A Keystone Gut Bacterium Christensenella minuta-A Potential Biotherapeutic Agent for Obesity and Associated Metabolic Diseases.

A new next-generation probiotic, Christensenella minuta was first discovered in 2012 from healthy human stool and described under the phylum Firmicutes. C. minuta is a subdominant commensal bacterium with highly heritable properties that exhibits mutual interactions with other heritable microbiomes, and its relative abundance is positively correlated with the lean host phenotype associated with a low BMI index. It has been the subject of numerous studies, owing to its potential health benefits. This article reviews the evidence from various studies of C. minuta interventions using animal models for managing metabolic diseases, such as obesity, inflammatory bowel disease, and type 2 diabetes, characterized by gut microbiota dysbiosis and disruption of host metabolism. Notably, more studies have presented the complex interaction between C. minuta and host metabolism when it comes to metabolic health. Therefore, C. minuta could be a potential candidate for innovative microbiome-based biotherapy via fecal microbiota transplantation or oral administration. However, the detailed underlying mechanism of action requires further investigation.

Methylation Profile of Cancer Testis Antigens in Colorectal Cancer.

Background: Cancer testis antigens (CTAs) are a class of immune-stimulating antigens often overexpressed in many types of cancers. The usage of the CTAs as immunotherapy targets have been widely investigated in different cancers including melanoma, hematological malignancies, and colorectal cancer. Studies have indicated that the epigenetic regulation of the CTAs such as the methylation status may affect the expression of the CTAs. However, the report on the methylation status of the CTAs is conflicting. The general methylation profile of the CTAs, especially in colorectal cancer, is still elusive. Objective: To determine the methylation profile of the selected CTAs in our colorectal cancer patients. Methods: A total of 54 pairs of colorectal cancer samples were subjected to DNA methylation profiling using the Infinium Human Methylation 450K bead chip. Results: We found that most of the CTAs were hypomethylated, and CCNA1 and TMEM108 genes were among the few CTAs that were hypermethylated. Conclusion: Overall, our brief report has managed to show the overall methylation profile in over the 200 CTAs in colorectal cancer and this could be used for further refining any immunotherapy targets.

SARS-CoV-2 genomic surveillance in Malaysia: displacement of B.1.617.2 with AY lineages as the dominant Delta variants and the introduction of Omicron during the fourth epidemic wave.

OBJECTIVES: This study reported SARS-CoV-2 whole genome sequencing results from June 2021 to January 2022 from seven genome sequencing centers in Malaysia as part of the national surveillance program. METHODS: COVID-19 samples that tested positive by reverse transcription polymerase chain reaction and with cycle threshold values <30 were obtained throughout Malaysia. Sequencing of SARS-CoV-2 complete genomes was performed using Illumina, Oxford Nanopore, or Ion Torrent platforms. A total of 6163 SARS-CoV-2 complete genome sequences were generated over the surveillance period. All sequences were submitted to the Global Initiative on Sharing All Influenza Data database. RESULTS: From June 2021 to January 2022, Malaysia experienced the fourth wave of COVID-19 dominated by the Delta variant of concern, including the original B.1.617.2 lineage and descendant AY lineages. The B.1.617.2 lineage was identified as the early dominant circulating strain throughout the country but over time, was displaced by AY.59 and AY.79 lineages in Peninsular (west) Malaysia, and the AY.23 lineage in east Malaysia. In December 2021, pilgrims returning from Saudi Arabia facilitated the introduction and spread of the BA.1 lineage (Omicron variant of concern) in the country. CONCLUSION: The changing trends of circulating SARS-CoV-2 lineages were identified, with differences observed between west and east Malaysia. This initiative highlighted the importance of leveraging research expertise in the country to facilitate pandemic response and preparedness.

Insights into Carbapenem Resistance in Vibrio Species: Current Status and Future Perspectives.

The increasing prevalence of resistance in carbapenems is an escalating concern as carbapenems are reserved as last-line antibiotics. Although indiscriminate antibiotic usage is considered the primary cause for resistance development, increasing evidence revealed that inconsequential strains without any direct clinical relevance to carbapenem usage are harboring carbapenemase genes. This phenomenon indirectly implies that environmental microbial populations could be the 'hidden vectors' propelling carbapenem resistance. This work aims to explore the carbapenem-resistance profile of Vibrio species across diverse settings. This review then proceeds to identify the different factors contributing to the dissemination of the resistance traits and defines the transmission pathways of carbapenem resistance. Deciphering the mechanisms for carbapenem resistance acquisition could help design better prevention strategies to curb the progression of antimicrobial resistance development. To better understand this vast reservoir selecting for carbapenem resistance in non-clinical settings, Vibrio species is also prospected as one of the potential indicator strains for carbapenem resistance in the environment.

