Development and Organization of the Secondary and Tertiary Lymphoid Organs: Influence of Microbial and Food Antigens. Magrone Thea,Jirillo Emilio Endocrine, metabolic & immune disorders drug targets BACKGROUND:Secondary lymphoid organs (SLO) are distributed in many districts of the body and, especially, lymph nodes, spleen and gut-associated lymphoid tissue are the main cellular sites. On the other hand, tertiary lymphoid organs (TLO) are formed in response to inflammatory, infectious, autoimmune and neoplastic events. Developmental Studies: In the present review, emphasis will be placed on the developmental differences of SLO and TLO between small intestine and colon and on the role played by various chemokines and cell receptors. Undoubtedly, microbiota is indispensable for the formation of SLO and its absence leads to their poor formation, thus indicating its strict interaction with immune and non immune host cells. Furthermore, food antigens (for example, tryptophan derivatives, flavonoids and byphenils) bind the aryl hydrocarbon receptor on innate lymphoid cells (ILCs), thus promoting the development of postnatal lymphoid tissues. Also retinoic acid, a metabolite of vitamin A, contributes to SLO development during embryogenesis. Vitamin A deficiency seems to account for reduction of ILCs and scarce formation of solitary lymphoid tissue. Translational Studies: The role of lymphoid organs with special reference to intestinal TLO in the course of experimental and human disease will also be discussed. Future Perspectives: Finally, a new methodology, the so-called "gut-in-a dish", which has facilitated the in vitro interaction study between microbe and intestinal immune cells, will be described. 10.2174/1871530319666181128160411
    Action and function of Akkermansia muciniphila in microbiome ecology, health and disease. Ottman Noora,Geerlings Sharon Y,Aalvink Steven,de Vos Willem M,Belzer Clara Best practice & research. Clinical gastroenterology The discovery of Akkermansia muciniphila has opened new avenues for the use of this abundant intestinal symbiont in next generation therapeutic products, as well as targeting microbiota dynamics. A. muciniphila is known to colonize the mucosal layer of the human intestine where it triggers both host metabolic and immune responses. A. muciniphila is particularly effective in increasing mucus thickness and increasing gut barrier function. As a result host metabolic markers ameliorate. The mechanism of host regulation is thought to involve the outer membrane composition, including the type IV pili of A. muciniphila, that directly signal to host immune receptors. At the same time the metabolic activity of A. muciniphila leads to the production of short chain fatty acids that are beneficial to the host and microbiota members. This contributes to host-microbiota and microbe-microbe syntrophy The mucolytic activity and metabolite production make A. muciniphila a key species in the mucus layer, stimulating beneficial mucosal microbial networks. This well studied member of the microbiota has been studied in three aspects that will be further described in this review: i) A. muciniphila characteristics and mucin adaptation, ii) its role as key species in the mucosal microbiome, and iii) its role in host health. 10.1016/j.bpg.2017.10.001
    Bifidobacteria and Butyrate-Producing Colon Bacteria: Importance and Strategies for Their Stimulation in the Human Gut. Rivière Audrey,Selak Marija,Lantin David,Leroy Frédéric,De Vuyst Luc Frontiers in microbiology With the increasing amount of evidence linking certain disorders of the human body to a disturbed gut microbiota, there is a growing interest for compounds that positively influence its composition and activity through diet. Besides the consumption of probiotics to stimulate favorable bacterial communities in the human gastrointestinal tract, prebiotics such as inulin-type fructans (ITF) and arabinoxylan-oligosaccharides (AXOS) can be consumed to increase the number of bifidobacteria in the colon. Several functions have been attributed to bifidobacteria, encompassing degradation of non-digestible carbohydrates, protection against pathogens, production of vitamin B, antioxidants, and conjugated linoleic acids, and stimulation of the immune system. During life, the numbers of bifidobacteria decrease from up to 90% of the total colon microbiota in vaginally delivered breast-fed infants to <5% in the colon of adults and they decrease even more in that of elderly as well as in patients with certain disorders such as antibiotic-associated diarrhea, inflammatory bowel disease, irritable bowel syndrome, obesity, allergies, and regressive autism. It has been suggested that the bifidogenic effects of ITF and AXOS are the result of strain-specific yet complementary carbohydrate degradation mechanisms within cooperating bifidobacterial consortia. Except for a bifidogenic effect, ITF and AXOS also have shown to cause a butyrogenic effect in the human colon, i.e., an enhancement of colon butyrate production. Butyrate is an essential metabolite in the human colon, as it is the preferred energy source for the colon epithelial cells, contributes to the maintenance of the gut barrier functions, and has immunomodulatory and anti-inflammatory properties. It has been shown that the butyrogenic effects of ITF and AXOS are the result of cross-feeding interactions between bifidobacteria and butyrate-producing colon bacteria, such as Faecalibacterium prausnitzii (clostridial cluster IV) and Anaerostipes, Eubacterium, and Roseburia species (clostridial cluster XIVa). These kinds of interactions possibly favor the co-existence of bifidobacterial strains with other bifidobacteria and with butyrate-producing colon bacteria in the human colon. 10.3389/fmicb.2016.00979
    Metabolism meets immunity: The role of free fatty acid receptors in the immune system. Alvarez-Curto Elisa,Milligan Graeme Biochemical pharmacology There are significant numbers of nutrient sensing G protein-coupled receptors (GPCRs) that can be found in cells of the immune system and in tissues that are involved in metabolic function, such as the pancreas or the intestinal epithelium. The family of free fatty acid receptors (FFAR1-4, GPR84), plus a few other metabolite sensing receptors (GPR109A, GPR91, GPR35) have been for this reason the focus of studies linking the effects of nutrients with immunological responses. A number of the beneficial anti-inflammatory effects credited to dietary fats such as omega-3 fatty acids are attributed to their actions on FFAR4.This might play an important protective role in the development of obesity, insulin resistance or asthma. The role of the short-chain fatty acids resulting from fermentation of fibre by the intestinal microbiota in regulating acute inflammatory responses is also discussed. Finally we assess the therapeutic potential of this family of receptors to treat pathologies where inflammation is a major factor such as type 2 diabetes, whether by the use of novel synthetic molecules or by the modulation of the individual's diet. 10.1016/j.bcp.2016.03.017
