Trimethylamine N-oxide detection by electrochemical sensor based on screen printed electrode modified with molecularly imprinted polypyrrole-molybdenum(III) sulfide nanosheets.

Trimethylamine N-oxide (TMAO) is a gut metabolite produced by dietary L-carnitine and choline metabolism. Its altered level in the serum has been implicated in human health and diseases such as colorectal cancer, chronic kidney diseases, cardiovascular diseases, etc. Early detection of TMAO in body fluids has been presumed to be significant in understanding the pathogenesis and treatment of many diseases. Hence, developing reliable and rapid technologies for its detection may augment our understanding of pathogenesis and diagnosis of diseases. Hence, in the present work, polypyrrole (Ppy)@molybdenum(III)sulfide (Mo2S3) nanosheets (NS) composite molecularly imprinted polymer (MIP) (Ppy@Mo2S3-MIP) based electrochemical sensor has been fabricated for the detection of TMAO. Polypyrrole (Ppy) and Mo2S3 NS have been synthesized by chemical oxidative polymerization and hydrothermal techniques, respectively. The synthesized nanocomposite has been validated using different techniques such as X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The fabricated Ppy@Mo2S3-MIP sensor showed a linear detection range from 30 µM to 210 µM, a sensitivity of 1.21 µA µM-1 cm-2 and a limit of detection as 1.4 µM for the detection of TMAO and found more robust and improved when compared with Ppy-MIP using identical parameters. The fabricated sensor is also highly selective towards TMAO. It can be further used to detect TMAO in human samples such as urine quickly.

Untargeted metabolomics in gastric and colorectal cancer patients - preliminary results.

Introduction: Recent years, microbiota-associated aspects have been analysed in multiple disorders regarding cancers. Existing evidence pints that gut microorganisms might take part in tumour origin and therapy efficacy. Nevertheless, to date, data on faecal metabolomics in cancer patients is still strongly limited. Therefore, we aimed to analyse gut untargeted metabolome in gastrointestinal cancer patients (i.e., gastric and colorectal cancer). Patients and methods: There were 12 patients with either gastric (n=4) or colorectal cancer (n=8) enrolled and 8 analysed (n=4 each). Stool samples were collected prior to anti-cancer treatments. Untargeted metabolomics analyses were conducted by means of mass spectrometry. Results: A plethora of metabolites in cancer patients we analysed were noted, with higher homogenity in case of gastric cancer patients. We found that the level of Deoxyguanosine,m/z 266.091,[M-H]-, Uridine,m/z 245.075,[M+H]+, Deoxyguanosine,m/z 268.104,[M]+, 3-Indoleacetic acid,m/z 176.07,[M+H]+, Indoxyl,m/z 132.031,[M-H]-, L-Phenylalanine,m/z 164.073,[M-H]-, L-Methionine,m/z 150.058,[M+NH4]+, was significantly higher in colorectal cancer patients and Ethyl hydrogen malonate,m/z 133.031,[M+H]+ in gastric cancer. Conclusion: The overall insights into untargeted metabolomics showed that most often higher levels of analysed metabolites were detected in colorectal cancer patients compared to gastric cancer patients. The link between gut metabolome and both local and distal metastasis might exist, however it requires confirmation in further multi-centre studies regarding larger sample size.

Critical role of the gut microbiota in immune responses and cancer immunotherapy.

The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.

Exploring the Role of Inulin in Targeting the Gut Microbiota: An Innovative Strategy for Alleviating Colonic Fibrosis Induced By Irradiation.

The use of radiation therapy to treat pelvic and abdominal cancers can lead to the development of either acute or chronic radiation enteropathy. Radiation-induced chronic colonic fibrosis is a common gastrointestinal disorder resulting from the above radiation therapy. In this study, we establish the efficacy of inulin supplements in safeguarding against colonic fibrosis caused by irradiation therapy. Studies have demonstrated that inulin supplements enhance the proliferation of bacteria responsible to produce short-chain fatty acids (SCFAs) and elevate the levels of SCFAs in feces. In a mouse model of chronic radiation enteropathy, the transplantation of gut microbiota and its metabolites from feces of inulin-treated mice were found to reduce colonic fibrosis in validation experiments. Administering inulin-derived metabolites from gut microbiota led to a notable decrease in the expression of genes linked to fibrosis and collagen production in mouse embryonic fibroblast cell line NIH/3T3. In the cell line, inulin-derived metabolites also suppressed the expression of genes linked to the extracellular matrix synthesis pathway. The results indicate a novel and practical approach to safeguarding against chronic radiation-induced colonic fibrosis.