Exploring the Potential of Human Milk and Formula Milk on Infants' Gut and Health.

Early-life gut microbiota plays a role in determining the health and risk of developing diseases in later life. Various perinatal factors have been shown to contribute to the development and establishment of infant gut microbiota. One of the important factors influencing the infant gut microbial colonization and composition is the mode of infant feeding. While infant formula milk has been designed to resemble human milk as much as possible, the gut microbiome of infants who receive formula milk differs from that of infants who are fed human milk. A diverse microbial population in human milk and the microbes seed the infant gut microbiome. Human milk contains nutritional components that promote infant growth and bioactive components, such as human milk oligosaccharides, lactoferrin, and immunoglobulins, which contribute to immunological development. In an attempt to encourage the formation of a healthy gut microbiome comparable to that of a breastfed infant, manufacturers often supplement infant formula with prebiotics or probiotics, which are known to have a bifidogenic effect and can modulate the immune system. This review aims to elucidate the roles of human milk and formula milk on infants' gut and health.

Ketogenic Diet: A Dietary Intervention via Gut Microbiome Modulation for the Treatment of Neurological and Nutritional Disorders (a Narrative Review).

The ketogenic diet (KD) has been important in treating epilepsy since the 1920s. The benefits of KD further expanded to other neurological diseases, including Alzheimer's diseases, autism spectrum disorder, and nutritional disorder (obesity). Although the therapeutic efficacy of KD has been generally accepted, there is limited knowledge about its underlying mechanism of action, particularly its effect on our gut microbiome. Gut dysbiosis has been proposed to be involved in those diseases, and KD can promote gut microbiota remodeling that may assist in recovery. This review explores the therapeutic applications of KD, the roles of the gut microbiome in neurological diseases and obesity, as well as the effect of KD on the gut microbiome. The present information suggests that KD has significant roles in altering the gut microbiome to improve disease symptoms, mainly by incrementing Bacteroidetes to Firmicutes (B/F) ratio and reducing Proteobacteria in certain cases. However, current gaps call for continued research to understand better the gut microbiota profile altered by KD.

Deciphering colorectal cancer immune microenvironment transcriptional landscape on single cell resolution - A role for immunotherapy.

Single cell RNA sequencing (scRNA-seq) is a novel high-throughput technique that enables the investigation of a single cell's entire transcriptome. It elucidates intricate cellular networks and generates indices that will eventually enable the development of more targeted and personalized medications. The importance of scRNA-seq has been highlighted in complex biological systems such as cancer and the immune system, which exhibit significant cellular heterogeneity. Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related death globally. Chemotherapy continues to be used to treat these patients. However, 5-FU has been utilized in chemotherapy regimens with oxaliplatin and irinotecan since the 1960s and is still used today. Additionally, chemotherapy-resistant metastatic CRCs with poor prognoses have been treated with immunotherapy employing monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapy and cancer vaccines. Personalized immunotherapy employing tumor-specific neoantigens allows for treating each patient as a distinct group. Sequencing and multi-omics approaches have helped us identify patients more precisely in the last decade. The introduction of modern methods and neoantigen-based immunotherapy may usher in a new era in treating CRC. The unmet goal is to better understand the cellular and molecular mechanisms that contribute to CRC pathogenesis and resistance to treatment, identify novel therapeutic targets, and make more stratified and informed treatment decisions using single cell approaches. This review summarizes current scRNA-seq utilization in CRC research, examining its potential utility in the development of precision immunotherapy for CRC.

MicroRNA Methylome Signature and Their Functional Roles in Colorectal Cancer Diagnosis, Prognosis, and Chemoresistance.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite significant advances in the diagnostic services and patient care, several gaps remain to be addressed, from early detection, to identifying prognostic variables, effective treatment for the metastatic disease, and the implementation of tailored treatment strategies. MicroRNAs, the short non-coding RNA species, are deregulated in CRC and play a significant role in the occurrence and progression. Nevertheless, microRNA research has historically been based on expression levels to determine its biological significance. The exact mechanism underpinning microRNA deregulation in cancer has yet to be elucidated, but several studies have demonstrated that epigenetic mechanisms play important roles in the regulation of microRNA expression, particularly DNA methylation. However, the methylation profiles of microRNAs remain unknown in CRC patients. Methylation is the next major paradigm shift in cancer detection since large-scale epigenetic alterations are potentially better in identifying and classifying cancers at an earlier stage than somatic mutations. This review aims to provide insight into the current state of understanding of microRNA methylation in CRC. The new knowledge from this study can be utilized for personalized health diagnostics, disease prediction, and monitoring of treatment.