    Inflammation in Renal Diseases: New and Old Players. Andrade-Oliveira Vinicius,Foresto-Neto Orestes,Watanabe Ingrid Kazue Mizuno,Zatz Roberto,Câmara Niels Olsen Saraiva Frontiers in pharmacology Inflammation, a process intimately linked to renal disease, can be defined as a complex network of interactions between renal parenchymal cells and resident immune cells, such as macrophages and dendritic cells, coupled with recruitment of circulating monocytes, lymphocytes, and neutrophils. Once stimulated, these cells activate specialized structures such as Toll-like receptor and Nod-like receptor (NLR). By detecting danger-associated molecules, these receptors can set in motion major innate immunity pathways such as nuclear factor ĸB (NF-ĸB) and NLRP3 inflammasome, causing metabolic reprogramming and phenotype changes of immune and parenchymal cells and triggering the secretion of a number of inflammatory mediators that can cause irreversible tissue damage and functional loss. Growing evidence suggests that this response can be deeply impacted by the crosstalk between the kidneys and other organs, such as the gut. Changes in the composition and/or metabolite production of the gut microbiota can influence inflammation, oxidative stress, and fibrosis, thus offering opportunities to positively manipulate the composition and/or functionality of gut microbiota and, consequentially, ameliorate deleterious consequences of renal diseases. In this review, we summarize the most recent evidence that renal inflammation can be ameliorated by interfering with the gut microbiota through the administration of probiotics, prebiotics, and postbiotics. In addition to these innovative approaches, we address the recent discovery of new targets for drugs long in use in clinical practice. Angiotensin II receptor antagonists, NF-ĸB inhibitors, thiazide diuretics, and antimetabolic drugs can reduce renal macrophage infiltration and slow down the progression of renal disease by mechanisms independent of those usually attributed to these compounds. Allopurinol, an inhibitor of uric acid production, has been shown to decrease renal inflammation by limiting activation of the NLRP3 inflammasome. So far, these protective effects have been shown in experimental studies only. Clinical studies will establish whether these novel strategies can be incorporated into the arsenal of treatments intended to prevent the progression of human disease. 10.3389/fphar.2019.01192
    Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions. Wirthgen Elisa,Hoeflich Andreas,Rebl Alexander,Günther Juliane Frontiers in immunology Tryptophan metabolites are known to participate in the regulation of many cells of the immune system and are involved in various immune-mediated diseases and disorders. Kynurenic acid (KYNA) is a product of one branch of the kynurenine pathway of tryptophan metabolism. The influence of KYNA on important neurophysiological and neuropathological processes has been comprehensively documented. In recent years, the link of KYNA to the immune system, inflammation, and cancer has become more apparent. Given this connection, the anti-inflammatory and immunosuppressive functions of KYNA are of particular interest. These characteristics might allow KYNA to act as a "double-edged sword." The metabolite contributes to both the resolution of inflammation and the establishment of an immunosuppressive environment, which, for instance, allows for tumor immune escape. Our review provides a comprehensive update of the significant biological functions of KYNA and focuses on its immunomodulatory properties by signaling G-protein-coupled receptor 35 (GPR35)- and aryl hydrocarbon receptor-mediated pathways. Furthermore, we discuss the role of KYNA-GPR35 interaction and microbiota associated KYNA metabolism for gut homeostasis. 10.3389/fimmu.2017.01957
    The Role of Succinate in the Regulation of Intestinal Inflammation. Connors Jessica,Dawe Nick,Van Limbergen Johan Nutrients Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation of dietary fiber. Elevated succinate levels within the gut lumen have been reported in association with microbiome disturbances (dysbiosis), as well as in patients with inflammatory bowel disease (IBD) and animal models of intestinal inflammation. Recent studies indicate that succinate can activate immune cells via its specific surface receptor, succinate receptor 1(SUCNR1), and enhance inflammation. However, the role of succinate in inflammatory processes within the gut mucosal immune system is unclear. This review includes current literature on the association of succinate with intestinal inflammation and the potential role of succinate⁻SUCNR1 signaling in gut immune functions. 10.3390/nu11010025
    Gastro-intestinal tract: The leading role of mucosal immunity. Steinert Anna,Radulovic Katarina,Niess Jan Swiss medical weekly An understanding of mucosal immunity is essential for the comprehension of intestinal diseases that are often caused by a complex interplay between host factors, environmental influences and the intestinal microbiota. Not only improvements in endoscopic techniques, but also advances in high throughput sequencing technologies, have expanded knowledge of how intestinal diseases develop. This review discusses how the host interacts with intestinal microbiota by the direct contact of host receptors with highly conserved structural motifs or molecules of microbes and also by microbe-derived metabolites (produced by the microbe during adaptation to the gut environment), such as short-chain fatty acids, vitamins, bile acids and amino acids. These metabolites are recognised by metabolite-sensing receptors expressed by immune cells to influence functions of macrophages, dendritic cells and T cells, such as migration, conversion and maintenance of regulatory T cells and regulation of proinflammatory cytokine production, which is essential for the maintenance of intestinal homeostasis and the development of intestinal diseases, such as inflammatory bowel diseases. First interventions in these complex interactions between microbe-derived metabolites and the host immune system for the treatment of gastrointestinal diseases, such as modification of the diet, treatment with antibiotics, application of probiotics and faecal microbiota transplantation, have been introduced into the clinic. Specific targeting of metabolite sensing receptors for the treatment of gastrointestinal diseases is in development. In future, precision medicine approaches that consider individual variability in genes, the microbiota, the environment and lifestyle will become increasingly important for the care of patients with gastrointestinal diseases. 10.4414/smw.2016.14293
