Integrating tumor genomics into studies of the microbiome in colorectal cancer

ABSTRACT

Although the gut microbiome has been linked to colorectal cancer (CRC) development, associations of microbial taxa with CRC status are often inconsistent across studies. We have recently shown that tumor genomics, a factor that is rarely incorporated in analyses of the CRC microbiome, has a strong effect on the composition of the microbiota. Here, we discuss these results in the wider context of studies characterizing interaction between host genetics and the microbiome, and describe the implications of our findings for understanding the role of the microbiome in CRC.     

肠道菌群与结直肠癌

近年来,肠道菌群在结直肠癌中的作用引起了广泛关注.越来越多的证据表明,肠道菌群与结直肠癌的发生、发展及治疗相关,潜在的致病菌和代谢标志物的发现将有助于结直肠癌的早期诊断和有效治疗.流行病学数据表明,不同地域人群结直肠癌发病率高低不一,西方化人群发病率普遍较高.西方化与非西方化人群有着不同的肠道菌群结构,因此考虑可能是饮...     

早产与阴道微生物群落关系的研究进展

早产作为5岁以下儿童死亡的首要原因,造成了严重的家庭和全球疾病负担,而预防早产的主要挑战是确定早产的危险因素。近年来,随着测序技术的发展,早产与微生物群落尤其是阴道微生物群落之间的关系成为了研究的热点。该文就早产与阴道微生物群落关系的研究进展作一简要综述。     

Microbiome in the primary prevention of allergic diseases and bronchial asthma

Tremendous progress in the ability to identify and test the function of microorganisms in recent years has led to a much better understanding of the role of environmental and host microbiome in the development of immune function, allergic sensitization and asthma. In this review, the most recent findings on the relationships between environmental microbiota, respiratory, intestinal microbiome, the consequences of early-life microbial exposure type and gut–lung microbial axis and the development of asthma and atopy are summarized. The current perspective on gut and airway microbiome manipulation for the primary prevention of allergic diseases and asthma is also discussed.     

The human gut microbiome: Implications for future health care

In their intestine, humans possess an “extended genome” of millions of microbial genes—the microbiome. Because this complex symbiosis influences host metabolism, physiology, and gene expression, it has been proposed that humans are complex biologic “superorganisms.” Advances in microbiologic analysis and systems biology are now beginning to implicate the gut microbiome in the etiology of localized intestinal diseases such as the irritable bowel syndrome, inflammatory bowel disease, and colon cancer. These approaches also suggest possible links between the gut and previously unassociated systemic conditions such as type 2 diabetes and obesity. The elucidation of the intestinal microbiome is therefore likely to underpin future disease prevention strategies, personalized health care regimens, and the development of novel therapeutic interventions. This review summarizes the research that is defining our understanding of the intestinal microbiome and highlights future areas of research in gastroenterology and human health in which the intestinal microbiome will play a significant role.     

Gut Immunity and Type 1 Diabetes: a Mélange of Microbes,Diet, and Host Interactions?

Type 1 diabetes (T1D) is a complex autoimmune disease, and first stages of the disease typically develop early in life. Genetic as well as environmental factors are thought to contribute to the risk of developing autoimmunity against pancreatic beta cells. Several environmental factors, such as breastfeeding or early introduction of solid food, have been associated with increased risk for developing T1D. During the first years of life, the gut microbial community is shaped by the environment, in particular by dietary factors. Moreover, the gut microbiome has been described for its role in shaping the immune system early in life and early data suggest associations between T1D risk and alterations in gut microbial communities. In this article, we discuss environmental factors influencing the colonization process of the gut microbial community. Furthermore, we review possible interactions between the microbiome and the host that might contribute to the risk of developing T1D.     