TCGA-My: A Systematic Repository for Systems Biology of Malaysian Colorectal Cancer.

Colorectal cancer (CRC) ranks second among the most commonly occurring cancers in Malaysia, and unfortunately, its pathobiology remains unknown. CRC pathobiology can be understood in detail with the implementation of omics technology that is able to generate vast amounts of molecular data. The generation of omics data has introduced a new challenge for data organization. Therefore, a knowledge-based repository, namely TCGA-My, was developed to systematically store and organize CRC omics data for Malaysian patients. TCGA-My stores the genome and metabolome of Malaysian CRC patients. The genome and metabolome datasets were organized using a Python module, pandas. The variants and metabolites were first annotated with their biological information using gene ontologies (GOs) vocabulary. The TCGA-My relational database was then built using HeidiSQL PorTable 9.4.0.512, and Laravel was used to design the web interface. Currently, TCGA-My stores 1,517,841 variants, 23,695 genes, and 167,451 metabolites from the samples of 50 CRC patients. Data entries can be accessed via search and browse menus. TCGA-My aims to offer effective and systematic omics data management, allowing it to become the main resource for Malaysian CRC research, particularly in the context of biomarker identification for precision medicine.

Epigenome-Wide DNA Methylation Profiling in Colorectal Cancer and Normal Adjacent Colon Using Infinium Human Methylation 450K.

The aims were to profile the DNA methylation in colorectal cancer (CRC) and to explore cancer-specific methylation biomarkers. Fifty-four pairs of CRCs and the adjacent normal tissues were subjected to Infinium Human Methylation 450K assay and analysed using ChAMP R package. A total of 26,093 differentially methylated probes were identified, which represent 6156 genes; 650 probes were hypermethylated, and 25,443 were hypomethylated. Hypermethylated sites were common in CpG islands, while hypomethylated sites were in open sea. Most of the hypermethylated genes were associated with pathways in cancer, while the hypomethylated genes were involved in the PI3K-AKT signalling pathway. Among the identified differentially methylated probes, we found evidence of four potential probes in CRCs versus adjacent normal; HOXA2 cg06786372, OPLAH cg17301223, cg15638338, and TRIM31 cg02583465 that could serve as a new biomarker in CRC since these probes were aberrantly methylated in CRC as well as involved in the progression of CRC. Furthermore, we revealed the potential of promoter methylation ADHFE1 cg18065361 in differentiating the CRC from normal colonic tissue from the integrated analysis. In conclusion, aberrant DNA methylation is significantly involved in CRC pathogenesis and is associated with gene silencing. This study reports several potential important methylated genes in CRC and, therefore, merit further validation as novel candidate biomarker genes in CRC.

Whole genome sequencing of Malaysian colorectal cancer patients reveals specific druggable somatic mutations.

The incidences of colorectal cancer (CRC) are continuously increasing in some areas of the world, including Malaysia. In this study, we aimed to characterize the landscape of somatic mutations using the whole-genome sequencing approach and identify druggable somatic mutations specific to Malaysian patients. Whole-genome sequencing was performed on the genomic DNA obtained from 50 Malaysian CRC patients' tissues. We discovered the top significantly mutated genes were APC, TP53, KRAS, TCF7L2 and ACVR2A. Four novel, non-synonymous variants were identified in three genes, which were KDM4E, MUC16 and POTED. At least one druggable somatic alteration was identified in 88% of our patients. Among them were two frameshift mutations in RNF43 (G156fs and P192fs) predicted to have responsive effects against the Wnt pathway inhibitor. We found that the exogenous expression of this RNF43 mutation in CRC cells resulted in increased cell proliferation and sensitivity against LGK974 drug treatment and G1 cell cycle arrest. In conclusion, this study uncovered our local CRC patients' genomic landscape and druggable alterations. It also highlighted the role of specific RNF43 frameshift mutations, which unveil the potential of an alternative treatment targeting the Wnt/ß-Catenin signalling pathway and could be beneficial, especially to Malaysian CRC patients.

Liquid Biopsy-Based Colorectal Cancer Screening via Surface Markers of Circulating Tumor Cells.

