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Journal ArticleDOI

Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment

TL;DR: It is concluded that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies.
Abstract: The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.

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Citations
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Journal ArticleDOI
TL;DR: Recent advances are reviewed and emerging strategies for microbiota-based cancer therapies are discussed, including faecal microbiota transplantation or dietary interventions that might be utilized clinically to improve the success rate of immunotherapy in patients with cancer.

18 citations

Journal ArticleDOI
TL;DR: In vitro and in vivo tests showed that polyphenols from berries are a promising source of bioactive compounds capable of modulating the intestinal microbiota, and therefore managing cancer and associated metabolic diseases.
Abstract: Berry-derived polyphenols are bioactive compounds synthesized and secreted by several berry fruits. These polyphenols feature a diversity of chemical compounds, including phenolic acids and flavonoids. Here, we report the beneficial health effects of berry-derived polyphenols and their therapeutical application on gut-microbiota-related diseases, including inflammation and cancer. Pharmacokinetic investigations have confirmed the absorption, availability, and metabolism of berry-derived polyphenols. In vitro and in vivo tests, as well as clinical trials, showed that berry-derived polyphenols can positively modulate the gut microbiota, inhibiting inflammation and cancer development. Indeed, these compounds inhibit the growth of pathogenic bacteria and also promote beneficial bacteria. Moreover, berry-derived polyphenols exhibit therapeutic effects against different gut-microbiota-related disorders such as inflammation, cancer, and metabolic disorders. Moreover, these polyphenols can manage the inflammation via various mechanisms, in particular the inhibition of the transcriptional factor Nf-κB. Berry-derived polyphenols have also shown remarkable effects on different types of cancer, including colorectal, breast, esophageal, and prostate cancer. Moreover, certain metabolic disorders such as diabetes and atherosclerosis were also managed by berry-derived polyphenols through different mechanisms. These data showed that polyphenols from berries are a promising source of bioactive compounds capable of modulating the intestinal microbiota, and therefore managing cancer and associated metabolic diseases. However, further investigations should be carried out to determine the mechanisms of action of berry-derived polyphenol bioactive compounds to validate their safety and examinate their clinical uses.

16 citations

Journal ArticleDOI
TL;DR: A review of the main approaches used to characterize the tumor microbiome, and of the recently proposed functions of intracellular bacteria identified in oncological entities is provided in this paper, where the therapeutic aspects of livepathogenic microbes are also discussed, regarding the tumor microenvironment of each cancer type.

14 citations

Journal ArticleDOI
TL;DR: In this paper, Cex-HSA/DOX/MDR1 siRNA (C-H/D/M) was characterized by dynamic light scattering and transmission electron microscopy.
Abstract: Background Breast cancer is the most prevalent cancer among women. Doxorubicin (DOX) is a common chemotherapeutic drug used to treat many different cancers. However, multidrug resistance limits the treatment of breast cancer. MDR1 siRNA (siMDR1) combinatorial therapy has attracted significant attention as a breakthrough therapy for multidrug resistance in tumors. However, naked siRNA is easily degraded by enzymatic hydrolysis requiring an siRNA carrier for its protection. Human serum albumin (HSA) was selected as the carrier due to its excellent biocompatibility, non-toxicity, and non-immunogenicity. Cetuximab was used to modify the HSA nanoparticles in order to target the tumor tissues. Methods This study used a central composite design response surface methodology (CCD-RSM) to investigate the optimal formula for HSA NPs preparation. Cex-HSA/DOX/MDR1 siRNA (C-H/D/M) was characterized by dynamic light scattering and transmission electron microscopy. The efficacy of C-H/D/M tumor growth inhibitory activity was investigated in vitro and in vivo using confocal imaging, MTT assay, and an MCF-7/ADR tumor-bearing mice model. RT-qPCR, ELISA analysis, and flow cytometry were used to investigate the in vitro antitumor mechanisms of C-H/D/M. Results The diameter and PDI of the C-H/D/M were 173.57 ± 1.30 nm and 0.027 ± 0.004, respectively. C-H/D/M promoted and maintained the sustained release and the uptake of DOX significantly. After transfection, the MDR1 mRNA and P-gp expression levels were down-regulated by 44.31 ± 3.6% (P < 0.01) and 38.08 ± 2.4% (P < 0.01) in an MCF-7/ADR cell line. The fluorescent images of the treated BALB/c nude mice revealed that C-H/D/M achieved targeted delivery of siMDR1 and DOX into the tumor tissue. The in vivo tumor inhibition results demonstrated that the tumor inhibition rate of the C-H/D/M treated group was 54.05% ± 1.25%. The biosafety results indicated that C-H/D/M did not induce significant damages to the main organs in vivo. Conclusion C-H/D/M can be used as an ideal non-viral tumor-targeting vector to overcome MDR and enhance the antitumor effect.