Metagenomics: key to human gut microbiota

The human gastrointestinal tract harbors the most complex human microbial ecosystem (intestinal microbiota). The comprehensive genome of these microbial populations (intestinal microbiome) is estimated to have a far greater genetic potential than the human genome itself. Correlations between changes in composition and activity of the gut microbiota and common disorders, such as inflammatory bowel diseases, obesity, diabetes, and atopic diseases, have been proposed, increasing the interest of the scientific community in this research field. In this perspective, a comprehensive and detailed view of the human gut microbiota, in terms of phylogenetic composition as well as genetic and metabolic potential, is essential to understand the dynamics and possible mechanisms of the cause/effect relationships between gut microbiota and pathology. Metagenomics has emerged as one of the most powerful sequence-driven approaches to study the composition and the genetic potential of this complex ecosystem, and efforts in this direction have been smoothed by the implementation of next generation sequencing platforms. Here, we highlight the potential of the newest high-throughput, culture-independent approaches for the characterization of the human gut microbiome in health and disease. Recent and promising results in this field are presented, underlining the perspectives and future research direction of human gut microbial ecology.     

Juvenile idiopathic arthritis and the gut microbiome: Where are we now?

In recent decades, because of advances in technology there has been an explosion of knowledge on how microbiome affects human health. In most chronic immune-inflammatory diseases, alterations in gut microbiome has been shown. The successful use of faecal microbial transplants for the treatment of clostridium difficile associated diarrhoea has also paved the way for novel therapies.Gut microbiome is affected by early life events like the mode of delivery, breast feeding, the use of antibiotics, etc. and that may have an indirect effect on the developing immune system as well as on the predisposition to juvenile idiopathic arthritis (JIA). Multiple studies have found altered gut microbiome in JIA though no single organism or microbial community has been found to be associated with JIA. In JIA, attempts to modify gut microbiome by using probiotics, exclusive enteral nutrition and other modalities have had variable success.The current review discusses the current data available on gut microbiome in different categories of JIA and how this knowledge can translate into new therapies.     

Microbial dysbiosis in spouses of ulcerative colitis patients: any clues to disease pathogenesis?

A number of alterations have been found within the gutmicrobial profile of patients with inflammatory bowel diseases when compared with the healthy population; however, it is unclear whether such dysbiosis is the cause or simply the consequence of the disease state. In ulcerative colitis, the environment seems to play a crucial role in disease etiology since monozygotic twins show a concordance rate of only 8%-10%-though it is unclear whether it does so by acting through the microbiome. In this study, the authors investigated the influence of cohabitation on the gut microbial community in healthy partners of ulcerative colitis patients-with the intent of clarifying some of these issues. As expected, ulcerative colitis patients had a significant dysbiosis and alterations in microbial metabolism. Interestingly, these abnormal fecal microbial communities were relatively similar amongst patients and their spouses. Thus, this study shows that the microbial profile might be partially transferred from ulcerative colitis patients to healthy individuals. Whether this finding impacts on disease development or has any implication for the role of the microbiome in inflammatory bowel disease etiology remains to be determined.     

Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer

The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and micro RNA expressions in colorectal cancer.     

下呼吸道微生态在支气管哮喘中的研究进展

随着二代测序的不断发展,过去人们认为无菌的下呼吸道现已被证实有多种不同的微生物群落定植.同时,越来越多的研究也证明,微生态在宿主免疫系统的发生发展中起着重要的作用.呼吸道微生态紊乱可能与多种呼吸道疾病密切相关,包括肺结核、COPD及支气管哮喘(简称哮喘)等.该研究主要回顾了近年来对哮喘患者及健康人群呼吸道微生态的研究,探讨在哮喘患者中呼吸道菌群定植的改变趋势,以及呼吸道微生态的改变与哮喘发病机制之间的关系,并且对呼吸道微生态在哮喘治疗中的研究进展进行讨论.     

Role of the microbiota in inflammatory bowel diseases

Studying the role of the human microbiome as it relates to human health status has revolutionized our view of microbial community contributions to a large number of diseases, particularly chronic inflammatory disorders. The lower gastrointestinal (GI) tract houses trillions of microbial cells representing a large diversity of species in relatively well-defined phylogenetic ratios that are associated with maintenance of key aspects of host physiology and immune homeostasis. It is not surprising, therefore, that many GI inflammatory diseases, including inflammatory bowel disease (IBD), are associated with substantial changes in the composition of these microbial assemblages, either as a cause or consequence of host inflammatory response. Here we review current knowledge in the emerging field of human microbiome research as it relates to IBD, specifically focusing on Crohn's disease (CD) and ulcerative colitis (UC). We discuss bacteriotherapeutic efforts to restore GI microbial assemblage integrity via probiotic supplementation of IBD patients, and speculate on future directions for the field.     