Colorectal cancer (CRC) is ranked second for cancer-related deaths worldwide with approximately half of the patients being diagnosed at the late stages. The untimely detection of CRC results in advancement to the metastatic stage and nearly 90% of cancer-related deaths. The early detection of CRC is crucial to decrease its overall incidence and mortality rates. The recent introduction of circulating tumor cells (CTCs) has enabled a less invasive sampling method from liquid biopsies, besides revealing key information toward CRC metastasis. The current gold standard for CTC identification is the CellSearch® system (Veridex). This first-generation instrumentation relies on a single cell surface marker (CSM) to capture and count CTCs. Detection of CTCs allows the identification of patients at risk for metastasis, whereas CTC enumeration could improve risk assessment, monitoring of systemic therapy, and detection of therapy resistance in advanced metastatic CRC. In this review, we compared the pros and cons between single CSM-based CTC enrichment techniques and multi-marker-based systems. We also highlighted the challenges faced in the routine implementation of CSM-dependent CTC detection methods in CRC screening, prediction, prognosis, disease monitoring, and therapy selection toward precision medicine, as well as the dwelling on post-CTC analysis and characterization methods.

Streptomyces sp.-A Treasure Trove of Weapons to Combat Methicillin-Resistant Staphylococcus aureus Biofilm Associated with Biomedical Devices.

Biofilms formed by methicillin-resistant S. aureus (MRSA) are among the most frequent causes of biomedical device-related infection, which are difficult to treat and are often persistent and recurrent. Thus, new and effective antibiofilm agents are urgently needed. In this article, we review the most relevant literature of the recent years reporting on promising anti-MRSA biofilm agents derived from the genus Streptomyces bacteria, and discuss the potential contribution of these newly reported antibiofilm compounds to the current strategies in preventing biofilm formation and eradicating pre-existing biofilms of the clinically important pathogen MRSA. Many efforts are evidenced to address biofilm-related infections, and some novel strategies have been developed and demonstrated encouraging results in preclinical studies. Nevertheless, more in vivo studies with appropriate biofilm models and well-designed multicenter clinical trials are needed to assess the prospects of these strategies.

Finding a Balance in the Vaginal Microbiome: How Do We Treat and Prevent the Occurrence of Bacterial Vaginosis?

Bacterial vaginosis (BV) has been reported in one-third of women worldwide at different life stages, due to the complex balance in the ecology of the vaginal microbiota. It is a common cause of abnormal vaginal discharge and is associated with other health issues. Since the first description of anaerobic microbes associated with BV like Gardnerella vaginalis in the 1950s, researchers have stepped up the game by incorporating advanced molecular tools to monitor and evaluate the extent of dysbiosis within the vaginal microbiome, particularly on how specific microbial population changes compared to a healthy state. Moreover, treatment failure and BV recurrence rate remain high despite the standard antibiotic treatment. Consequently, researchers have been probing into alternative or adjunct treatments, including probiotics or even vaginal microbiota transplants, to ensure successful treatment outcomes and reduce the colonization by pathogenic microbes of the female reproductive tract. The current review summarizes the latest findings in probiotics use for BV and explores the potential of vaginal microbiota transplants in restoring vaginal health.

Unveiling the Impact of Antibiotics and Alternative Methods for Animal Husbandry: A Review.

Since the 1950s, antibiotics have been used in the field of animal husbandry for growth promotion, therapy and disease prophylaxis. It is estimated that up to 80% of the antibiotics produced by the pharmaceutical industries are used in food production. Most of the antibiotics are used as feed additives at sub-therapeutic levels to promote growth. However, studies show the indiscriminate use of antibiotics has led to the emergence of multidrug-resistant pathogens that threaten both animal health and human health, including vancomycin-resistant Enterococcus (VRE), Methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae (CRE). This scenario is further complicated by the slow progress in achieving scientific breakthroughs in uncovering novel antibiotics following the 1960s. Most of the pharmaceutical industries have long diverted research funds away from the field of antibiotic discovery to more lucrative areas of drug development. If this situation is allowed to continue, humans will return to the pre-antibiotics era and potentially succumb to huge health and economic consequences. Fortunately, studies investigating various alternatives to antibiotics use in livestock show promising results. These alternatives include the application of bacteriophages and phage derived peptidoglycan degrading enzymes, engineered peptides, egg yolk antibodies, probiotics, prebiotics and synbiotics, as well as quorum quenching molecules. Therefore, this review aims to discuss the use of growth-promoting antibiotics and their impact on livestock and provide insights on the alternative approaches for animal husbandry.

Microsatellite Instability in Colorectal Cancer Liquid Biopsy-Current Updates on Its Potential in Non-Invasive Detection, Prognosis and as a Predictive Marker.