Roles of microbiota in pancreatic cancer development and treatment.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. This is due to the fact that most cases are only diagnosed at an advanced and palliative disease stage, and there is a high incidence of therapy resistance. Despite ongoing efforts, to date, the mechanisms underlying PDAC oncogenesis and its poor responses to treatment are still largely unclear. As the study of the microbiome in cancer progresses, growing evidence suggests that bacteria or fungi might be key players both in PDAC oncogenesis as well as in its resistance to chemo- and immunotherapy, for instance through modulation of the tumor microenvironment and reshaping of the host immune response. Here, we review how the microbiota exerts these effects directly or indirectly via microbial-derived metabolites. Finally, we further discuss the potential of modulating the microbiota composition as a therapy in PDAC.

Investigating the Influence of Gut Microbiota-related Metabolites in Gastrointestinal Cancer.

Gastrointestinal (GI) cancer is a major health concern due to its prevalence, impact on well-being, high mortality rate, economic burden, and potential for prevention and early detection. GI cancer research has made remarkable strides in understanding biology, risk factors, and treatment options. An emerging area of research is the gut microbiome's role in GI cancer development and treatment response. The gut microbiome, vital for digestion, metabolism, and immune function, is increasingly linked to GI cancers. Dysbiosis and alterations in gut microbe composition may contribute to cancer development. Scientists study how specific bacteria or microbial metabolites influence cancer progression and treatment response. Modulating the gut microbiota shows promise in enhancing treatment efficacy and preventing GI cancers. Gut microbiota dysbiosis can impact GI cancer through inflammation, metabolite production, genotoxicity, and immune modulation. Microbes produce metabolites like short-chain fatty acids, bile acids, and secondary metabolites. These affect host cells, influencing processes like cell proliferation, apoptosis, DNA damage, and immune regulation, all implicated in cancer development. This review explores the latest research on gut microbiota metabolites and their molecular mechanisms in GI cancers. The hope is that this attempt will help in conducting other relevant research to unravel the precise mechanism involved, identify microbial signatures associated with GI cancer, and develop targets.

Impact of a one-year supervised physical activity program on long-term cancer-related fatigue and mediating effects of the gut microbiota in metastatic testicular cancer patients: protocol of the prospective multicentre, randomized controlled phase-III STARTER trial.

BACKGROUND: Testicular germ cell tumours (TGCTs) are the most common malignancy in men aged 15-40 years, with increasing incidence worldwide. About 33 ~ 50% of the patients present with metastatic disease at diagnosis. TGCT survivors experience short- and long-term sequelae, including cancer-related fatigue (CRF). Physical activity (PA) has established effects on reducing CRF and other sequelae and improving health-related quality of life (HRQoL). However, its impact on TGCT survivors has so far received little attention. The gut microbiota plays a crucial role in various physiological functions, including cognition and metabolism, and may mediate the effects of PA on CRF and other sequelae, but this has not been investigated in randomized controlled trials. METHODS: This national, multicentre, phase-III trial will evaluate the impact of a one-year supervised PA program on CRF and other short- and long-term sequelae in metastatic TGCT patients receiving cisplatin-based chemotherapy combined with etoposide+/-bleomycin. It will also investigate potential mediating effects of the gut microbiota and its metabolites involved in the gut-brain axis on the relationship between PA and CRF and other sequelae. A total of 236 men ≥ 18 years of age with metastatic TGCT (seminoma and non-seminoma) will be enrolled before starting first-line chemotherapy in several French hospitals. The primary (CRF) and secondary (cognitive/psychological/metabolic sequelae, HRQoL, etc.) outcomes and gut microbiota and relevant metabolites will be assessed at inclusion, during and at the end of the one-year intervention, and annually until 10 years since inclusion to assess long-term sequelae, more specifically CRF, cardiovascular toxicities, and second primary cancer occurrence in this population. DISCUSSION: This trial will provide comprehensive and novel insights into the effects of a long-term supervised PA program on CRF and other sequelae in metastatic TGCT patients receiving first-line chemotherapy. It will also contribute to understanding the potential role of the gut microbiota and its metabolites in mediating the effects of PA on these outcomes. The findings of this study will help the development of effective PA interventions to improve the health of TGCT survivors and may have implications for other cancer populations as well. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov (NCT05588700) on 20 Oct. 2022.

