Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly( ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma( HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer( such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies.

The female reproductive tract (FRT), similar to other mucosal sites, harbours a site-specific microbiome, which has an essential role in maintaining health and homeostasis. In the majority of women of reproductive age, the microbiota of the lower FRT (vagina and cervix) microenvironment is dominated by Lactobacillus species, which benefit the host through symbiotic relationships. By contrast, the upper FRT (uterus, Fallopian tubes and ovaries) might be sterile in healthy individuals or contain a low-biomass microbiome with a diverse mixture of microorganisms. When dysbiosis occurs, altered immune and metabolic signalling can affect hallmarks of cancer, including chronic inflammation, epithelial barrier breach, changes in cellular proliferation and apoptosis, genome instability, angiogenesis and metabolic dysregulation. These pathophysiological changes might lead to gynaecological cancer. Emerging evidence shows that genital dysbiosis and/or specific bacteria might have an active role in the development and/or progression and metastasis of gynaecological malignancies, such as cervical, endometrial and ovarian cancers, through direct and indirect mechanisms, including modulation of oestrogen metabolism. Cancer therapies might also alter microbiota at sites throughout the body. Reciprocally, microbiota composition can influence the efficacy and toxic effects of cancer therapies, as well as quality of life following cancer treatment. Modulation of the microbiome via probiotics or microbiota transplant might prove useful in improving responsiveness to cancer treatment and quality of life. Elucidating these complex host-microbiome interactions, including the crosstalk between distal and local sites, will translate into interventions for prevention, therapeutic efficacy and toxic effects to enhance health outcomes for women with gynaecological cancers.

Within the first few days of life, humans are colonized by commensal intestinal microbiota. Here, we review recent findings showing that microbiota are important in normal healthy brain function. We also discuss the relation between stress and microbiota, and how alterations in microbiota influence stress-related behaviors. New studies show that bacteria, including commensal, probiotic, and pathogenic bacteria, in the gastrointestinal (GI) tract can activate neural pathways and central nervous system (CNS) signaling systems. Ongoing and future animal and clinical studies aimed at understanding the microbiota-gut-brain axis may provide novel approaches for prevention and treatment of mental illness, including anxiety and depression.Copyright © 2013 Elsevier Ltd. All rights reserved.

Ulcerative colitis (UC), a subtype of inflammatory bowel disease, is characterized by repetitive remission and relapse. Gut microbiome is critically involved in pathogenesis of UC. The shifts in microbiome profile during disease remission remain under-investigated. Recent studies revealed that UC pathogenesis is likely to originate in the mucosal barrier. Therefore, we investigated the effectiveness of mucosal tissue microbiomes to differentiate patients with subclinical UC from healthy individuals. The microbiomes of cecal and rectal biopsies and feces were characterized from 13 healthy individuals and 45 patients with subclinical UC. Total genomic DNA was extracted from the samples, and their microbial communities determined using next-generation sequencing. We found that changes in relative abundance of subclinical UC were marked by a decrease in Proteobacteria and an increase in Bacteroidetes phyla in microbiome derived from rectal tissues but not cecal tissue nor feces. Only in the microbiome of rectal tissue had significantly higher community richness and evenness in subclinical UC patients than controls. Twenty-seven operational taxonomic units were enriched in subclinical UC cohort with majority of the taxa from the Firmicutes phylum. Inference of putative microbial functional pathways from rectal biopsy microbiome suggested a differential increase in interleukin-17 signaling and T-helper cell differentiation pathways. Rectal biopsy tissue was suggested to be more suitable than fecal samples for microbiome assays to distinguish patients with subclinical UC from healthy adults. Assessment of the rectal biopsy microbiome may offer clinical insight into UC disease progression and predict relapse of the diseases.

Metagenomics is an emerging field focused on characterizing the structures, functions and dynamic operations of microbial communities sampled in their native habitats without the need for culture. Here, we present findings from a 16S rRNA gene sequence‐ and whole community DNA shotgun sequencing‐based analysis of the adult human gut microbiomes of lean and obese mono‐ and dizygotic twins. Our findings indicate that a core microbiome can be found at the gene level, despite large variation in community membership, and that variations from the core are associated with obesity. These findings have implications for ongoing Human Microbiome Project(s), and highlight important challenges to the field of metagenomics.

A host's microbiota may increase, diminish, or have no effect at all on cancer susceptibility. Assigning causal roles in cancer to specific microbes and microbiotas, unraveling host-microbiota interactions with environmental factors in carcinogenesis, and exploiting such knowledge for cancer diagnosis and treatment are areas of intensive interest. This Review considers how microbes and the microbiota may amplify or mitigate carcinogenesis, responsiveness to cancer therapeutics, and cancer-associated complications. Copyright © 2015, American Association for the Advancement of Science.

生命早期不良事件暴露，包括受精卵、胚胎、婴儿乃至儿童期，尤其生命早期1000天（宫内及出生后前2年）所暴露的宫内及外环境不良因素，可能对后代远期的健康和疾病风险产生影响，这一理论被称为健康与疾病的发育起源（the developmental origin of health and diseases，DOHaD）学说。浏览更多请关注本刊微信公众号及当期杂志。

Within the human gut reside diverse microbes coexisting with the host in a mutually advantageous relationship. Evidence has revealed the pivotal role of the gut microbiota in shaping the immune system. To date, only a few of these microbes have been shown to modulate specific immune parameters. Herein, we broadly identify the immunomodulatory effects of phylogenetically diverse human gut microbes. We monocolonized mice with each of 53 individual bacterial species and systematically analyzed host immunologic adaptation to colonization. Most microbes exerted several specialized, complementary, and redundant transcriptional and immunomodulatory effects. Surprisingly, these were independent of microbial phylogeny. Microbial diversity in the gut ensures robustness of the microbiota's ability to generate a consistent immunomodulatory impact, serving as a highly important epigenetic system. This study provides a foundation for investigation of gut microbiota-host mutualism, highlighting key players that could identify important therapeutics.Copyright © 2017 Elsevier Inc. All rights reserved.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.Published by Elsevier Inc.