    Mining the microbiota for microbial and metabolite-based immunotherapies. Skelly Ashwin N,Sato Yuko,Kearney Sean,Honda Kenya Nature reviews. Immunology 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. 10.1038/s41577-019-0144-5
    Personalized microbiome-based approaches to metabolic syndrome management and prevention. Shapiro Hagit,Suez Jotham,Elinav Eran Journal of diabetes Personalized or precision medicine is a novel clinical approach targeted to the individual patient and based on integration of clinical, genetic, and environmental factors that define a patient uniquely from other individuals featuring similar clinical symptoms. Such a personalized medicine approach is increasingly applied for diagnosis, clinical stratification, and treatment of metabolic syndrome (MetS)-associated risks and diseases, including obesity, type 2 diabetes, non-alcoholic fatty liver disease, and their complications. One emerging factor that governs MetS manifestations is the microbiome, the composition, function, growth dynamics, associated metabolite profile and diverse effects of which on host immune and metabolic systems can all significantly affect metabolic homeostasis. Interindividual differences in microbiome composition and function, as well as personal variations in microbial-derived products, pave the way towards microbiome-based personalized medicine in treating MetS-related diseases. 10.1111/1753-0407.12501
    GPCR-Mediated Signaling of Metabolites. Husted Anna Sofie,Trauelsen Mette,Rudenko Olga,Hjorth Siv A,Schwartz Thue W Cell metabolism In addition to their bioenergetic intracellular function, several classical metabolites act as extracellular signaling molecules activating cell-surface G-protein-coupled receptors (GPCRs), similar to hormones and neurotransmitters. "Signaling metabolites" generated from nutrients or by gut microbiota target primarily enteroendocrine, neuronal, and immune cells in the lamina propria of the gut mucosa and the liver and, through these tissues, the rest of the body. In contrast, metabolites from the intermediary metabolism act mainly as metabolic stress-induced autocrine and paracrine signals in adipose tissue, the liver, and the endocrine pancreas. Importantly, distinct metabolite GPCRs act as efficient pro- and anti-inflammatory regulators of key immune cells, and signaling metabolites may thus function as important drivers of the low-grade inflammation associated with insulin resistance and obesity. The concept of key metabolites as ligands for specific GPCRs has broadened our understanding of metabolic signaling significantly and provides a number of novel potential drug targets. 10.1016/j.cmet.2017.03.008
    Fine-tuning of the mucosal barrier and metabolic systems using the diet-microbial metabolite axis. Nagai Motoyoshi,Obata Yuuki,Takahashi Daisuke,Hase Koji International immunopharmacology The human intestinal microbiota has profound effects on human physiology, including the development and maintenance of the host immune and metabolic systems. Under physiological conditions, the intestinal microbiota maintains a symbiotic relationship with the host. Abnormalities in the host-microbe relationship, however, have been implicated in multiple disorders such as inflammatory bowel diseases (IBDs), metabolic syndrome, and autoimmune diseases. There is a close correlation between dietary factors and the microbial composition in the gut. Long-term dietary habits influence the composition of the gut microbial community and consequently alter microbial metabolic activity. The diet-microbiota axis plays a vital role in the regulation of the host immune system, at least partly through altering microbial metabolism. In this review, we will describe the current findings regarding how dietary factors and microbial metabolites regulate the host immune system. 10.1016/j.intimp.2016.04.001
    Type 3 regulatory T cells at the interface of symbiosis. Park Joo-Hong,Eberl Gérard Journal of microbiology (Seoul, Korea) The mammalian gastrointestinal tract accommodates trillions of bacteria, many of which provide beneficial effects to the host, including protection from pathogenic microorganisms and essential metabolites. However, the intestinal immune system needs to adapt to the constantly fluctuating microbial environment at mucosal surfaces in order to maintain homeostasis. In particular, the gut microbiota induces the differentiation of effector Th17 cells and regulatory T cells (Tregs) that express RORγt, the master regulator of antimicrobial type 3 immunity. RORγt Tregs constitute a major population of colonic Tregs that is distinct from thymusderived Tregs and require bacterial antigens for differentiation. The balance between Th17 cells and RORγt Tregs, that is, the tone of the local type 3 immune response, is regulated by the vitamin A metabolite retinoic acid produced by the host. Furthermore, Th17 cells and RORγt Tregs regulate intestinal type 2 immune responses, explaining how bacteria block allergic reactions. Here, we review the cellular and molecular mechanisms involved in the differentiation, regulation and function of RORγt (type 3) Tregs, and discuss the multiple equilibria that exist between effector T cells and Tregs, as well as between different types of immune responses, which are necessary to maintain homeostasis and health. 10.1007/s12275-018-7565-x
