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Microbiome data should be incorporated into the prevention, diagnosis, and treatment of colon cancer The human microbiota is the collection of microorganisms—bacteria, archaea, viruses, fungi, protozoa, and helminths—that populate the human body. They are emerging as an important feature of human health and disease. Currently, access to the genomic data of human cells and of microbiota (microbiomes) is more affordable and accessible than ever before. A major challenge is to unravel how we integrate microbiome data into precision medicine approaches for the prevention, diagnosis, and treatment of diseases such as cancer. The gastrointestinal (GI) tract is densely populated with microorganisms. Colorectal cancer (CRC) is the third most prevalent cancer worldwide. It is increasing in individuals less than 50 years old and is associated with specific dietary factors and eating patterns that affect the gut microbiota. Therefore, CRC seems ripe for microbiome-based prevention, diagnostics, and therapeutics.

Cancer cells originate from a series of acquired genetic mutations that can drive their uncontrolled cell proliferation and immune evasion. Environmental factors, including the microorganisms that colonize the human body, can shift the metabolism, growth pattern and function of neoplastic cells and shape the tumour microenvironment. Dysbiosis of the gut microbiome is now recognized as a hallmark of cancer by the scientific community. However, only a few microorganisms have been identified that directly initiate tumorigenesis or skew the immune system to generate a tumour-permissive milieu. Over the past two decades, research on the human microbiome and its functionalities within and across individuals has revealed microbiota-focused strategies for health and disease. Here, we review the evolving understanding of the mechanisms by which the microbiota acts in cancer initiation, promotion and progression. We explore the roles of bacteria in gastrointestinal tract malignancies and cancers of the lung, breast and prostate. Finally, we discuss the promises and limitations of targeting or harnessing bacteria in personalized cancer prevention, diagnostics and treatment.The role of the microbiota in tumorigenesis has garnered considerable attention over the past two decades. In this Review, El Tekle and Garrett explore the current and evolving understanding of microbiota in cancers of various internal organs, as well as highlighting opportunities for targeting bacteria for cancer prevention, diagnostics and treatment.

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.

In this Review, Brennan and Garrett discuss the multifaceted associations of Fusobacterium nucleatum with its human host that range from symbiotic in oral biofilms to potential infectious pathogen at several sites and cancer-promoting member of the microbiota in the gut.

Key Points Whole metagenomic and metatranscriptomic sequencing endeavours are defining the functional potential and real-time activity of microbiomes and revealing interactions between microbial metabolism and host development. Gut microorganisms produce a diverse metabolite repertoire from the anaerobic fermentation of undigested dietary components that reach the colon, as well as from endogenous compounds that are generated by the microorganisms themselves and their hosts. Complex carbohydrates are abundant substrates for bacterial fermentation in the colon, and their major metabolic end-products are short-chain fatty acids (SCFAs). SCFAs inhibit histone deacetylases (HDACs) and are ligands for G protein-coupled receptors; therefore, they act as signalling molecules that influence the expansion and function of haematopoietic and non-haematopoietic cell lineages. SCFA-driven HDAC inhibition tends to promote a tolerogenic, anti-inflammatory cell phenotype that is crucial for maintaining immune homeostasis and supports the concept that the microbiota can function as an epigenetic regulator of host physiology. D-glycero-β-D-manno-heptose-1,7-bisphosphate (HBP), an intermediate in the lipopolysaccharide biosynthetic pathway of Gram-negative bacteria, initiates a novel innate immune signalling axis without first requiring bacterial lysis — a phenomenon that is so far unique to Neisseria gonorrhoeae . Meta-omics and evolving computational frameworks are leading to the prediction and discovery of more microbial metabolites and components that are relevant to immune system function. It is also important to probe how well-known microbial metabolites (such as SCFAs) and co-metabolites (such as polyamines and aryl hydrocarbon receptor ligands) influence immune cell subsets and their functions. The microbiota and host immune system engage in a complex crosstalk that is being increasingly revealed thanks to advances in technological and computational approaches. Here, the authors highlight some of the microbial metabolites and components that are vital for immune system development and homeostasis. The microbiota — the collection of microorganisms that live within and on all mammals — provides crucial signals for the development and function of the immune system. Increased availability of technologies that profile microbial communities is facilitating the entry of many immunologists into the evolving field of host–microbiota studies. The microbial communities, their metabolites and components are not only necessary for immune homeostasis, they also influence the susceptibility of the host to many immune-mediated diseases and disorders. In this Review, we discuss technological and computational approaches for investigating the microbiome, as well as recent advances in our understanding of host immunity and microbial mutualism with a focus on specific microbial metabolites, bacterial components and the immune system.