Gut dysbiosis and heart failure: navigating the universe within

Alternations in gut microbial composition (i.e. loss of microbial diversity or ‘gut dysbiosis’) have been associated with heart failure with reduced ejection fraction (HFrEF). It has also been suggested that increased chronic low‐level inflammation and immune system dysregulation seen in patients with HFrEF could be related to gut dysbiosis and increased intestinal permeability. Hence, the concept of modulating gut microbial composition with the goal of reducing systemic inflammation and controlling HFrEF progression has generated a substantial interest in the scientific community. However, several challenges to the gut dysbiosis theory remain as the exact gut microbial composition in HFrEF patients in these studies is not the same and a common microbiome linked to HFrEF is not yet established. With the advances in culture independent sequencing techniques it has also become evident that the gut microbiome may be much more diverse than previously believed. Further, various ‘omic’ technologies have enabled us to appreciate the potential role of gut microbial metabolites in various physiological processes in the host. Hence, identification of specific gut microbial metabolites may offer an alternative approach at solving this gut microbiome‐HFrEF puzzle. In the current review, we evaluate the concept of gut symbiosis, the potential role of gut dysbiosis in systemic inflammation and HFrEF, and finally highlight the challenges faced by the gut dysbiosis theory in HFrEF and provide a framework for the possible solutions.     

Metagenomic systems biology and metabolic modeling of the human microbiome: From species composition to community assembly rules

The human microbiome is a key contributor to health and development. Yet little is known about the ecological forces that are at play in defining the composition of such host-associated communities. Metagenomics-based studies have uncovered clear patterns of community structure but are often incapable of distinguishing alternative structuring paradigms. In a recent study, we integrated metagenomic analysis with a systems biology approach, using a reverse ecology framework to model numerous human microbiota species and to infer metabolic interactions between species. Comparing predicted interactions with species composition data revealed that the assembly of the human microbiome is dominated at the community level by habitat filtering. Furthermore, we demonstrated that this habitat filtering cannot be accounted for by known host phenotypes or by the metabolic versatility of the various species. Here we provide a summary of our findings and offer a brief perspective on related studies and on future approaches utilizing this metagenomic systems biology framework.     

饮食、肠道微生态与结直肠癌

结直肠癌是全球最常见的恶性肿瘤之一,在西方国家尤其常见。饮食是结直肠癌的重要影响因素之一。大量的研究证据显示饮食可以通过改变肠道微生态从而影响结直肠癌的发生与发展。它既能通过病原菌产生一系列致癌活动,也能通过改变肠道微生态代谢从而影响肠道上皮细胞。近年来有数据表明,以丁酸盐为代表的短链脂肪酸具有抑制炎症及抗肿瘤作用;而以次级胆汁酸为代表的肠道菌群其他代谢产物,具有促进肿瘤发生发展的作用。在本文中,我们将围绕饮食对肠道微生态及其代谢产物的影响、肠道微生态与结直肠癌的相关作用以及结直肠癌的饮食预防进行介绍和讨论,呼吁未来需要更深入的研究探索饮食、肠道微生态与代谢组学、免疫学、基因宿主反应等的相互作用关系。     

Human behavior,not race or geography,is the strongest predictor of microbial succession in the gut bacteriome of infants

ABSTRACT

Colonization of the gastrointestinal tract with microorganisms during infancy represents a critical control point for shaping life-long immune-mediated disease susceptibility. Abnormal colonization or an imbalance of microbes, termed dysbiosis, is implicated in several diseases. Consequently, recent research has aimed at understanding ways to manipulate a dysbiotic microbiome during infancy to resemble a normal, healthy microbiome. However, one of the fundamental issues in microbiome research is characterizing what a “normal” infant microbiome is based on geography, ethnicity and cultural variations. This review provides a comprehensive account of what is currently known about the infant microbiome from a global context. In general, this review shows that the influence of cultural variations in feeding practices, delivery modes and hygiene are the biggest contributors to microbial variability. Despite geography or race, all humans have similar microbial succession during infancy.     