    Microbe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity. Meng Xiang,Zhou Hao-Yue,Shen Hui-Hui,Lufumpa Eniya,Li Xiao-Mei,Guo Biao,Li Bao-Zhu Autoimmunity reviews The role of microorganism in human diseases cannot be ignored. These microorganisms have evolved together with humans and worked together with body's mechanism to maintain immune and metabolic function. Emerging evidence shows that gut microbe and their metabolites open up new doors for the study of human response mechanism. The complexity and interdependence of these microbe-metabolite-host interactions are rapidly being elucidated. There are various changes of microbial levels in models or in patients of various autoimmune diseases (AIDs). In addition, the relevant metabolites involved in mechanism mainly include short-chain fatty acids (SCFAs), bile acids (BAs), and polysaccharide A (PSA). Meanwhile, the interaction between microbes and host genes is also a factor that must be considered. It has been demonstrated that human microbes are involved in the development of a variety of AIDs, including organ-specific AIDs and systemic AIDs. At the same time, microbes or related products can be used to remodel body's response to alleviate or cure diseases. This review summarizes the latest research of microbes and their related metabolites in AIDs. More importantly, it highlights novel and potential therapeutics, including fecal microbial transplantation, probiotics, prebiotics, and synbiotics. Nonetheless, exact mechanisms still remain elusive, and future research will focus on finding a specific strain that can act as a biomarker of an autoimmune disease. 10.1016/j.autrev.2019.03.006
    Microbiome-Host Immune System Interactions. Smolinska Sylwia,O'Mahony Liam Seminars in liver disease The intestinal immune system recognizes and responds to the vast diversity of microbes present within the gut. Highly sophisticated cellular and molecular networks are continuously coordinated to tolerate the presence of a large number and diversity of bacteria on mucosal surfaces. Different types of bacteria induce different immune responses, and bacterial metabolism of dietary factors generates metabolites that have significant effects on host immune responses. Dendritic cells, epithelial cells, innate lymphoid cells, T-regulatory cells, effector lymphocytes, natural killer T cells, and B-cell responses can all be influenced by the microbiome. Many of the mechanisms being described are bacterial strain or metabolite-specific. A better understanding of the mechanisms governing microbiome-host immune responses will likely lead to novel therapeutics for inflammatory disorders. 10.1055/s-0036-1593883
    Microbiome-Modulated Metabolites at the Interface of Host Immunity. Blacher Eran,Levy Maayan,Tatirovsky Evgeny,Elinav Eran Journal of immunology (Baltimore, Md. : 1950) The mammalian gastrointestinal tract and associated mucosal immune system harbor a large repertoire of metabolites of prokaryotic and eukaryotic origin that play important roles in eukaryotic development and physiology. These often bioactive small molecules originate from nutrition- and environmental-related sources, or are endogenously produced and modulated by the host and its microbiota. A complex network of interactions exists between the intestinal mucosal immune system and the microbiota. This intimate cross-talk may be driven by metabolite secretion and signaling, and features profound influences on host immunity and physiology, including the endocrine, metabolic, and nervous system function in health and disease. Alterations in microbiome-associated metabolite levels and activity are implicated in the pathogenesis of a growing number of illnesses. In this review we discuss the origin and influence of microbiome-modulated metabolites, with an emphasis on immune cell development and function. We further highlight the emerging data potentially implicating metabolite misbalance with host-microbiome-associated disease. 10.4049/jimmunol.1601247
    Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. Sivaprakasam Sathish,Prasad Puttur D,Singh Nagendra Pharmacology & therapeutics Epidemiological studies have linked increased incidence of inflammatory diseases and intestinal cancers in the developed parts of the world to the consumption of diets poor in dietary fibers and rich in refined carbohydrates. Gut bacteria residing in the intestinal lumen exclusively metabolize dietary fibers. Butyrate, propionate and acetate, which are collectively called short-chain fatty acids (SCFAs), are generated by fermentation of dietary fibers by gut microbiota. Evidences indicate that SCFAs are key players in regulating beneficial effect of dietary fibers and gut microbiota on our health. SCFAs interact with metabolite-sensing G protein-coupled receptors GPR41, GPR43 and GPR109A expressed in gut epithelium and immune cells. These interactions induce mechanisms that play a key role in maintaining homeostasis in gut and other organs. This review summarizes the protective roles of GPR41, GPR43 and GPR109A in dietary fibers-, gut microbiota- and SCFAs-mediated suppression of inflammation and carcinogenesis in gut and other organs. 10.1016/j.pharmthera.2016.04.007
    Microbial Metabolites Determine Host Health and the Status of Some Diseases. Sittipo Panida,Shim Jae-Won,Lee Yun Kyung International journal of molecular sciences The gastrointestinal (GI) tract is a highly complex organ composed of the intestinal epithelium layer, intestinal microbiota, and local immune system. Intestinal microbiota residing in the GI tract engages in a mutualistic relationship with the host. Different sections of the GI tract contain distinct proportions of the intestinal microbiota, resulting in the presence of unique bacterial products in each GI section. The intestinal microbiota converts ingested nutrients into metabolites that target either the intestinal microbiota population or host cells. Metabolites act as messengers of information between the intestinal microbiota and host cells. The intestinal microbiota composition and resulting metabolites thus impact host development, health, and pathogenesis. Many recent studies have focused on modulation of the gut microbiota and their metabolites to improve host health and prevent or treat diseases. In this review, we focus on the production of microbial metabolites, their biological impact on the intestinal microbiota composition and host cells, and the effect of microbial metabolites that contribute to improvements in inflammatory bowel diseases and metabolic diseases. Understanding the role of microbial metabolites in protection against disease might offer an intriguing approach to regulate disease. 10.3390/ijms20215296