The importance of the microbiota in the development of colorectal cancer (CRC) is increasingly evident, but identifying specific microbial features that influence CRC initiation and progression remains a central task for investigators. Studies determining the microbial mechanisms that directly contribute to CRC development or progression are revealing bacterial factors such as toxins that contribute to colorectal carcinogenesis. However, even when investigators have identified bacteria that express toxins, questions remain about the host determinants of a toxin's cancer-potentiating effects. For other cancer-correlating bacteria that lack toxins, the challenge is to define cancer-relevant virulence factors. Herein, we evaluate three CRC-correlating bacteria, colibactin-producing Escherichia coli, enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum, for their virulence features relevant to CRC. We also consider the beneficial bioactivity of gut microbes by highlighting a microbial metabolite that may enhance CRC antitumor immunity. In doing so, we aim to elucidate unique and shared mechanisms underlying the microbiota's contributions to CRC and to accelerate investigation from target validation to CRC therapeutic discovery.

Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth.

The bacterial toxin colibactin causes double-stranded DNA breaks and is associated with the occurrence of bacterially induced colorectal cancer in humans. However, isolation of colibactin is difficult, and its mode of action is poorly understood. Wilson et al. studied Escherichia coli that contain the biosynthetic gene island called pks , which is associated with colibactin production (see the Perspective by Bleich and Arthur). They identified the DNA adducts that resulted from incubating pks + E. coli in human cells. To overcome the lack of colibactin for direct analysis, mimics of the pks product were synthesized. From the resulting synthetic adenine-colibactin adducts, it became evident that alkylation via a cyclopropane “warhead” breaks the DNA strands. Similar DNA adducts were then identified in the gut epithelia of mice infected with pks + E. coli. Science , this issue p. eaar7785 ; see also p. 689 DNA adducts in cells and animals exposed to colibactin-producing gut microbes shed light on the mode of action of a cancer-linked genotoxin. Certain Escherichia coli strains residing in the human gut produce colibactin, a small-molecule genotoxin implicated in colorectal cancer pathogenesis. However, colibactin’s chemical structure and the molecular mechanism underlying its genotoxic effects have remained unknown for more than a decade. Here we combine an untargeted DNA adductomics approach with chemical synthesis to identify and characterize a covalent DNA modification from human cell lines treated with colibactin-producing E. coli . Our data establish that colibactin alkylates DNA with an unusual electrophilic cyclopropane. We show that this metabolite is formed in mice colonized by colibactin-producing E. coli and is likely derived from an initially formed, unstable colibactin-DNA adduct. Our findings reveal a potential biomarker for colibactin exposure and provide mechanistic insights into how a gut microbe may contribute to colorectal carcinogenesis.

The intestinal epithelium forms an essential barrier between a host and its microbiota. Protozoa and helminths are members of the gut microbiota of mammals, including humans, yet the many ways that gut epithelial cells orchestrate responses to these eukaryotes remain unclear. Here we show that tuft cells, which are taste-chemosensory epithelial cells, accumulate during parasite colonization and infection. Disruption of chemosensory signaling through the loss of TRMP5 abrogates the expansion of tuft cells, goblet cells, eosinophils, and type 2 innate lymphoid cells during parasite colonization. Tuft cells are the primary source of the parasite-induced cytokine interleukin-25, which indirectly induces tuft cell expansion by promoting interleukin-13 production by innate lymphoid cells. Our results identify intestinal tuft cells as critical sentinels in the gut epithelium that promote type 2 immunity in response to intestinal parasites.

In this study, the authors show that host microbiota play a key role in modulating microglia homeostasis. Germ-free mice or mice with only limited microbiota complexity displayed defects in microglial cell proportions and maturation, leading to impaired innate immune responses. The authors find that short-chain fatty acid signaling regulates these effects in vivo . As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings suggest that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be rectified to some extent by complex microbiota.