The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. Here, we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.

Anti–programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti–PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti–PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti–PD-1 in patients with PD-1–refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti–PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma.

Objective Despite widespread use of antibiotics for the treatment of life-threatening infections and for research on the role of commensal microbiota, our understanding of their effects on the host is still very limited. Design Using a popular mouse model of microbiota depletion by a cocktail of antibiotics, we analysed the effects of antibiotics by combining intestinal transcriptome together with metagenomic analysis of the gut microbiota. In order to identify specific microbes and microbial genes that influence the host phenotype in antibiotic-treated mice, we developed and applied analysis of the transkingdom network. Results We found that most antibiotic-induced alterations in the gut can be explained by three factors: depletion of the microbiota; direct effects of antibiotics on host tissues and the effects of remaining antibiotic-resistant microbes. Normal microbiota depletion mostly led to downregulation of different aspects of immunity. The two other factors (antibiotic direct effects on host tissues and antibiotic-resistant microbes) primarily inhibited mitochondrial gene expression and amounts of active mitochondria, increasing epithelial cell death. By reconstructing and analysing the transkingdom network, we discovered that these toxic effects were mediated by virulence/quorum sensing in antibiotic-resistant bacteria, a finding further validated using in vitro experiments. Conclusions In addition to revealing mechanisms of antibiotic-induced alterations, this study also describes a new bioinformatics approach that predicts microbial components that regulate host functions and establishes a comprehensive resource on what, why and how antibiotics affect the gut in a widely used mouse model of microbiota depletion by antibiotics.

Commensal microorganisms colonize barrier surfaces of all multicellular organisms, including those of humans. For more than 500 million years, commensal microorganisms and their hosts have coevolved and adapted to each other. As a result, the commensal microbiota affects many immune and nonimmune functions of their hosts, and de facto the two together comprise one metaorganism. The commensal microbiota communicates with the host via biologically active molecules. Recently, it has been reported that microbial imbalance may play a critical role in the development of multiple diseases, such as cancer, autoimmune conditions, and increased susceptibility to infection. In this review, we focus on the role of the commensal microbiota in the development, progression, and immune evasion of cancer, as well as some modulatory effects on the treatment of cancer. In particular, we discuss the mechanisms of microbiota-mediated regulation of innate and adaptive immune responses to tumors, and the consequences on cancer progression and whether tumors subsequently become resistant or susceptible to different anticancer therapeutic regiments. Keywords:Cancer r Cancer Therapy r Cancerogenesis r Inflammation r Microbiota IntroductionEukaryotes evolved from a process of endosymbiosis between different prokaryotic cells (reviewed in [1]). The initial eukaryotes evolved surrounded by microorganisms, such as archaea, bacteria, fungi, and viruses and cross-signaling between eukaryotic cells and commensal microbes mostly regulated nutrition, metabolism, and morphogenesis (reviewed in [2]). In our bodies, commensal microorganisms inhabit all the barrier surfaces with the largest number in the distal ileum and colon and they outnumber the human cells by a ratio of 10:1 [3]. Furthermore, the number of microbial genes is at least 100 times higher than that of human Correspondence: Dr. Giorgio Trinchieri e-mail: trinchig@mail.nih.gov genes, although many of the microbial genes have equivalent functions [4]. Viewed from this perspective, we are symbionts or metaorganisms composed of host and microbial cells, each with their own genes (metagenome) and shared metabolic processes and products (metabolome) [5,6].The cohabitation of early eukaryotes with microorganisms was regulated in part by signaling through Toll/IL-1 receptor domaincontaining proteins that later evolved in higher animal species into the innate Toll-like receptors (TLRs) [7]. The family of cytoplasmic NOD-like receptors developed after multicellularity was established [8]. In higher vertebrates, the innate receptor signaling played an increasingly important role in innate and adaptive immunity against pathogens while still regulating the symbiotic interaction with commensal microorganisms [9]. The interaction of the higher organisms with the commensal microbiota C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 18Amiran Dzutsev et al. Eur. J. Immunol. 2015. 45: 17-31 maintains an important role in regulating nutrition, metabolism, homeostasis, development ...

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BackgroundEffective treatment of Mycobacterium tuberculosis (Mtb) infection requires at least 6 months of daily therapy with multiple orally administered antibiotics. Although this drug regimen is administered annually to millions worldwide, the impact of such intensive antimicrobial treatment on the host microbiome has never been formally investigated. Here, we characterized the longitudinal outcome of conventional isoniazid-rifampin-pyrazinamide (HRZ) TB drug administration on the diversity and composition of the intestinal microbiota in Mtb-infected mice by means of 16S rRNA sequencing. We also investigated the effects of each of the individual antibiotics alone and in different combinations.ResultsWhile inducing only a transient decrease in microbial diversity, HRZ treatment triggered a marked, immediate and reproducible alteration in community structure that persisted for the entire course of therapy and for at least 3 months following its cessation. Members of order Clostridiales were among the taxa that decreased in relative frequencies during treatment and family Porphyromonadaceae significantly increased post treatment. Experiments comparing monotherapy and different combination therapies identified rifampin as the major driver of the observed alterations induced by the HRZ cocktail but also revealed unexpected effects of isoniazid and pyrazinamide in certain drug pairings.ConclusionsThis report provides the first detailed analysis of the longitudinal changes in the intestinal microbiota due to anti-tuberculosis therapy. Importantly, many of the affected taxa have been previously shown in other systems to be associated with modifications in immunologic function. Together, our findings reveal that the antibiotics used in conventional TB treatment induce a distinct and long lasting dysbiosis. In addition, they establish a murine model for studying the potential impact of this dysbiosis on host resistance and physiology.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0286-2) contains supplementary material, which is available to authorized users.

Shifts in the composition of the commensal microbiota are emerging as a hallmark of gastrointestinal inflammation. In particular, outgrowth of γ-proteobacteria has been linked to the etiology of inflammatory bowel disease and the pathologic consequences of infections. Here we show that, following gastrointestinal infection, control of commensal outgrowth is a highly coordinated process involving both the host response and microbial signals. Notably, neutrophil emigration to the lumen results in the generation of organized intra-luminal structures that encapsulate commensals and limit their contact with the epithelium. Formation of these luminal casts depends upon the high-affinity N-formyl peptide receptor, Fpr1. Consequently, after infection, mice deficient in Fpr1 display increased microbial translocation, poor commensal containment and increased mortality. Altogether, our present study describes a novel mechanism by which the host rapidly contains outgrowth of commensal pathobionts during infection. Further, these results reveal Fpr1 as a major mediator of host commensal interaction during dysbiosis.

Summary While commensal flora is involved in the regulation of immunity, the interplay between cytokine signaling and microbiota in atherosclerosis remains unknown. We found that interleukin (IL)-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Augmented disease in the absence of the IL-23-IL-22 pathway was mediated in part by pro-atherogenic osteopontin, controlled by microbial metabolites. Microbiota transfer from IL-23 deficient mice accelerated atherosclerosis, whereas microbial depletion or IL-22 supplementation reduced inflammation and ameliorated disease. Our work uncovers the IL-23-IL-22 signaling as a regulator of atherosclerosis that restrains expansion of pro-atherogenic microbiota, and argues for informed use of cytokine blockers to avoid cardiovascular side effects driven by microbiota and inflammation.