The effect of metformin on gut microbiota has been reported, but whether metformin can suppress colorectal cancer (CRC) by affecting gut microbiota composition and rescue F. nucleatum-induced ...tumourigenicity remains unclear.
To identify microbiota associated with both CRC occurrence and metformin treatment, first, we reanalyzed the gut microbiome of our previous data on two human cohorts of normal and CRC individuals. Subsequently, we summarized microbiota altered by metformin from published literatures. Several taxa, including Fusobacterium, were associated with both CRC occurrence and metformin treatment. We investigated the effect of metformin on APCMin/+ mice given with or without F. nucleatum. 16S rRNA gene sequencing was performed.
We summarized 131 genera altered by metformin from 18 published literatures. Five genera reported to be changed by metformin, including Bacteroides, Streptococcus, Achromobacter, Alistipes and Fusobacterium, were associated with CRC in both of our human cohorts. Metformin relieved the symptoms caused by F. nucleatum administration in APCMin/+ mice, and showed promise in suppressing intestinal tumour formation and rescuing F. nucleatum-induced tumourigenicity. Administration of F. nucleatum and/or metformin had effect on gut microbiome structure, composition and functions of APCMin/+ mice.
This study pioneers in predicting critical CRC-associated taxa contributing to the antitumour effect of metformin, and correlating gut microbiome with the antitumour effect of metformin in experimental animals. We presented a basis for future investigations into metformin's potential effect on suppressing F. nucleatum-induced tumor formation in vivo.
This work was supported by grants from the National Natural Science Foundation of China (31701250).
Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the ...contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.
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•Specific gut microbes track with post-chemotherapy recurrence of colorectal cancer•F. nucleatum orchestrates the Toll-like receptor, microRNAs, and autophagy network to control cancer chemoresistance•Measuring and targeting F. nucleatum may be useful for patient prognosis and management
Reducing a specific gut microbe in colorectal cancer patients may improve their response to chemotherapy and reduce cancer recurrence.
Microbiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation ...between the gut microbiota and glucose metabolism is unknown in CRC.
F-FDG (
F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in
-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1.
We have found
.
abundance correlated with high glucose metabolism in patients with CRC. Furthermore,
supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically,
activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function.
and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated
.
Accumulated studies have highlighted the diverse roles of 5-hydroxytryptamine (5-HT), or serotonin, in cancer biology, particularly in colorectal cancer (CRC). While 5-HT primarily exerts its effects ...through binding to various 5-HT receptors, receptor-independent mechanisms such as serotonylation remain unclear. This study revealed that depleting 5-HT, either through genetic silencing of Tph1 or using a selective TPH1 inhibitor, effectively reduced the growth of CRC tumors. Interestingly, although intrinsic 5-HT synthesis exists in CRC, it is circulating 5-HT that mediates the cancer-promoting function of 5-HT. Blocking the function of 5-HT receptors showed that the oncogenic roles of 5-HT in CRC operate through a mechanism that is separate from its receptor. Instead, serotonylation of histone H3Q5 (H3Q5ser) was found in CRC cells and cancer-associated fibroblasts (CAFs). H3Q5ser triggers a phenotypic switch of CAFs towards an inflammatory-like CAF (iCAF) subtype, which further enhances CRC cell proliferation, invasive characteristics, and macrophage polarization. Knockdown of the 5-HT transporter SLC22A3 or inhibition of TGM2 reduces H3Q5ser levels and reverses the tumor-promoting phenotypes of CAFs in CRC. Collectively, this study sheds light on the serotonylation-dependent mechanisms of 5-HT in CRC progression, offering insights into potential therapeutic strategies targeting the serotonin pathway for CRC treatment.Accumulated studies have highlighted the diverse roles of 5-hydroxytryptamine (5-HT), or serotonin, in cancer biology, particularly in colorectal cancer (CRC). While 5-HT primarily exerts its effects through binding to various 5-HT receptors, receptor-independent mechanisms such as serotonylation remain unclear. This study revealed that depleting 5-HT, either through genetic silencing of Tph1 or using a selective TPH1 inhibitor, effectively reduced the growth of CRC tumors. Interestingly, although intrinsic 5-HT synthesis exists in CRC, it is circulating 5-HT that mediates the cancer-promoting function of 5-HT. Blocking the function of 5-HT receptors showed that the oncogenic roles of 5-HT in CRC operate through a mechanism that is separate from its receptor. Instead, serotonylation of histone H3Q5 (H3Q5ser) was found in CRC cells and cancer-associated fibroblasts (CAFs). H3Q5ser triggers a phenotypic switch of CAFs towards an inflammatory-like CAF (iCAF) subtype, which further enhances CRC cell proliferation, invasive characteristics, and macrophage polarization. Knockdown of the 5-HT transporter SLC22A3 or inhibition of TGM2 reduces H3Q5ser levels and reverses the tumor-promoting phenotypes of CAFs in CRC. Collectively, this study sheds light on the serotonylation-dependent mechanisms of 5-HT in CRC progression, offering insights into potential therapeutic strategies targeting the serotonin pathway for CRC treatment.
Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating antitumor immunity, suggesting it could be used to overcome ...immunosuppression in colorectal cancer. Herein, using single-cell RNA sequencing (scRNA-seq), we showed that metformin remodels the immune landscape of colorectal cancer. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the colorectal cancer tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in colorectal cancer cells and increased in CD8+ T cells. Untreated colorectal cancer cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T-cell function. Metformin in turn reduced tryptophan uptake by colorectal cancer cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in colorectal cancer cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating colorectal cancer.
Analysis of the impact of metformin on the colorectal cancer immunometabolic landscape at a single-cell resolution shows that metformin alters cancer cell tryptophan metabolism to stimulate CD8+ T-cell antitumor activity.
Maladaptation of host-microbiota metabolic interplay plays a critical role in colorectal cancer initiation. Here, through a combination of single-cell transcriptomics, microbiome profiling, ...metabonomics, and clinical analysis on colorectal adenoma and carcinoma tissues, we demonstrate that host’s urea cycle metabolism is significantly activated during colorectal tumorigenesis, accompanied by the absence of beneficial bacteria with ureolytic capacity, such as Bifidobacterium, and the overabundance of pathogenic bacteria lacking ureolytic function. Urea could enter into macrophages, inhibit the binding efficiency of p-STAT1 to SAT1 promotor region, and further skew macrophages toward a pro-tumoral phenotype characterized by the accumulation of polyamines. Treating a murine model using urea cycle inhibitors or Bifidobacterium-based supplements could mitigate urea-mediated tumorigenesis. Collectively, this study highlights the utility of urea cycle inhibitors or therapeutically manipulating microbial composition using probiotics to prevent colorectal cancer.
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•Urea cycle is activated through colorectal adenoma-to-carcinoma sequence•Urea cycle activation depends on the absence of gut microbes with ureolytic capacity•Overabundant intestinal urea is a driving force for colorectal cancer initiation•Urea skews macrophages toward a pro-tumoral phenotype through the accumulation of polyamines
Chen et al. report that host’s urea cycle metabolism is activated during colorectal carcinogenesis, accompanied by the absence of gut microbes with ureolytic capacity, represented by Bifidobacterium, and the overabundance of pathogenic bacteria that lack ureolytic function. Urea can skew macrophages toward a pro-tumoral phenotype characterized by the accumulation of polyamines.
Temperature, flow and pressure are critical parameters that influence the performance of fuel cells, in terms of potential, current and power density, for example. Hence, the monitoring of ...non-uniform temperature/flow rate/pressure within a proton exchange membrane fuel cell (PEMFC) is crucial. To prevent degradation of the performance of a PEMFC, the size of sensors is reduced herein to a μm scale using micro-electro-mechanical systems (MEMS). Integrated flexible micro sensors were fabricated and embedded in a PEMFC to measure local pressure, temperature, and flow rate. The temperatures upstream and downstream of the PEMFC were respectively 64.8°C and 64.7°C at RH50% and 0.1 A/cm 2 , and 62.7°C and 64.3°C at RH100% and 0.1 A/cm 2 .
Pressure and flow rate are critical parameters associated with the performance of proton exchange membrane fuel cells (PEMFCs). Fuel cell flooding can be diagnosed by monitoring pressure drops. Flow ...rate is related to optimized operation of fuel cells and fuel cell aging. Previous research measured pressures at the flow channel inlet and outlet. However, determining the pressure distribution and flow rate inside PEMFCs is difficult. In this study, flexible micro-sensors are embedded into the flow channels to measure internal in situ pressures and flows of PEMFCs. These micro-sensors integrate micro pressure sensors and flow sensors via the micro-electromechanical systems (MEMS).
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