Gut microbiota in colorectal cancer development and therapy

Fusobacterium nucleatum, a key pathogenic factor and microbial biomarker for colorectal cancer.

Simple Summary Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. In this review article, we examine the role of gut microbiota in the development and progression of CRC. We also examine the use of gut microbiota as a biomarker to predict CRC and its possible therapeutic outcome. Abstract Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer to the ~40 trillion microorganisms that inhabit the human gut. Advances in next-generation sequencing technologies and metagenomics have provided new insights into the gut microbial ecology and have helped in linking gut microbiota to CRC. Many studies carried out in humans and animal models have emphasized the role of certain gut bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, in the onset and progression of CRC. Metagenomic studies have opened up new avenues for the application of gut microbiota in the diagnosis, prevention, and treatment of CRC. This review article summarizes the role of gut microbiota in CRC development and its use as a biomarker to predict the disease and its potential therapeutic applications.

https://www.mdpi.com/2072-6694/15/3/866/pdf?version=1675335612

Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities

Abstract RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N 6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets. 

Methyltransferase-like proteins in cancer biology and potential therapeutic targeting

Commensal bacteria and other microorganisms that reside in the human body are closely associated with the development and treatment of cancers. Recently, tumor microbiome (TM) has been identified in a variety of cancers such as pancreatic, lung, and breast cancers. TM has different compositions in different tumors and has different effects on tumors. TM plays an important role in the formation of the tumor microenvironment, regulation of local immunity, and modification of tumor cell biology, and directly affects the efficacy of drug treatment for tumors. TM is expected to be a biomarker for tumors, and engineered tumor-targeting bacteria and anti-cancer microbial agents (GEN-001) have an important role in the treatment of tumors. This paper reviews the relevant studies on TM in recent years and describes its distribution in different tumors, its correlation with clinical features, its effect on local immunity, and the research directions of TM in tumor treatment. 

The Role of The Tumor Microbiome in Tumor Development and Its Treatment

Microbiota-host interactions play critical roles in colorectal cancer (CRC) progression, however, the underlying mechanisms remain elusive. Here, we uncover that Fusobacterium nucleatum (F. nucleatum) induces a dramatic decline of m6A modifications in CRC cells and patient-derived xenograft (PDX) tissues by downregulation of an m6A methyltransferase METTL3, contributing to inducation of CRC aggressiveness. Mechanistically, we characterized forkhead box D3 (FOXD3) as a transcription factor for METTL3. F. nucleatum activates YAP signaling, inhibits FOXD3 expression, and subsequently reduces METTL3 transcription. Downregulation of METTL3 promotes its target kinesin family member 26B (KIF26B) expression by reducing its m6A levels and diminishing YTHDF2-dependent mRNA degradation, which contributes to F. nucleatum-induced CRC metastasis. Moreover, METTL3 expression is negatively correlated with F. nucleatum and KIF26B levels in CRC tissues. A high expression of KIF26B is also significantly correlated with a shorter survival time of CRC patients. Together, our findings provide insights into modulating human m6A epitranscriptome by gut microbiota, and its significance in CRC progression. 

/pdf/fusobacterium-nucleatum-reduces-mettl3-mediated-m6a-18dhohmw.pdf

Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis

Akkermansia muciniphila ( A. muciniphila ), a gram-negative anaerobic bacterium, is selectively decreased in the fecal microbiota of patients with colorectal cancer (CRC), but its molecular mechanism in CRC development remains inconclusive. In this study, we first confirmed the inhibitory effect of A. muciniphila on CRC formation and analyzed the metabolic role of intestinal flora in human Polyps, A-CRA (advanced colorectal adenoma) and CRC samples. To better clarify the role of A. muciniphila in CRC development, a pseudo-germ-free (GF) azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model was established, followed by infection with or without A. muciniphila . Metabolomic analysis and RNA-seq analysis showed tryptophan-mediated aryl hydrocarbon receptor (AhR) was significantly down-regulated in A. muciniphila -infected CRC mice. Then, mice with intestinal specific AhR deficiency (AhR fl/fl Cre) were generated and were used in 2 murine models: AOM/DSS treatment as a model of carcinogen-induced colon cancer and a genetically induced model using Apc Min/+ mice. Notably, AhR deficiency inhibited CRC growth in the AOM/DSS and Apc Min/+ mouse model. Moreover, AhR deficiency inhibited, rather than enhanced, tumor formation and tumor-derived organoids in Apc-deficient cells both in vivo and in vitro by activating Wnt/ β -catenin signaling and TCF4/LEF1-dependent transcription. Furthermore, the antitumor effectiveness of A. muciniphila was abolished either in a human colon cancer tumor model induced by subcutaneous transplantation of AhR-silenced CRC cells, or AhR-deficienty spontaneous colorectal cancer model. In conclusion, supplementation with A. muciniphila . protected mice from CRC development by specifically inhibiting tryptophan-mediated AhR/ β -catenin signaling.

Akkermansia muciniphila inhibits tryptophan metabolism via the AhR/β-catenin signaling pathway to counter the progression of colorectal cancer

The purpose of this article is to introduce the measurements of phase coupling between spikes and rhythmic oscillations of local field potentials (LFPs). Multi-channel in vivo recording techniques allow us to record ensemble neuronal activity and LFPs simultaneously from the same sites in the brain. Neuronal activity is generally characterized by temporal spike sequences, while LFPs contain oscillatory rhythms in different frequency ranges. Phase coupling analysis can reveal the temporal relationships between neuronal firing and LFP rhythms. As the first step, the instantaneous phase of LFP rhythms can be calculated using Hilbert transform, and then for each time-stamped spike occurred during an oscillatory epoch, we marked instantaneous phase of the LFP at that time stamp. Finally, the phase relationships between the neuronal firing and LFP rhythms were determined by examining the distribution of the firing phase. Phase-locked spikes are revealed by the non-random distribution of spike phase. Theta phase precession is a unique phase relationship between neuronal firing and LFPs, which is one of the basic features of hippocampal place cells. Place cells show rhythmic burst firing following theta oscillation within a place field. And phase precession refers to that rhythmic burst firing shifted in a systematic way during traversal of the field, moving progressively forward on each theta cycle. This relation between phase and position can be described by a linear model, and phase precession is commonly quantified with a circular-linear coefficient. Phase coupling analysis helps us to better understand the temporal information coding between neuronal firing and LFPs.

[Multi-channel in vivo recording techniques: analysis of phase coupling between spikes and rhythmic oscillations of local field potentials]

Motion artifact removal in coronary CT angiography based on generative adversarial networks

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Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis

Akkermansia muciniphila inhibits tryptophan metabolism via the AhR/β-catenin signaling pathway to counter the progression of colorectal cancer

[Multi-channel in vivo recording techniques: analysis of phase coupling between spikes and rhythmic oscillations of local field potentials]

Motion artifact removal in coronary CT angiography based on generative adversarial networks