Gut microbiota, microbiota-derived metabolites, and graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation is one of the most effective treatment strategies for leukemia, lymphoma, and other hematologic malignancies. However, graft-versus-host disease (GVHD) can significantly reduce the survival rate and quality of life of patients after transplantation, and is therefore the greatest obstacle to transplantation. The recent development of new technologies, including high-throughput sequencing, metabolomics, and others, has facilitated great progress in understanding the complex interactions between gut microbiota, microbiota-derived metabolites, and the host. Of these interactions, the relationship between gut microbiota, microbial-associated metabolites, and GVHD has been most intensively researched. Studies have shown that GVHD patients often suffer from gut microbiota dysbiosis, which mainly manifests as decreased microbial diversity and changes in microbial composition and microbiota-derived metabolites, both of which are significant predictors of poor prognosis in GVHD patients. Therefore, the purpose of this review is to summarize what is known regarding changes in gut microbiota and microbiota-derived metabolites in GVHD, their relationship to GVHD prognosis, and corresponding clinical strategies designed to prevent microbial dysregulation and facilitate treatment of GVHD.

Effect of dietary supplementation with Lactobacillus helveticus R0052 on seizure thresholds and antiseizure potency of sodium valproate in mice.

OBJECTIVE: Both animal and human studies, though limited, showed that multi-strain probiotic supplementation may reduce the number of seizures and/or seizure severity. Here, we evaluated the effect of a single strain probiotic supplementation on seizure susceptibility, antiseizure efficacy of sodium valproate, and several behavioral parameters in mice. METHODS: Lactobacillus helveticus R0052 was given orally for 28 days. Its influence on seizure thresholds was evaluated in the ivPTZ- and electrically-induced seizure tests. The effect on the antiseizure potency of valproate was assessed in the scPTZ test. We also investigated the effects of probiotic supplementation on anxiety-related behavior (in the elevated plus maze and light/dark box tests), motor coordination (in the accelerating rotarod test), neuromuscular strength (in the grip-strength test), and spontaneous locomotor activity. Serum and brain concentrations of valproate as well as cecal contents of SCFAs and lactate were determined using HPLC method. RESULTS: L. helveticus R0052 significantly increased the threshold for the 6 Hz-induced psychomotor seizure. There was also a slight increase in the threshold for myoclonic and clonic seizure in the ivPTZ test. L. helveticus R0052 did not affect the threshold for tonic seizures both in the maximal electroshock- and ivPTZ-induced seizure tests. No changes in the antiseizure potency of valproate against the PTZ-induced seizures were reported. Interestingly, L. helveticus R0052 increased valproate concentration in serum, but not in the brain. Moreover, L. helveticus R0052 did not produce any significant effects on anxiety-related behavior, motor coordination, neuromuscular strength, and locomotor activity. L. helveticus R0052 supplementation resulted in increased concentrations of total SCFAs, acetate, and butyrate. CONCLUSIONS: Altogether, this study shows that a single-strain probiotic - L. helveticus R0052 may decrease seizure susceptibility and this effect can be mediated, at least in part, by increased production of SCFAs. In addition, L. helveticus R0052 may affect bioavailability of valproate, which warrants further investigations.

Immune modulation of gut microbiota and its metabolites in chronic hepatitis B.

The gut microbiota is a diverse ecosystem consisting of 100 trillion microbiomes. The interaction between the host's gut and distal organs profoundly impacts various functions such as metabolism, immunity, neurology, and nutrition within the human body. The liver, as the primary immune organ, plays a crucial role in maintaining immune homeostasis by receiving a significant influx of gut-derived components and toxins. Perturbations in gut microbiota homeostasis have been linked to a range of liver diseases. The advancements in sequencing technologies, such as 16S rRNA and metagenomics, have opened up new avenues for comprehending the intricate physiological interplay between the liver and the intestine. Metabolites produced by the gut microbiota function as signaling molecules and substrates, influencing both pathological and physiological processes. Establishing a comprehensive host-bacterium-metabolism axis holds tremendous potential for investigating the mechanisms underlying liver diseases. In this review, we have provided a summary of the detrimental effects of the gut-liver axis in chronic liver diseases, primarily focusing on hepatitis B virus-related chronic liver diseases. Moreover, we have explored the potential mechanisms through which the gut microbiota and its derivatives interact with liver immunity, with implications for future clinical therapies.

Role of the intratumoral microbiome in tumor progression and therapeutics implications.