    Dietary SCFAs, IL-22, and GFAP: The Three Musketeers in the Gut-Neuro-Immune Network in Type 1 Diabetes. Jayasimhan Abhirup,Mariño Eliana Frontiers in immunology Microbial metabolites have a profound effect on the development of type 1 diabetes (T1D). The cross-talk between the gut microbiota, the nervous system, and immune system is necessary to establish and maintain immune and gut tolerance. As quoted by Hippocrates, "All disease begins in the gut." Although this has been recognized for 2,000 years, the connection between the gut and autoimmune T1D is not yet well-understood. Here, we outline new advances supported by our research and others that have contributed to elucidate the impact of microbial metabolites on the physiology of the pancreas and the gut through their remarkable effect on the immune and nervous system. Among many of the mechanisms involved in the gut-beta-cell-immune cross-talk, glial fibrillary acidic protein (GFAP)-expressing cells are critical players in the development of invasive insulitis. Besides, this review reveals a novel mechanism for microbial metabolites by stimulating IL-22, an essential cytokine for gut homeostasis and beta-cell survival. The close connections between the gut and the pancreas are highlighted through our review as microbial metabolites recirculate through the whole body and intimately react with the nervous system, which controls essential disorders associated with diabetes. As such, we discuss the mechanisms of action of microbial metabolites or short-chain fatty acids (SCFAs), IL-22, and GFAP on beta-cells, gut epithelial cells, neurons, and glial cells via metabolite sensing receptors or through epigenetic effects. The fine-tuned gut-neuro-immune network may be profoundly affected by SCFA deficiency related to dysbiosis and diet alterations at very early stages of the initiation of the disease. Thus, dampening the initial immune response or preventing the perpetuation of the immune response by maintaining the integrity of the gut is among the alternative approaches to prevent T1D. 10.3389/fimmu.2019.02429
    Metabolite-Sensing G Protein-Coupled Receptors-Facilitators of Diet-Related Immune Regulation. Tan Jian K,McKenzie Craig,Mariño Eliana,Macia Laurence,Mackay Charles R Annual review of immunology Nutrition and the gut microbiome regulate many systems, including the immune, metabolic, and nervous systems. We propose that the host responds to deficiency (or sufficiency) of dietary and bacterial metabolites in a dynamic way, to optimize responses and survival. A family of G protein-coupled receptors (GPCRs) termed the metabolite-sensing GPCRs bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. Members of this family include GPR43, GPR41, GPR109A, GPR120, GPR40, GPR84, GPR35, and GPR91. In addition, bile acid receptors such as GPR131 (TGR5) and proton-sensing receptors such as GPR65 show similar features. A consistent feature of this family of GPCRs is that they provide anti-inflammatory signals; many also regulate metabolism and gut homeostasis. These receptors represent one of the main mechanisms whereby the gut microbiome affects vertebrate physiology, and they also provide a link between the immune and metabolic systems. Insufficient signaling through one or more of these metabolite-sensing GPCRs likely contributes to human diseases such as asthma, food allergies, type 1 and type 2 diabetes, hepatic steatosis, cardiovascular disease, and inflammatory bowel diseases. 10.1146/annurev-immunol-051116-052235
    Biology of the Microbiome 1: Interactions with the Host Immune Response. Smolinska Sylwia,Groeger David,O'Mahony Liam Gastroenterology clinics of North America The intestinal immune system is intimately connected with the vast diversity of microbes present within the gut and the diversity of food components that are consumed daily. The discovery of novel molecular mechanisms, which mediate host-microbe-nutrient communication, have highlighted the important roles played by microbes and dietary factors in influencing mucosal immune responses. Dendritic cells, epithelial cells, innate lymphoid cells, T regulatory cells, effector lymphocytes, natural killer T cells, and B cells can all be influenced by the microbiome. Many of the mechanisms being described are bacterial strain or metabolite specific. 10.1016/j.gtc.2016.09.004
    Role of gut microbial metabolites in nonalcoholic fatty liver disease. Zhao Ze Hua,Lai Jonathan King-Lam,Qiao Liang,Fan Jian Gao Journal of digestive diseases Nonalcoholic fatty liver disease (NAFLD) is a common, multifactorial liver disease that has emerged as a global challenge due to its increasing prevalence and lack of sustainable treatment options. Gut microbiota possess vital functions in fermenting dietary nutrients and synthesizing bioactive molecules. This function is of great importance in maintaining health because these microbial metabolites are essential in regulating energy metabolism, immune response, and other vital physiological processes. Altered gut flora can result in a change in gut microbial metabolites, affecting the onset and progression of multiple diseases. In this review we summarize the metabolites that may have beneficial or harmful effects on the development and progression of NAFLD. This will help us better understand the possible mechanisms underlying the pathogenesis of NAFLD and facilitate the identification of potential therapeutic approaches for NAFLD. 10.1111/1751-2980.12709
    Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. Sun Mingming,Wu Wei,Liu Zhanju,Cong Yingzi Journal of gastroenterology Gut microbiota has been well recognized in regulation of intestinal homeostasis and pathogenesis of inflammatory bowel diseases. However, the mechanisms involved are still not completely understood. Further, the components of the microbiota which are critically responsible for such effects are also largely unknown. Accumulating evidence suggests that, in addition to pathogen-associated molecular patterns, nutrition and bacterial metabolites might greatly impact the immune response in the gut and beyond. Short chain fatty acids (SCFA), which are metabolized by gut bacteria from otherwise indigestible fiber-rich diets, have been shown to ameliorate diseases in animal models of inflammatory bowel diseases (IBD) and allergic asthma. Although the exact mechanisms for the action of SCFA are still not completely clear, most notable among the SCFA targets is the mammalian G protein-coupled receptor pair of GPR41 and GPR43. In addition to the well-documented inhibition of histone deacetylases activity mainly by butyrate and propionate, which causes anti-inflammatory activities on IEC, macrophages, and dendritic cells, SCFA has recently been implicated in promoting development of Treg cells and possibly other T cells. In addition to animal models, the beneficial effects have also been reported from the clinical studies that used SCFA therapeutically in controlled trial settings in inflammatory disease, in that application of SCFA improved indices of IBD and therapeutic efficacy was demonstrated in acute radiation proctitis. In this review article, we will summarize recent progresses of SCFA in regulation of intestinal homeostasis as well as in pathogenesis of IBD. 10.1007/s00535-016-1242-9
