The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease
TL;DR: It is discussed how the metabolic alterations of uremia favor pathogen overgrowth (dysbiosis) in the gut and an increased translocation of living bacteria and bacterial components has the potential to activate innate immunity and systemic inflammation.
About: This article is published in Kidney International.The article was published on 2013-06-01 and is currently open access. It has received 366 citations till now. The article focuses on the topics: Dysbiosis & Acquired immune system.
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TL;DR: A narrative review explores the relevant contemporary scientific literature to provide a general perspective of the role of diet and other environmental factors in modulating the composition and metabolic activity of the human gut microbiota, which in turn can impact health.
Abstract: There is growing recognition of the role of diet and other environmental factors in modulating the composition and metabolic activity of the human gut microbiota, which in turn can impact health. This narrative review explores the relevant contemporary scientific literature to provide a general perspective of this broad area. Molecular technologies have greatly advanced our understanding of the complexity and diversity of the gut microbial communities within and between individuals. Diet, particularly macronutrients, has a major role in shaping the composition and activity of these complex populations. Despite the body of knowledge that exists on the effects of carbohydrates there are still many unanswered questions. The impacts of dietary fats and protein on the gut microbiota are less well defined. Both short- and long-term dietary change can influence the microbial profiles, and infant nutrition may have life-long consequences through microbial modulation of the immune system. The impact of environmental factors, including aspects of lifestyle, on the microbiota is particularly poorly understood but some of these factors are described. We also discuss the use and potential benefits of prebiotics and probiotics to modify microbial populations. A description of some areas that should be addressed in future research is also presented.
1,045 citations
TL;DR: Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival and chronic dietary exposures that increase TmaO directly contributes to progressive renal fibrosis and dysfunction in animal models.
Abstract: Rationale: Trimethylamine- N -oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and l-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis. Objective: To both investigate the clinical prognostic value of TMAO in subjects with versus without CKD, and test the hypothesis that TMAO plays a direct contributory role in the development and progression of renal dysfunction. Methods and Results: We first examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in 521 stable subjects with CKD (estimated glomerular filtration rate, 2 ). Median TMAO level among CKD subjects was 7.9 μmol/L (interquartile range, 5.2–12.4 μmol/L), which was markedly higher ( P P P P =0.036). Among non-CKD subjects, elevated TMAO levels portend poorer prognosis within cohorts of high and low cystatin C. In animal models, elevated dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction. Conclusions: Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival. Chronic dietary exposures that increase TMAO directly contributes to progressive renal fibrosis and dysfunction in animal models.
811 citations
Cites background from "The intestinal microbiota, a leaky ..."
...have been identified as potential microbial by-products capable of initiating proinflammatory cytokine/chemokine cascades seen in the setting of CKD and end-stage renal disease.(4) Thus, it has been hypothesized that gut-microbiota–derived uremic toxins may serve as both therapeutic targets and assessment tools for renal diseases in this vulnerable population....
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TL;DR: This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions.
Abstract: The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system-intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp-microbiome-immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature.
687 citations
Cites background from "The intestinal microbiota, a leaky ..."
...The connection between microbes and the host immune system is mediated by a series of molecules (Anders et al., 2013) and signaling processes, which can impact the gut, liver, brain, and other organs....
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TL;DR: The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease.
Abstract: The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.
536 citations
TL;DR: The variety of factors contribute to chronic inflammatory status in CKD, including increased production and decreased clearance of pro-inflammatory cytokines, oxidative stress and acidosis, chronic and recurrent infections, including those related to dialysis access, altered metabolism of adipose tissue, and intestinal dysbiosis.
Abstract: Background: Despite recent advances in chronic kidney disease (CKD) and end-stage renal disease (ESRD) management, morbidity and mortality in this population rema
380 citations
References
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TL;DR: The Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals are described, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species.
Abstract: To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, ~150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively
9,268 citations
TL;DR: Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.
Abstract: Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.
4,107 citations
TL;DR: Findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut are discussed, and the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms is raised.
Abstract: Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host–symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.
4,079 citations
TL;DR: The authors showed that colonisation of mice with a segmented filamentous bacterium (SFB) is sufficient to induce the appearance of CD4+ T helper cells that produce IL-17 and IL-22 (Th17 cells) in the lamina propria.
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TL;DR: Advances in understanding of the interactions between resident microbes and the immune system are reviewed and the implications for human health are reviewed.
Abstract: The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity. Here, we review advances in our understanding of the interactions between resident microbes and the immune system and the implications of these findings for human health.
3,330 citations