Microbes are widely present in various organs of the human body and play important roles in numerous physiological and pathological processes. Nevertheless, owing to multiple limiting factors, such as contamination and low biomass, the current understanding of the intratumoral microbiome is limited. The intratumoral microbiome exerts tumor-promoting or tumor-suppressive effects by engaging in metabolic reactions within the body, regulating signaling cancer-related pathways, and impacting both host cells function and immune system. It is important to emphasize that intratumoral microbes exhibit substantial heterogeneity in terms of composition and abundance across various tumor types, thereby potentially influencing diverse aspects of tumorigenesis, progression, and metastasis. These findings suggest that intratumoral microbiome have great potential as diagnostic and prognostic biomarkers. By manipulating the intratumoral microbes to employ cancer therapy, the efficacy of chemotherapy or immunotherapy can be enhanced while minimizing adverse effects. In this review, we comprehensively describe the composition and function of the intratumoral microbiome in various human solid tumors. Combining recent advancements in research, we discuss the origins, mechanisms, and prospects of the clinical applications of intratumoral microbiome.

Causal associations between gut microbiota, gut microbiota-derived metabolites, and cerebrovascular diseases: a multivariable Mendelian randomization study.

Background: Mounting evidence has demonstrated the associations between gut microbiota, gut microbiota-derived metabolites, and cerebrovascular diseases (CVDs). The major categories of CVD are ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). However, the causal relationship is still unclear. Methods: A two-sample Mendelian randomization (MR) study was conducted leveraging the summary data from genome-wide association studies. The inverse variance-weighted, maximum likelihood, weighted median, and MR.RAPS methods were performed to detect the causal relationship. Several sensitivity analyses were carried out to evaluate potential horizontal pleiotropy and heterogeneity. Finally, reverse MR analysis was conducted to examine the likelihood of reverse causality, and multivariable MR was performed to adjust the potential confounders. Results: We collected 1,505 host single nucleotide polymorphisms (SNPs) linked to 119 gut microbiota traits and 1,873 host SNPs associated with 81 gut metabolite traits as exposure data. Among these, three gut bacteria indicated an elevated risk of IS, two of ICH, and one of SAH. In contrast, five gut bacteria were associated with a reduced risk of IS, one with ICH, and one with SAH. Our study also demonstrated the potential causal associations between 11 gut microbiota-derived metabolites and CVD. Conclusions: This study provided evidence of the causal relationship between gut microbiota, gut microbiota-derived metabolites, and CVD, thereby offering novel perspectives on gut biomarkers and targeted prevention and treatment for CVD.

Alterations in gut microbiota and metabolite profiles in patients with infantile cholestasis.

BACKGROUND: Infantile cholestasis (IC) is the most common hepatobiliary disease in infants, resulting in elevated direct bilirubin levels. Indeed, hepatointestinal circulation impacts bile acid and bilirubin metabolism. This study evaluates changes in the gut microbiota composition in children with IC and identifies abnormal metabolite profiles associated with microbial alterations. RESULTS: The gut microbiota in the IC group exhibits the higher abundance of Veillonella, Streptococcus and Clostridium spp. (P < 0.05), compared to healthy infants (CON) group. Moreover, the abundance of Ruminococcus, Vibrio butyricum, Eubacterium coprostanogenes group, Intestinibacter, and Faecalibacterium were lower (P < 0.05). In terms of microbiota-derived metabolites, the levels of fatty acids (palmitoleic, α-linolenic, arachidonic, and linoleic) (P < 0.05) increased and the levels of amino acids decreased in IC group. Furthermore, the abundances of Ruminococcus, Eubacterium coprostanoligenes group, Intestinibacter and Butyrivibrio are positively correlated with proline, asparagine and aspartic acid, but negatively correlated with the α-linolenic acid, linoleic acid, palmitoleic acid and arachidonic acid. For analysis of the relationship between the microbiota and clinical index, it was found that the abundance of Veillonella and Streptococcus was positively correlated with serum bile acid content (P < 0.05), while APTT, PT and INR were negatively correlated with Faecalibalum and Ruminococcus (P < 0.05). CONCLUSION: Microbiota dysbiosis happened in IC children, which also can lead to the abnormal metabolism, thus obstructing the absorption of enteral nutrition and aggravating liver cell damage. Veillonella, Ruminococcus and Butyrivibrio may be important microbiome related with IC and need further research.

