In the mucosa, the immune system's T cells and B cells have position-specific phenotypes and functions that are influenced by the microbiota. These cells play pivotal parts in the maintenance of ...immune homeostasis by suppressing responses to harmless antigens and by enforcing the integrity of the barrier functions of the gut mucosa. Imbalances in the gut microbiota, known as dysbiosis, can trigger several immune disorders through the activity of T cells that are both near to and distant from the site of their induction. Elucidation of the mechanisms that distinguish between homeostatic and pathogenic microbiota-host interactions could identify therapeutic targets for preventing or modulating inflammatory diseases and for boosting the efficacy of cancer immunotherapy.
Trillions of microorganisms transit through and reside in the mammalian gastrointestinal tract each day, collectively producing thousands of small molecules and metabolites with local and systemic ...effects on host physiology. Identifying effector microorganisms that causally affect host phenotype and deciphering the underlying mechanisms have become foci of microbiome research and have begun to enable the development of microbiota-based therapeutics. Two complementary, reductionist approaches have commonly been used: the first starts with an immune phenotype and narrows down the microbiota to identify responsible effector bacteria, while the second starts with bacteria-derived molecules and metabolites and seeks to understand their effects on the host immune system. Together, these strategies provide the basis for the rational design of microbial and metabolite-based therapeutics that target and ameliorate immune deficits in patients.
The effects of oral microbiota on health Tuganbaev, Timur; Yoshida, Koji; Honda, Kenya
Science (American Association for the Advancement of Science),
2022-May-27, 2022-05-27, 20220527, Letnik:
376, Številka:
6596
Journal Article
Recenzirano
Oral microbiota form complex biofilms that can affect local and systemic health.
The mammalian alimentary tract harbors hundreds of species of commensal microorganisms (microbiota) that intimately interact with the host and provide it with genetic, metabolic, and immunological ...attributes. Recent reports have indicated that the microbiota composition and its collective genomes (microbiome) are major factors in predetermining the type and robustness of mucosal immune responses. In this review, we discuss the recent advances in our understanding of host-microbiota interactions and their effect on the health and disease susceptibility of the host.
There is currently much interest in defining how the microbiota shapes immune responses in the context of cancer. Various studies in both mice and humans have associated particular commensal species ...with better (or worse) outcomes in different cancer types and following treatment with cancer immunotherapies. However, the mechanisms involved remain ill-defined and even controversial. In this Viewpoint, Nature Reviews Immunology has invited six eminent scientists in the field to share their thoughts on the key questions and challenges for the field.
Abstract
The collection of micro-organisms living in the mammalian gastrointestinal tract, termed the gut microbiota, has been shown to have profound impacts on host health and increasingly is ...regarded as a viable therapeutic target. Clinical studies of fecal microbiota transplantation have demonstrated potential efficacy of microbiota-based therapies for diseases including Clostridioides difficile infections, inflammatory bowel disease, graft-versus-host disease and cancer. However, the lack of understanding of the active ingredients and potential risks of such therapies pose challenges for clinical application. Meanwhile, efforts are being made to identify effector microbes directly associated with a given phenotype, to establish causality and to devise well-characterized microbial therapeutics for clinical use. Strategies based on defined microbial components will likely enhance the potential of microbiota-targeted therapies.
Induction of type I interferons (IFNs) by viruses and other pathogens is crucial for innate immunity, and it is mediated by the activation of pattern-recognition receptors, such as Toll-like ...receptors and cytosolic receptors such as RIG-I and MDA5. The type I IFN induction is primarily controlled at the gene transcriptional level, wherein a family of transcription factors, interferon regulatory factors (IRFs), plays central roles. Here, we summarize the recent studies on IRFs, providing a paradigm of how genes are ingeniously regulated during immune responses. We also consider some evolutional aspects on the IFN-IRF system.
Fundamental asymmetries between the host and its microbiome in enzymatic activities and nutrient storage capabilities have promoted mutualistic adaptations on both sides. As a result, the enteric ...immune system has evolved so as not to cause a zero‐sum sterilization of non‐self, but rather achieve a non‐zero‐sum self‐reinforcing cooperation with its evolutionary partner the microbiome. In this review, we attempt to integrate the accumulated knowledge of immune—microbiome interactions into an evolutionary framework and trace the pattern of positive immune—microbiome feedback loops across epithelial, enteric nervous system, innate, and adaptive immune circuits. Indeed, the immune system requires commensal signals for its development and function, and reciprocally protects the microbiome from nutrient shortage and pathogen outgrowth. In turn, a healthy microbiome is the result of immune system curatorship as well as microbial ecology. The paradigms of host–microbiome asymmetry and the cooperative nature of their interactions identified in the gut are applicable across all tissues influenced by microbial activities. Incorporation of immune system influences into models of microbiome ecology will be a step forward toward defining what constitutes a healthy human microbiome and guide discoveries of novel host–microbiome mutualistic adaptations that may be harnessed for the promotion of human health.
Immune circuits of microbiome perception and response mediated by gut innate and adaptive immune systems, epithelial cells, and enteric nervous system have evolved to protect not only the host, but commensal microbiome as well. The immune curatorship together with the laws of microbial ecology defines the healthy microbiome.
Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases
. Here we show that centenarians have a distinct gut microbiome that is ...enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.
Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide ...obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.
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