    Tryptophan: A gut microbiota-derived metabolites regulating inflammation. Etienne-Mesmin Lucie,Chassaing Benoit,Gewirtz Andrew T World journal of gastrointestinal pharmacology and therapeutics Inflammatory bowel diseases (IBD), which comprise Crohn's disease and ulcerative colitis, are chronic intestinal disorders with an increased prevalence and incidence over the last decade in many different regions over the world. The etiology of IBD is still not well defined, but evidence suggest that it results from perturbation of the homeostasis between the intestinal microbiota and the mucosal immune system, with the involvement of both genetic and environmental factors. Genome wide association studies, which involve large-scale genome-wide screening of potential polymorphism, have identified several mutations associated with IBD. Among them, , a gene encoding an adapter molecule involved in innate immune response to fungi ( type C-lectin sensing) through the activation of IL-22 signaling pathway, has been identified as one IBD susceptible genes. Dietary compounds, which represent a source of energy and metabolites for gut bacteria, are also appreciated to be important actors in the etiology of IBD, for example by altering gut microbiota composition and by regulating the generation of short chain fatty acids. A noteworthy study published in the June 2016 issue of by Lamas and colleagues investigates the interaction between and the gut microbiota in the generation of the microbiota-derived tryptophan metabolite. This study highlights the role of tryptophan in dampening intestinal inflammation in susceptible hosts. 10.4292/wjgpt.v8.i1.7
    Metabolite-Sensing G Protein-Coupled Receptors Connect the Diet-Microbiota-Metabolites Axis to Inflammatory Bowel Disease. Melhem Hassan,Kaya Berna,Ayata C Korcan,Hruz Petr,Niess Jan Hendrik Cells Increasing evidence has indicated that diet and metabolites, including bacteria- and host-derived metabolites, orchestrate host pathophysiology by regulating metabolism, immune system and inflammation. Indeed, autoimmune diseases such as inflammatory bowel disease (IBD) are associated with the modulation of host response to diets. One crucial mechanism by which the microbiota affects the host is signaling through G protein-coupled receptors (GPCRs) termed metabolite-sensing GPCRs. In the gut, both immune and nonimmune cells express GPCRs and their activation generally provide anti-inflammatory signals through regulation of both the immune system functions and the epithelial integrity. Members of GPCR family serve as a link between microbiota, immune system and intestinal epithelium by which all these components crucially participate to maintain the gut homeostasis. Conversely, impaired GPCR signaling is associated with IBD and other diseases, including hepatic steatosis, diabetes, cardiovascular disease, and asthma. In this review, we first outline the signaling, function, expression and the physiological role of several groups of metabolite-sensing GPCRs. We then discuss recent findings on their role in the regulation of the inflammation, their existing endogenous and synthetic ligands and innovative approaches to therapeutically target inflammatory bowel disease. 10.3390/cells8050450
    Role of intestinal microbiota and metabolites in inflammatory bowel disease. Dong Li-Na,Wang Mu,Guo Jian,Wang Jun-Ping Chinese medical journal OBJECTIVE:The metabolites produced by the gut microbiota are of interest to scientists. The objective of this review was to provide an updated summary of progress regarding the microbiota and their metabolites and influences on the pathogenesis of inflammatory bowel disease (IBD). DATA SOURCES:The author retrieved information from the PubMed database up to January 2018, using various combinations of search terms, including IBD, microbiota, and metabolite. STUDY SELECTION:Both clinical studies and animal studies of intestinal microbiota and metabolites in IBD were selected. The information explaining the possible pathogenesis of microbiota in IBD was organized. RESULTS:In IBD patients, the biodiversity of feces/mucosa-associated microbiota is decreased, and the probiotic microbiota is also decreased, whereas the pathogenic microbiota are increased. The gut microbiota may be a target for diagnosis and treatment of IBD. Substantial amounts of data support the view that the microbiota and their metabolites play pivotal roles in IBD by affecting intestinal permeability and the immune response. CONCLUSIONS:This review highlights the advances in recent gut microbiota research and clarifies the importance of the gut microbiota in IBD pathogenesis. Future research is needed to study the function of altered bacterial community compositions and the roles of metabolites. 10.1097/CM9.0000000000000290
    The nutrition-gut microbiome-physiology axis and allergic diseases. McKenzie Craig,Tan Jian,Macia Laurence,Mackay Charles R Immunological reviews Dietary and bacterial metabolites influence immune responses. This raises the question whether the increased incidence of allergies, asthma, some autoimmune diseases, cardiovascular disease, and others might relate to intake of unhealthy foods, and the decreased intake of dietary fiber. In recent years, new knowledge on the molecular mechanisms underpinning a 'diet-gut microbiota-physiology axis' has emerged to substantiate this idea. Fiber is fermented to short chain fatty acids (SCFAs), particularly acetate, butyrate, and propionate. These metabolites bind 'metabolite-sensing' G-protein-coupled receptors such as GPR43, GPR41, and GPR109A. These receptors play fundamental roles in the promotion of gut homeostasis and the regulation of inflammatory responses. For instance, these receptors and their metabolites influence Treg biology, epithelial integrity, gut homeostasis, DC biology, and IgA antibody responses. The SCFAs also influence gene transcription in many cells and tissues, through their inhibition of histone deacetylase expression or function. Contained in this mix is the gut microbiome, as commensal bacteria in the gut have the necessary enzymes to digest dietary fiber to SCFAs, and dysbiosis in the gut may affect the production of SCFAs and their distribution to tissues throughout the body. SCFAs can epigenetically modify DNA, and so may be one mechanism to account for diseases with a 'developmental origin', whereby in utero or post-natal exposure to environmental factors (such as nutrition of the mother) may account for disease later in life. If the nutrition-gut microbiome-physiology axis does underpin at least some of the Western lifestyle influence on asthma and allergies, then there is tremendous scope to correct this with healthy foodstuffs, probiotics, and prebiotics. 