Investigating causal associations among gut microbiota, gut microbiota-derived metabolites, and gestational diabetes mellitus: a bidirectional Mendelian randomization study.

BACKGROUND: Previous studies have shown that gut microbiota (GM) and gut microbiota-derived metabolites are associated with gestational diabetes mellitus (GDM). However, the causal associations need to be treated with caution due to confounding factors and reverse causation. METHODS: This study obtained genetic variants from genome-wide association study including GM (N = 18,340), GM-derived metabolites (N = 7,824), and GDM (5,687 cases and 117,89 controls). To examine the causal association, several methods were utilized, including inverse variance weighted, maximum likelihood, weighted median, MR-Egger, and MR.RAPS. Additionally, reverse Mendelian Randomization (MR) analysis and multivariable MR were conducted to confirm the causal direction and account for potential confounders, respectively. Furthermore, sensitivity analyses were performed to identify any potential heterogeneity and horizontal pleiotropy. RESULTS: Greater abundance of Collinsella was detected to increase the risk of GDM. Our study also found suggestive associations among Coprobacter, Olsenella, Lachnoclostridium, Prevotella9, Ruminococcus2, Oscillibacte, and Methanobrevibacter with GDM. Besides, eight GM-derived metabolites were found to be causally associated with GDM. For the phenylalanine metabolism pathway, phenylacetic acid was found to be related to the risk of GDM. CONCLUSIONS: The study first used the MR approach to explore the causal associations among GM, GM-derived metabolites, and GDM. Our findings may contribute to the prevention and treatment strategies for GDM by targeting GM and metabolites, and offer novel insights into the underlying mechanism of the disease.

Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study.

Objective: There is some evidence for an association between gut microbiota and nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis, but no studies have explored their causal relationship. Methods: Instrumental variables of the gut microbiota (N = 13266) and gut microbiota-derived metabolites (N = 7824) were acquired, and a Mendelian randomization study was performed to explore their influence on NAFLD (1483 European cases and 17,781 European controls), ALD (2513 European cases and 332,951 European controls), and viral hepatitis risk (1971 European cases and 340,528 European controls). The main method for examining causality is inverse variance weighting (IVW). Results: IVW results confirmed that Anaerotruncus (p = 0.0249), Intestinimonas (p = 0.0237), Lachnoclostridium (p = 0.0245), Lachnospiraceae NC2004 group (p = 0.0083), Olsenella (p = 0.0163), and Peptococcus (p = 0.0472) were protective factors for NAFLD, and Ruminococcus 1 (p = 0.0120) was detrimental for NAFLD. The higher abundance of three genera, Lachnospira (p = 0.0388), Desulfovibrio (p = 0.0252), and Ruminococcus torques group (p = 0.0364), was correlated with a lower risk of ALD, while Ruminococcaceae UCG 002 level was associated with a higher risk of ALD (p = 0.0371). The Alistipes (p = 0.0069) and Ruminococcaceae NK4A214 group (p = 0.0195) were related to a higher risk of viral hepatitis. Besides, alanine (p = 0.0076) and phenyllactate (p = 0.0100) were found to be negatively correlated with NAFLD, while stachydrine (Op = 0.0244) was found to be positively associated with NAFLD. The phenylacetate (p = 0.0353) and ursodeoxycholate (p = 0.0144) had a protective effect on ALD, while the threonate (p = 0.0370) exerted a detrimental influence on ALD. The IVW estimates of alanine (p = 0.0408) and cholate (p = 0.0293) showed their suggestive harmful effects against viral hepatitis, while threonate (p = 0.0401) displayed its suggestive protective effect against viral hepatitis. Conclusion: In conclusion, our research supported causal links between the gut microbiome and its metabolites and NAFLD, ALD, and viral hepatitis.

Distinct Signatures of Tumor-Associated Microbiota and Metabolome in Low-Grade vs. High-Grade Dysplastic Colon Polyps: Inference of Their Role in Tumor Initiation and Progression.