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 ( = 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 ( = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (< 0.01) and relative abundance of bacteria of the Ruminococcaceae family (< 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.Copyright © 2018, American Association for the Advancement of Science.

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 Oral supplementation with after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9CXCR3CD4 T lymphocytes into mouse tumor beds.Copyright © 2018, American Association for the Advancement of Science.

Microbiota and host form a complex 'super-organism' in which symbiotic relationships confer benefits to the host in many key aspects of life. However, defects in the regulatory circuits of the host that control bacterial sensing and homeostasis, or alterations of the microbiome, through environmental changes (infection, diet or lifestyle), may disturb this symbiotic relationship and promote disease. Increasing evidence indicates a key role for the bacterial microbiota in carcinogenesis. In this Opinion article, we discuss links between the bacterial microbiota and cancer, with a particular focus on immune responses, dysbiosis, genotoxicity, metabolism and strategies to target the microbiome for cancer prevention.

Increasing evidence links the gut microbiota with colorectal cancer. Metagenomic analyses indicate that symbiotic Fusobacterium spp. are associated with human colorectal carcinoma, but whether this is an indirect or causal link remains unclear. We find that Fusobacterium spp. are enriched in human colonic adenomas relative to surrounding tissues and in stool samples from colorectal adenoma and carcinoma patients compared to healthy subjects. Additionally, in the Apc(Min/+) mouse model of intestinal tumorigenesis, Fusobacterium nucleatum increases tumor multiplicity and selectively recruits tumor-infiltrating myeloid cells, which can promote tumor progression. Tumors from Apc(Min/+) mice exposed to F. nucleatum exhibit a proinflammatory expression signature that is shared with human fusobacteria-positive colorectal carcinomas. However, unlike other bacteria linked to colorectal carcinoma, F. nucleatum does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, fusobacteria generate a proinflammatory microenvironment that is conducive for colorectal neoplasia progression. Copyright © 2013 Elsevier Inc. All rights reserved.

The fine line between human health and disease can be driven by the interplay between host and microbial factors. This "metagenome" regulates cancer initiation, progression, and response to therapies. Besides the capacity of distinct microbial species to modulate the pharmacodynamics of chemotherapeutic drugs, symbiosis between epithelial barriers and their microbial ecosystems has a major impact on the local and distant immune system, markedly influencing clinical outcome in cancer patients. Efficacy of cancer immunotherapy with immune checkpoint antibodies can be diminished with administration of antibiotics, and superior efficacy is observed with the presence of specific gut microbes. Future strategies of precision medicine will likely rely on novel diagnostic and therapeutic tools with which to identify and correct defects in the microbiome that compromise therapeutic efficacy.Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16 ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included,, and Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients.Copyright © 2018, American Association for the Advancement of Science.

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade. Copyright © 2015, American Association for the Advancement of Science.

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.

The essential role of the gut microbiota for health has generated tremendous interest in modulating its composition and metabolic function. One of these strategies is prebiotics, which typically refer to selectively fermented nondigestible food ingredients or substances that specifically support the growth and/or activity of health-promoting bacteria that colonize the gastrointestinal tract. In this Perspective, we argue that advances in our understanding of diet-microbiome-host interactions challenge important aspects of the current concept of prebiotics, and especially the requirement for effects to be 'selective' or 'specific'. We propose to revise this concept in an effort to shift the focus towards ecological and functional features of the microbiota more likely to be relevant for host physiology. This revision would provide a more rational basis for the identification of prebiotic compounds, and a framework by which the therapeutic potential of modulating the gut microbiota could be more fully materialized.

The gut microbiota has been implicated in cancer and shown to modulate anticancer drug efficacy. Altered gut microbiota is associated with resistance to chemo drugs or immune checkpoint inhibitors (ICIs), whereas supplementation of distinct bacterial species restores responses to the anticancer drugs. Accumulating evidence has revealed the potential of modulating the gut microbiota to enhance the efficacy of anticancer drugs. Regardless of the valuable findings by preclinical models and clinical data of patients with cancer, a more thorough understanding of the interactions of the microbiota with cancer therapy helps researchers identify novel strategy for cancer prevention, stratify patients for more effective treatment and reduce treatment complication. In this review, we discuss the scientific evidence on the role of gut microbiota in cancer treatment, and highlight the latest knowledge and technologies leveraged to target specific bacteria that contribute to tumourigenesis. First, we provide an overview of the role of the gut microbiota in cancer, establishing the links between bacteria, inflammation and cancer treatment. Second, we highlight the mechanisms used by distinct bacterial species to modulate cancer growth, immune responses, as well as the efficacy of chemotherapeutic drugs and ICIs. Third, we demonstrate various approaches to modulate the gut microbiota and their potential in translational research. Finally, we discuss the limitations of current microbiome research in the context of cancer treatment, ongoing efforts to overcome these challenges and future perspectives.© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

The gut microbiota operates at the interface of host–environment interactions to influence human homoeostasis and metabolic networks1–4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5–9. However, the systemic impact of the gut microbiome on the germline—and consequently on the F1 offspring it gives rise to—is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory ‘gut–germline axis’ in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.