http://aiocm.org/member/Immunity,%20Inflammation,%20and%20Cancer.pdf

Immunity, Inflammation, and Cancer

The human endogenous intestinal microflora is an essential “organ” in providing nourishment, regulating epithelial development, and instructing innate immunity; yet, surprisingly, basic features remain poorly described. We examined 13,355 prokaryotic ribosomal RNA gene sequences from multiple colonic mucosal sites and feces of healthy subjects to improve our understanding of gut microbial diversity. A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms. We discovered significant intersubject variability and differences between stool and mucosa community composition. Characterization of this immensely diverse ecosystem is the first step in elucidating its role in health and disease.

/pdf/diversity-of-the-human-intestinal-microbial-flora-55fejkfhx2.pdf

Diversity of the human intestinal microbial flora.

Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

http://science.sciencemag.org/content/sci/331/6024/1565.full.pdf

Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion

Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Origin and Physiological Roles of Inflammation

The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

https://www.cell.com/cell/pdf/S0092-8674(04)00661-0.pdf

Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis

Toll-like receptors (TLRs) are a family of pattern recognition receptors that are best-known for their role in host defence from infection. Emerging evidence also suggests that TLRs have an important role in maintaining tissue homeostasis by regulating the inflammatory and tissue repair responses to injury. The development of cancer has been associated with microbial infection, injury, inflammation and tissue repair. Here we discuss how the function of TLRs may relate to these processes in the context of carcinogenesis.

Toll-like receptors and cancer.

The human body carries vast communities of microbes that provide many benefits. Our microbiome is complex and challenging to understand, but evolutionary theory provides a universal framework with which to analyse its biology and health impacts. Here we argue that to understand a given microbiome feature, such as colonization resistance, host nutrition or immune development, we must consider how hosts and symbionts evolve. Symbionts commonly evolve to compete within the host ecosystem, while hosts evolve to keep the ecosystem on a leash. We suggest that the health benefits of the microbiome should be understood, and studied, as an interplay between microbial competition and host control.

/pdf/the-evolution-of-the-host-microbiome-as-an-ecosystem-on-a-5ff2urkxo2.pdf

The evolution of the host microbiome as an ecosystem on a leash

Inflammation is increasingly recognized as an important component of tumorigenesis, although the mechanisms and pathways involved are not well understood Tumor development is regulated by products of several modifier genes, but instructions for their tumor-specific expression are currently unknown We show that the signaling through the adaptor protein MyD88 has a critical role in spontaneous tumor development in mice with heterozygous mutation in the adenomatous polyposis coli (APC) gene We found that MyD88-dependent signaling controls the expression of several key modifier genes of intestinal tumorigenesis and has a critical role in both spontaneous and carcinogen-induced tumor development This study thus reveals the important role of an innate immune signaling pathway in intestinal tumorigenesis

https://science.sciencemag.org/content/sci/317/5834/124.full.pdf

Regulation of Spontaneous Intestinal Tumorigenesis Through the Adaptor Protein MyD88

Cooperative phenotypes are considered central to the functioning of microbial communities in many contexts, including communication via quorum sensing, biofilm formation, antibiotic resistance, and pathogenesis. The human intestine houses a dense and diverse microbial community critical to health, yet we know little about cooperation within this important ecosystem. Here we test experimentally for evolved cooperation within the Bacteroidales, the dominant Gram-negative bacteria of the human intestine. We show that during growth on certain dietary polysaccharides, the model member Bacteroides thetaiotaomicron exhibits only limited cooperation. Although this organism digests these polysaccharides extracellularly, mutants lacking this ability are outcompeted. In contrast, we discovered a dedicated cross-feeding enzyme system in the prominent gut symbiont Bacteroides ovatus, which digests polysaccharide at a cost to itself but at a benefit to another species. Using in vitro systems and gnotobiotic mouse colonization models, we find that extracellular digestion of inulin increases the fitness of B. ovatus owing to reciprocal benefits when it feeds other gut species such as Bacteroides vulgatus. This is a rare example of naturally-evolved cooperation between microbial species. Our study reveals both the complexity and importance of cooperative phenotypes within the mammalian intestinal microbiota.

/pdf/the-evolution-of-cooperation-within-the-gut-microbiota-28scumd1z7.pdf

Seth Rakoff-Nahoum

Papers

Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis

Toll-like receptors and cancer.

The evolution of the host microbiome as an ecosystem on a leash

Regulation of Spontaneous Intestinal Tumorigenesis Through the Adaptor Protein MyD88

The evolution of cooperation within the gut microbiota