11 citations

Journal ArticleDOI
27 Jul 2021-Cancers
TL;DR: A review of the available published evidence of the microbiome association with pancreatic ductal adenocarcinoma (PDAC) and explore its potential as a target for therapeutic manipulation is presented in this paper.
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the second most common cause of cancer-related death by 2030, with an overall 5-year survival rate between 7% and 9%. Despite recent advances in surgical, chemotherapy, and radiotherapy techniques, the outcome for patients with PDAC remains poor. Poor prognosis is multifactorial, including the likelihood of sub-clinical metastatic disease at presentation, late-stage at presentation, absence of early and reliable diagnostic biomarkers, and complex biology surrounding the extensive desmoplastic PDAC tumour micro-environment. Microbiota refers to all the microorganisms found in an environment, whereas microbiome is the collection of microbiota and their genome within an environment. These organisms reside on body surfaces and within mucosal layers, but are most abundantly found within the gut. The commensal microbiome resides in symbiosis in healthy individuals and contributes to nutritive, metabolic and immune-modulation to maintain normal health. Dysbiosis is the perturbation of the microbiome that can lead to a diseased state, including inflammatory bowel conditions and aetiology of cancer, such as colorectal and PDAC. Microbes have been linked to approximately 10% to 20% of human cancers, and they can induce carcinogenesis by affecting a number of the cancer hallmarks, such as promoting inflammation, avoiding immune destruction, and microbial metabolites can deregulate host genome stability preceding cancer development. Significant advances have been made in cancer treatment since the advent of immunotherapy. The microbiome signature has been linked to response to immunotherapy and survival in many solid tumours. However, progress with immunotherapy in PDAC has been challenging. Therefore, this review will focus on the available published evidence of the microbiome association with PDAC and explore its potential as a target for therapeutic manipulation.

10 citations

References
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Journal ArticleDOI
TL;DR: Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
Abstract: As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.

37,898 citations

Journal ArticleDOI
TL;DR: A new method for metagenomic biomarker discovery is described and validates by way of class comparison, tests of biological consistency and effect size estimation to address the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities.
Abstract: This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.

9,057 citations

Journal ArticleDOI
29 Aug 2013-Nature
TL;DR: The authors' classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.
Abstract: We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.

3,448 citations


"Intestinal microbiota influences cl..." refers methods in this paper

  • ...processed for rarefaction and normalization and further analysis using the MetaOMineR package [57]....

    [...]

Journal ArticleDOI
05 Jan 2018-Science
TL;DR: It is found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition, and Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer.
Abstract: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.

3,258 citations


"Intestinal microbiota influences cl..." refers background in this paper

  • ...to immune checkpoint inhibitors [11, 19] (Fig....

    [...]

  • ...melanoma [12, 14], kidney [19], and lung [11] cancer....

    [...]

  • ...Accumulating evidence points to the capacity of the intestinal ecosystem, and more specifically specific health-associated bacteria commensals to dampen systemic inflammation [5, 6], to shape the innate and adaptive immune tonus [7–10], and reprogram the tumor microenvironment in tumor bearing mice [11, 12] and patients treated with immunotherapy [13, 14]....

    [...]

Journal ArticleDOI
05 Jan 2018-Science
TL;DR: Examination of the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients.
Abstract: Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

2,791 citations

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