Colorectal cancer (CRC) is the third most commonly-diagnosed cancer in the world and ranked second for cancer-related mortality in humans. Microsatellite instability (MSI) is an indicator for Lynch syndrome (LS), an inherited cancer predisposition, and a prognostic marker which predicts the response to immunotherapy. A recent trend in immunotherapy has transformed cancer treatment to provide medical alternatives that have not existed before. It is believed that MSI-high (MSI-H) CRC patients would benefit from immunotherapy due to their increased immune infiltration and higher neo-antigenic loads. MSI testing such as immunohistochemistry (IHC) and PCR MSI assay has historically been a tissue-based procedure that involves the testing of adequate tissue with a high concentration of cancer cells, in addition to the requirement for paired normal tissues. The invasive nature and specific prerequisite of such tests might hinder its application when surgery is not an option or when the tissues are insufficient. The application of next-generation sequencing, which is highly sensitive, in combination with liquid biopsy, therefore, presents an interesting possibility worth exploring. This review aimed to discuss the current body of evidence supporting the potential of liquid biopsy as a tool for MSI testing in CRC.

COVID-19: Insights into Potential Vaccines.

People around the world ushered in the new year 2021 with a fear of COVID-19, as family members have lost their loved ones to the disease. Millions of people have been infected, and the livelihood of many has been jeopardized due to the pandemic. Pharmaceutical companies are racing against time to develop an effective vaccine to protect against COVID-19. Researchers have developed various types of candidate vaccines with the release of the genetic sequence of the SARS-CoV-2 virus in January. These include inactivated viral vaccines, protein subunit vaccines, mRNA vaccines, and recombinant viral vector vaccines. To date, several vaccines have been authorized for emergency use and they have been administered in countries across the globe. Meanwhile, there are also vaccine candidates in Phase III clinical trials awaiting results and approval from authorities. These candidates have shown positive results in the previous stages of the trials, whereby they could induce an immune response with minimal side effects in the participants. This review aims to discuss the different vaccine platforms and the clinical trials of the candidate vaccines.

Parvimonas micra, Peptostreptococcus stomatis, Fusobacterium nucleatum and Akkermansia muciniphila as a four-bacteria biomarker panel of colorectal cancer.

Dysbiosis of the gut microbiome has been associated with the pathogenesis of colorectal cancer (CRC). We profiled the microbiome of gut mucosal tissues from 18 CRC patients and 18 non-CRC controls of the UKM Medical Centre (UKMMC), Kuala Lumpur, Malaysia. The results were then validated using a species-specific quantitative PCR in 40 CRC and 20 non-CRC tissues samples from the UMBI-UKMMC Biobank. Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were found to be over-represented in our CRC patients compared to non-CRC controls. These four bacteria markers distinguished CRC from controls (AUROC = 0.925) in our validation cohort. We identified bacteria species significantly associated (cut-off value of > 5 fold abundance) with various CRC demographics such as ethnicity, gender and CRC staging; however, due to small sample size of the discovery cohort, these results could not be further verified in our validation cohort. In summary, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were enriched in our local CRC patients. Nevertheless, the roles of these bacteria in CRC initiation and progression remains to be investigated.

Global metabolomics profiling of colorectal cancer in Malaysian patients.

Introduction: The serum metabolomics approach has been used to identify metabolite biomarkers that can diagnose colorectal cancer (CRC) accurately and specifically. However, the biomarkers identified differ between studies suggesting that more studies need to be performed to understand the influence of genetic and environmental factors. Therefore, this study aimed to identify biomarkers and affected metabolic pathways in Malaysian CRC patients. Methods: Serum from 50 healthy controls and 50 CRC patients were collected at UKM Medical Centre. The samples were deproteinized with acetonitrile and untargeted metabolomics profile determined using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOFMS, Agilent USA). The data were analysed using Mass Profiler Professional (Agilent, USA) software. The panel of biomarkers determined were then used to identify CRC from a new set of 20 matched samples. Results: Eleven differential metabolites were identified whose levels were significantly different between CRC patients compared to normal controls. Based on the analysis of the area under the curve, 7 of these metabolites showed high sensitivity and specificity as biomarkers. The use of the 11 metabolites on a new set of samples was able to differentiate CRC from normal samples with 80% accuracy. These metabolites were hypoxanthine, acetylcarnitine, xanthine, uric acid, tyrosine, methionine, lysoPC, lysoPE, citric acid, 5-oxoproline, and pipercolic acid. The data also showed that the most perturbed pathways in CRC were purine, catecholamine, and amino acid metabolisms. Conclusion: Serum metabolomics profiling can be used to identify distinguishing biomarkers for CRC as well as to further our knowledge of its pathophysiological mechanisms.