According to the driver-passenger model for colorectal cancer (CRC), the tumor-associated microbiota is a dynamic ecosystem of bacterial species where bacteria with carcinogenic features linked to CRC initiation are defined as "drivers", while opportunistic bacteria colonizing more advanced tumor stages are known as "passengers". We reasoned that also gut microbiota-associated metabolites may be differentially enriched according to tumor stage, and be potential determinants of CRC development. Thus, we characterized the mucosa- and lumen-associated microbiota (MAM and LAM, respectively) and mucosa-associated metabolites in low- vs. high-grade dysplastic colon polyps from 78 patients. We show that MAM, obtained with a new biopsy-preserving approach, and LAM differ in composition and α/ß-diversity. By stratifying patients for polyp histology, we found that bacteria proposed as passengers by previous studies colonized high-grade dysplastic adenomas, whereas driver taxa were enriched in low-grade polyps. Furthermore, we report altered "mucosa-associated metabolite" levels in low- vs. high-grade groups. Integrated microbiota-metabolome analysis suggests the involvement of the gut microbiota in the production and consumption of these metabolites. Altogether, our findings support the involvement of bacterial species and associated metabolites in CRC mucosal homeostasis in a tumor-stage-specific manner. These distinct signatures may be used to distinguish low-grade from high-grade dysplastic polyps.

The Impact of Gut Microbiota-Derived Metabolites on the Tumor Immune Microenvironment.

Prevention of the effectiveness of anti-tumor immune responses is one of the canonical cancer hallmarks. The competition for crucial nutrients within the tumor microenvironment (TME) between cancer cells and immune cells creates a complex interplay characterized by metabolic deprivation. Extensive efforts have recently been made to understand better the dynamic interactions between cancer cells and surrounding immune cells. Paradoxically, both cancer cells and activated T cells are metabolically dependent on glycolysis, even in the presence of oxygen, a metabolic process known as the Warburg effect. The intestinal microbial community delivers various types of small molecules that can potentially augment the functional capabilities of the host immune system. Currently, several studies are trying to explore the complex functional relationship between the metabolites secreted by the human microbiome and anti-tumor immunity. Recently, it has been shown that a diverse array of commensal bacteria synthetizes bioactive molecules that enhance the efficacy of cancer immunotherapy, including immune checkpoint inhibitor (ICI) treatment and adoptive cell therapy with chimeric antigen receptor (CAR) T cells. In this review, we highlight the importance of commensal bacteria, particularly of the gut microbiota-derived metabolites that are capable of shaping metabolic, transcriptional and epigenetic processes within the TME in a therapeutically meaningful way.

Microbiota-Derived Natural Products Targeting Cancer Stem Cells: Inside the Gut Pharma Factory.

Cancer stem cells (CSCs) have drawn much attention as important tumour-initiating cells that may also be crucial for recurrence after chemotherapy. Although the activity of CSCs in various forms of cancer is complex and yet to be fully elucidated, opportunities for therapies targeting CSCs exist. CSCs are molecularly distinct from bulk tumour cells, so they can be targeted by exploiting their signature molecular pathways. Inhibiting stemness has the potential to reduce the risk posed by CSCs by limiting or eliminating their capacity for tumorigenesis, proliferation, metastasis, and recurrence. Here, we briefly described the role of CSCs in tumour biology, the mechanisms involved in CSC therapy resistance, and the role of the gut microbiota in cancer development and treatment, to then review and discuss the current advances in the discovery of microbiota-derived natural compounds targeting CSCs. Collectively, our overview suggests that dietary intervention, toward the production of those identified microbial metabolites capable of suppressing CSC properties, is a promising approach to support standard chemotherapy.

A Review of Gut Microbiota-Derived Metabolites in Tumor Progression and Cancer Therapy.

Gut microbiota-derived metabolites are key hubs connecting the gut microbiome and cancer progression, primarily by remodeling the tumor microenvironment and regulating key signaling pathways in cancer cells and multiple immune cells. The use of microbial metabolites in radiotherapy and chemotherapy mitigates the severe side effects from treatment and improves the efficacy of treatment. Immunotherapy combined with microbial metabolites effectively activates the immune system to kill tumors and overcomes drug resistance. Consequently, various novel strategies have been developed to modulate microbial metabolites. Manipulation of genes involved in microbial metabolism using synthetic biology approaches directly affects levels of microbial metabolites, while fecal microbial transplantation and phage strategies affect levels of microbial metabolites by altering the composition of the microbiome. However, some microbial metabolites harbor paradoxical functions depending on the context (e.g., type of cancer). Furthermore, the metabolic effects of microorganisms on certain anticancer drugs such as irinotecan and gemcitabine, render the drugs ineffective or exacerbate their adverse effects. Therefore, a personalized and comprehensive consideration of the patient's condition is required when employing microbial metabolites to treat cancer. The purpose of this review is to summarize the correlation between gut microbiota-derived metabolites and cancer, and to provide fresh ideas for future scientific research.