10.1111/imr.12556
    Gut microbiota metabolite regulation of host defenses at mucosal surfaces: implication in precision medicine. Bilotta Anthony J,Cong Yingzi Precision clinical medicine The gut microbiota has a well-established role in the regulation of host homeostasis. Multiple factors control the composition and function of the microbiota. The westernization of diet, a shift away from nutrient-dense foods toward diets high in saturated fats, has been implicated in the rise of chronic inflammatory diseases such as inflammatory bowel disease (IBD). Diet is critical in the development and maintenance of a healthy microbiome, where dietary fiber (found in the highest amounts in fruits, vegetables, and legumes) is metabolized by the microbiome. In turn, the bacterial metabolites of dietary fiber, short chain fatty acids (SCFAs), regulate gut homeostasis. SCFAs engage G-protein coupled receptors (GPRs) and act as histone deacetylase inhibitors (HDACi) to module epithelial and immune cell functions in the intestines, where they generally promote an anti-inflammatory state. This review highlights the functions of SCFAs and their roles in the pathogenesis of IBD to provide insights into their potential therapeutic application for the treatment of IBD for the purposes of precision medicine. 10.1093/pcmedi/pbz008
    Gut Microbiota and Atherosclerosis. Li Daniel Y,Tang W H Wilson Current atherosclerosis reports PURPOSE OF REVIEW:Studies in microbiota-mediated health risks have gained traction in recent years since the compilation of the Human Microbiome Project. No longer do we believe that our gut microbiota is an inert set of microorganisms that reside in the body without consequence. In this review, we discuss the recent findings which further our understanding of the connection between the gut microbiota and the atherosclerosis. RECENT FINDINGS:We evaluate studies which illustrate the current understanding of the relationship between infection, immunity, altered metabolism, and bacterial products such as immune activators or dietary metabolites and their contributions to the development of atherosclerosis. In particular, we critically examine rec ent clinical and mechanistic findings for the novel microbiota-dependent dietary metabolite, trimethylamine N-oxide (TMAO), which has been implicated in atherosclerosis. These discoveries are now becoming integrated with advances in microbiota profiling which enhance our ability to interrogate the functional role of the gut microbiome and develop strategies for targeted therapeutics. The gut microbiota is a multi-faceted system that is unraveling novel contributors to the development and progression of atherosclerosis. In this review, we discuss historic and novel contributors while highlighting the TMAO story mainly as an example of the various paths taken beyond deciphering microbial composition to elucidate downstream mechanisms that promote (or protect from) atherogenesis in the hopes of translating these findings from bench to bedside. 10.1007/s11883-017-0675-9
    Diet and Gut Microbiota in Health and Disease. Shen Ting-Chin David Nestle Nutrition Institute workshop series Gut microbiota plays an important role in host health maintenance and disease pathogenesis. The development of a stable and diverse gut microbiota is essential to various host physiologic functions such as immunoregulation, pathogen prevention, energy harvest, and metabolism. At the same time, a dysbiotic gut microbiota associated with disease is altered in structure and function, and often characterized by a decrease in species richness and proliferation of pathogenic bacterial taxa. As a shared substrate between the host and the gut microbiota, diet significantly impacts the health and disease states of the host both directly and through gut microbial metabolite production. This is demonstrated in the examples of short-chain fatty acid and trimethylamine production via bacterial metabolism of dietary complex carbohydrates and choline, respectively. In disorders related to mucosal immune dysregulation such as inflammatory bowel disease, the dysbiotic gut microbiota and diet contribute to its pathogenesis. Reversal of dysbiosis through fecal microbiota transplantation and dietary interventions may thus represent important strategies to modify the gut microbiota and its metabolite production for health maintenance as well as disease prevention and management. 10.1159/000455220
    The Gut Microbiota and the Hepatologist: Will Our Bugs Prove to be the Missing Link? Pallen Mark J,Quraishi Mohammed N Digestive diseases (Basel, Switzerland) The advent of next-generation sequencing has enabled in-depth analysis to study the composition and function of the gut microbiota in a culture-independent manner. Consequently, this has led to rapid interest in understanding the pathogenesis and progression of chronic liver disease in relation to perturbations of the gut microbiota. Animal models and human studies have demonstrated its crucial role in contributing to disease mechanisms in alcoholic and non-alcoholic liver disease and more recently in primary sclerosing cholangitis. There is increasing evidence to suggest that the gut microbiota and its components influence the development and modulation of chronic liver damage through direct communication via the portal system, metabolite production, alterations in gut barrier integrity, liver/gut immune axis and bile acid metabolism. The impact of microbiota-directed therapies for liver disease is still in its infancy. Better understanding of its role in disease mechanisms will lead to a more targeted approach in modulation of gut microbiota to influence both progression and complications of liver disease. This review discusses the current evidence for the gut microbiota-liver axis and its role in the development, progression and treatment of liver disease. 10.1159/000456590