Metagenomic systems biology and metabolic modeling of the human microbiome

The human microbiome is a key contributor to health and development. Yet little is known about the ecological forces that are at play in defining the composition of such host-associated communities. Metagenomics-based studies have uncovered clear patterns of community structure but are often incapable of distinguishing alternative structuring paradigms. In a recent study, we integrated metagenomic analysis with a systems biology approach, using a reverse ecology framework to model numerous human microbiota species and to infer metabolic interactions between species. Comparing predicted interactions with species composition data revealed that the assembly of the human microbiome is dominated at the community level by habitat filtering. Furthermore, we demonstrated that this habitat filtering cannot be accounted for by known host phenotypes or by the metabolic versatility of the various species. Here we provide a summary of our findings and offer a brief perspective on related studies and on future approaches utilizing this metagenomic systems biology framework.     

Inflammation and colorectal cancer,when microbiota-host mutualism breaks

Structural changes in the gut microbial community have been shown to accompany the progressive development of colorectal cancer.In this review we discuss recent hypotheses on the mechanisms involved in the bacteria-mediated carcinogenesis,as well as the triggering factors favoring the shift of the gut microbiota from a mutualistic to a pro-carcinogenic configuration.The possible role of inflammation,bacterial toxins and toxic microbiota metabolites in colorectal cancer onset is specifically discussed.On the other hand,the strategic role of inflammation as the keystone factor in driving microbiota to become carcinogenic is suggested.As a common outcome of different environmental and endogenous triggers,such as diet,aging,pathogen infection or genetic predisposition,inflammation can compromise the microbiota-host mutualism,forcing the increase of pathobionts at the expense of health-promoting groups,and allowing the microbiota to acquire an overall pro-inflammatory configuration.Consolidating inflammation in the gut,and favoring the bloom of toxigenic bacterial drivers,these changes in the gut microbial ecosystem have been suggested as pivotal in promoting carcinogenesis.In this context,it will become of primary importance to implement dietary or probiotics-based interventions aimed at preserving the microbiota-host mutualism along aging,counteracting deviations that favor a pro-carcinogenic microbiota asset.     

Upper gastrointestinal microbiota and digestive diseases

Metagenomics which combines the power of genomics,bioinformatics,and systems biology,provide new access to the microbial world.Metagenomics permit the genetic analysis of complex microbial populations without requiring prior cultivation.Through the conceptual innovations in metagenomics and the improvements in DNA high-throughput sequencing and bioinformatics analysis technology,gastrointestinal microbiology has entered the metagenomics era and become a hot topic worldwide.Human microbiome research is underway,however,most studies in this area have focused on the composition and function of the intestinal microbiota and the relationship between intestinal microbiota and metabolic diseases(obesity,diabetes,metabolic syndrome,etc.) and intestinal disorders [inflammatory bowel disease,colorectal cancer,irritable bowel syndrome(IBS),etc.].Few investigations on microbiota have been conducted within the upper gastrointestinal tract(esophagus,stomach and duodenum).The upper gastrointestinal microbiota is essential for several gastrointestinal illnesses,including esophagitis,Barrett’s esophagus,and esophageal carcinoma,gastritis and gastric cancer,small intestinal bacterial overgrowth,IBS and celiac disease.However,the constitution and diversity of the microbiota in different sections of the upper gastrointestinal tract under health and various disease states,as well as the function of microbiota in the pathogenesis of various digestive diseases are still undefined.The current article provides an overview of the recent findings regarding the relationship between upper gastrointestinal microbiota and gastrointestinal diseases;and discusses the study limitations and future directions of upper gastrointestinal microbiota research.     

Microbiome: Should we diversify from diversity?

Studies on microbiome diversity are flooding the current literature, yet lessons from ecology clearly demonstrate that diversity is just one factor to consider when analyzing an ecosystem, along with its stability, structure and function. Measures of diversity may be a useful tool for interpreting metagenomic data but the question remains as to how informative they are and what insight they may provide into the state of the microbiome. A study utilizing mathematical modeling to investigate the ecological dynamics of microbial communities has shown that diversity and stability may not always be concomitant. This finding is pertinent to the gut microbiome field, especially since diversity comparisons between healthy and pathological states frequently yield contradictory results. There is a need to broaden our approach to the analysis of microbiome data if we are to better understand this complex ecological community and its role in human health and disease.