxaliplatin in mice was dependent on macrophages. Furthermore, oxaliplatin-mediated toxicity was exacerbated in Il10-/- mice, but not attenuated in Rag1-/- mice. Adoptive transfer of macrophage into Il10-/- mice confirmed the role of macrophage-derived IL-10 in the improvement of oxaliplatin-induced toxicity. Depletion of fecal Lactobacillus and Bifidobacterium was associated with the exacerbation of oxaliplatin-mediated toxicity, whereas supplementation with these probiotics alleviated chemotherapy-induced toxicity. Importantly, IL-10 administration and probiotics supplementation did not attenuate the antitumor efficacy of chemotherapy. Clinically, patients with colorectal cancer exposed to oxaliplatin exhibited downregulation of peripheral CD45+IL-10+ cells. Collectively, our findings indicate that microbiota-mediated IL-10 production influences tolerance to chemotherapy, and thus represents a potential clinical target.

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.

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.

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.

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.