    Gut Microbiota-Derived Components and Metabolites in the Progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Ji Yun,Yin Yue,Li Ziru,Zhang Weizhen Nutrients Human gut microbiota has been increasingly recognized as a pivotal determinant of non-alcoholic fatty liver disease (NAFLD). Apart from the changes in the composition of gut microbiota, the components and metabolites derived from intestinal microbiota have emerged as key factors in modulating the pathological process of NAFLD. Compelling evidences have revealed that gut microbiota generates a variety of bioactive substances that interact with the host liver cells through the portal vein. These substances include the components derived from bacteria such as lipopolysaccharides, peptidoglycan, DNA, and extracellular vesicles, as well as the metabolites ranging from short-chain fatty acids, indole and its derivatives, trimethylamine, secondary bile acids, to carotenoids and phenolic compounds. The mechanisms underlying the hepatic responses to the bioactive substances from gut bacteria have been associated with the regulation of glycolipid metabolism, immune signaling response, and redox homeostasis. Illuminating the interplay between the unique factors produced from gut microbiome and the liver will provide a novel therapeutical target for NAFLD. The current review highlights the recent advances on the mechanisms by which the key ingredients and metabolites from gut microbiota modulate the development and progression of NAFLD. 10.3390/nu11081712
    Cross-Talk between Gut Microbiota and Heart via the Routes of Metabolite and Immunity. Bu Jin,Wang Zhaohui Gastroenterology research and practice Considering the prevalence of cardiovascular disease (CVD), significant interest has been focused on the gut microbiota-heart interaction because the gut microbiota has been recognized as a barometer of human health. Dysbiosis, characterized by changes in the gut microbiota in CVD, has been reported in cardiovascular pathologies, such as atherosclerosis, hypertension, and heart failure. Conversely, gut microbiota-derived metabolites, such as trimethylamine/trimethylamine -oxide (TMA/TMAO), can impact host physiology. Further, bacterial dysbiosis can disturb gut immunity, which increases the risk of acute arterial events. Moreover, studies of germ-free mice have provided evidence that microbiota diversity and the presence of a specific microbe in the gut can affect immune cells in hosts. Therefore, the changes in the composition of the gut microbiota can affect host metabolism and immunity. Importantly, these effects are not only confined to the gut but also spreaded to distal organs. The purpose of the current review is to highlight the complex interplay between the microbiota and CVD via TMAO and different immune cells and discuss the roles of probiotics and nutrition interventions in modulating the intestinal microbiota as novel therapeutic targets of CVD. 10.1155/2018/6458094
    Implication of gut microbiota metabolites in cardiovascular and metabolic diseases. Brial Francois,Le Lay Aurélie,Dumas Marc-Emmanuel,Gauguier Dominique Cellular and molecular life sciences : CMLS Evidence from the literature keeps highlighting the impact of mutualistic bacterial communities of the gut microbiota on human health. The gut microbita is a complex ecosystem of symbiotic bacteria which contributes to mammalian host biology by processing, otherwise, indigestible nutrients, supplying essential metabolites, and contributing to modulate its immune system. Advances in sequencing technologies have enabled structural analysis of the human gut microbiota and allowed detection of changes in gut bacterial composition in several common diseases, including cardiometabolic disorders. Biological signals sent by the gut microbiota to the host, including microbial metabolites and pro-inflammatory molecules, mediate microbiome-host genome cross-talk. This rapidly expanding line of research can identify disease-causing and disease-predictive microbial metabolite biomarkers, which can be translated into novel biodiagnostic tests, dietary supplements, and nutritional interventions for personalized therapeutic developments in common diseases. Here, we review results from the most significant studies dealing with the association of products from the gut microbial metabolism with cardiometabolic disorders. We underline the importance of these postbiotic biomarkers in the diagnosis and treatment of human disorders. 10.1007/s00018-018-2901-1
    Regulation of the effector function of CD8 T cells by gut microbiota-derived metabolite butyrate. Luu Maik,Weigand Katharina,Wedi Fatana,Breidenbend Carina,Leister Hanna,Pautz Sabine,Adhikary Till,Visekruna Alexander Scientific reports The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs) that regulate the energy homeostasis and impact on immune cell function of the host. Recently, innovative approaches based on the oral administration of SCFAs have been discussed for therapeutic modification of inflammatory immune responses in autoimmune diseases. So far, most studies have investigated the SCFA-mediated effects on CD4 T cells and antigen presenting cells. Here we show that butyrate and, to a lesser degree, propionate directly modulate the gene expression of CD8 cytotoxic T lymphocytes (CTLs) and Tc17 cells. Increased IFN-γ and granzyme B expression by CTLs as well as the molecular switch of Tc17 cells towards the CTL phenotype was mediated by butyrate independently of its interaction with specific SCFA-receptors GPR41 and GPR43. Our results indicate that butyrate strongly inhibited histone-deacetylases (HDACs) in CD8 T cells thereby affecting the gene expression of effector molecules. Accordingly, the pan-HDAC inhibitors trichostatin A (TSA) and sodium valproate exerted similar influence on CD8 T cells. Furthermore, higher acetate concentrations were also able to increase IFN-γ production in CD8 T lymphocytes by modulating cellular metabolism and mTOR activity. These findings might have significant implications in adoptive immunotherapy of cancers and in anti-viral immunity. 10.1038/s41598-018-32860-x