Objective Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum may promote colorectal tumour growth and inhibit T cell-mediated immune responses against colorectal tumours. Thus, we hypothesised that the amount of F. nucleatum in colorectal carcinoma might be associated with worse clinical outcome. Design We used molecular pathological epidemiology database of 1069 rectal and colon cancer cases in the Nurses’ Health Study and the Health Professionals Follow-up Study, and measured F. nucleatum DNA in carcinoma tissue. Cox proportional hazards model was used to compute hazard ratio (HR), controlling for potential confounders, including microsatellite instability (MSI, mismatch repair deficiency), CpG island methylator phenotype (CIMP), KRAS , BRAF , and PIK3CA mutations, and LINE-1 hypomethylation (low-level methylation). Results Compared with F. nucleatum -negative cases, multivariable HRs (95% CI) for colorectal cancer-specific mortality in F. nucleatum -low cases and F. nucleatum -high cases were 1.25 (0.82 to 1.92) and 1.58 (1.04 to 2.39), respectively, (p for trend=0.020). The amount of F. nucleatum was associated with MSI-high (multivariable odd ratio (OR), 5.22; 95% CI 2.86 to 9.55) independent of CIMP and BRAF mutation status, whereas CIMP and BRAF mutation were associated with F. nucleatum only in univariate analyses (p Conclusions The amount of F. nucleatum DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker. Our data may have implications in developing cancer prevention and treatment strategies through targeting GI microflora by diet, probiotics and antibiotics.

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Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis

Inflammatory bowel disease (IBD) is an intestinal inflammatory condition that affects more than 2 million people in the United States. Although the etiology and pathogenesis of IBD are still largely unknown, dysregulated host/enteric microbial interactions are requisite for the development of IBD. So far, many researchers have tried to identify a precise relationship between IBD and an imbalance of the intestinal microbiota, termed "dysbiosis." Despite extensive efforts, it is still largely unknown about the interplay among microbes, their hosts, and their environments, and whether dysbiosis is a causal factor or an effect of IBD. Recently, deep-sequencing analyses of the microbiota in patients with IBD patients have been instrumental in characterizing the strong association between dysbiosis and IBD development, although it is still unable to identify specific-associated species level changes in most cases. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, including IBD, obesity, and allergic disorders, in both human and animal models. In this review article, the authors have focused on explaining the multiple types of dysbiosis, as well as dysbiosis-related diseases and potential treatments to apply this knowledge to understand a possible cause and potentially find therapeutic strategies for IBD as well as the other dysbiosis-related diseases.

Current Understanding of Dysbiosis in Disease in Human and Animal Models.

Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut-brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.

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Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome.

Several studies point towards alteration in gut microbiota composition and function in coeliac disease, some of which can precede the onset of disease and/or persist when patients are on a gluten-free diet. Evidence also exists that the gut microbiota might promote or reduce coeliac-disease-associated immunopathology. However, additional studies are required in humans and in mice (using gnotobiotic technology) to determine cause-effect relationships and to identify agents for modulating the gut microbiota as a therapeutic or preventative approach for coeliac disease. In this Review, we summarize the current evidence for altered gut microbiota composition in coeliac disease and discuss how the interplay between host genetics, environmental factors and the intestinal microbiota might contribute to its pathogenesis. Moreover, we highlight the importance of utilizing animal models and long-term clinical studies to gain insight into the mechanisms through which host-microbial interactions can influence host responses to gluten.

Novel players in coeliac disease pathogenesis: role of the gut microbiota

Gut microbiota interacts with host immune system in ways that influence the development of disease Advances in respiratory immune system also broaden our knowledge of the interaction between host and microbiome in the lung Increasing evidence indicated the intimate relationship between the gastrointestinal tract and respiratory tract Exacerbations of chronic gut and lung disease have been shown to share key conceptual features with the disorder and dysregulation of the microbial ecosystem In this review, we discuss the impact of gut and lung microbiota on disease exacerbation and progression, and the recent understanding of the immunological link between the gut and the lung, the gut-lung axis

Gut-lung axis: The microbial contributions and clinical implications.

The microbiota of the human metaorganism is not a mere bystander. These microbes have coevolved with us and are pivotal to normal development and homoeostasis. Dysbiosis of the GI microbiota is associated with many disease susceptibilities, including obesity, malignancy, liver disease and GI pathology such as IBD. It is clear that there is direct and indirect crosstalk between this microbial community and host immune response. However, the precise mechanism of this microbial influence in disease pathogenesis remains elusive and is now a major research focus. There is emerging literature on the role of the microbiota in the pathogenesis of autoimmune disease, with clear and increasing evidence that changes in the microbiota are associated with some of these diseases. Examples include type 1 diabetes, coeliac disease and rheumatoid arthritis, and these contribute significantly to global morbidity and mortality. Understanding the role of the microbiota in autoimmune diseases may offer novel insight into factors that initiate and drive disease progression, stratify patient risk for complications and ultimately deliver new therapeutic strategies. This review summarises the current status on the role of the microbiota in autoimmune diseases.

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Lindsey M. Miller

Papers

Does the microbiota play a role in the pathogenesis of autoimmune diseases