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.
In addition to the immune system’s traditional roles of conferring anti-infectious and anti-neoplastic protection, it has been recently implicated in the regulation of systemic metabolic homeostasis. ...This cross-talk between the immune and the metabolic systems is pivotal in promoting “metabolic health” throughout the life of an organism and plays fundamental roles in its adaptation to ever-changing environmental makeups and nutritional availability. Perturbations in this intricate immune-metabolic cross-talk contribute to the tendency to develop altered metabolic states that may culminate in metabolic disorders such as malnutrition, obesity, type 2 diabetes mellitus (T2DM), and other features of the metabolic syndrome. Regulators of immune-metabolic interactions include host genetics, nutritional status, and the intestinal microbiome. In this Perspective, we highlight current understanding of immune-metabolism interactions, illustrate differences among individuals and between populations in this respect, and point toward future avenues of research possibly enabling immune harnessing as means of personalized treatment for common metabolic disorders.
The immune and metabolic systems intertwine to govern crucial physiological and pathological processes throughout the life of an organism. Zmora et al. delineate the role of individual endogenous and exogenous factors in shaping immune-metabolic interactions in homeostasis and disease settings and suggest that personally tailored immune targeted approaches may tackle metabolic disorders.
The mammalian intestine harbors one of the largest microbial densities on Earth, necessitating the implementation of control mechanisms by which the host evaluates the state of microbial colonization ...and reacts to deviations from homeostasis. While microbial recognition by the innate immune system has been firmly established as an efficient means by which the host evaluates microbial presence, recent work has uncovered a central role for bacterial metabolites in the orchestration of the host immune response. In this review, we highlight examples of how microbiota-modulated metabolites control the development, differentiation, and activity of the immune system and classify them into functional categories that illustrate the spectrum of ways by which microbial metabolites influence host physiology. A comprehensive understanding of how microbiota-derived metabolites shape the human immune system is critical for the rational design of therapies for microbiota-driven diseases.
Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity ...and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.
Over the last decade, our understanding of the composition and functions of the gut microbiota has greatly increased. To a large extent, this has been due to the development of high-throughput ...genomic analyses of microbial communities, which have identified the critical contributions of the microbiome to human health. Consequently, the intestinal microbiota has emerged as an attractive therapeutic target. The large majority of microbiota-targeted therapies aim at engineering the intestinal ecosystem by means of probiotics or prebiotics. Recently, a novel therapeutic approach has emerged which focuses on molecules that are secreted, modulated, or degraded by the microbiome and act directly on the host. Here, we discuss the advantages and challenges associated with the metabolite-based "postbiotic" approach, highlighting recent progress and the areas that need intensive attention and investigation over the next 5 years. The time is ripe for postbiotic therapies to be developed in the near future.
Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While ...inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted “postbiotic” metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.
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•Microbiota-modulated metabolites regulate NLRP6 inflammasome and intestinal IL-18•Inflammasome-derived IL-18 orchestrates colonic anti-microbial peptide expression•Inflammasome modulation by metabolites enables dysbiotic community transfer•Integrated metabolite signaling determines the severity of intestinal inflammation
Microbiota-associated metabolites shape the host-microbiome interface by modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and the generation of downstream anti-microbial peptides. This axis, therefore, determines both host indigenous microbiome profiles and the susceptibility to intestinal inflammation.
Highlights • Host and microbiota communicate by recognition of metabolic mediators. • Microbiota metabolites influence the development and function of the immune system. • Immunomodulatory function ...of microbiota metabolites impacts inflammatory disease.
All domains of life feature diverse molecular clock machineries that synchronize physiological processes to diurnal environmental fluctuations. However, no mechanisms are known to cross-regulate ...prokaryotic and eukaryotic circadian rhythms in multikingdom ecosystems. Here, we show that the intestinal microbiota, in both mice and humans, exhibits diurnal oscillations that are influenced by feeding rhythms, leading to time-specific compositional and functional profiles over the course of a day. Ablation of host molecular clock components or induction of jet lag leads to aberrant microbiota diurnal fluctuations and dysbiosis, driven by impaired feeding rhythmicity. Consequently, jet-lag-induced dysbiosis in both mice and humans promotes glucose intolerance and obesity that are transferrable to germ-free mice upon fecal transplantation. Together, these findings provide evidence of coordinated metaorganism diurnal rhythmicity and offer a microbiome-dependent mechanism for common metabolic disturbances in humans with aberrant circadian rhythms, such as those documented in shift workers and frequent flyers.
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•Intestinal microbiota exhibit diurnal oscillations in composition and function•Feeding rhythms direct microbiota oscillations•Chronic jet lag is associated with loss of microbiota rhythms and dysbiosis•Jet-lag-associated dysbiosis in mice and humans promotes metabolic imbalances
Gut microbiota undergo rhythmic oscillations in composition and function concordant with feeding behaviors in the host. Circadian disruption in the host leads to aberrant microbiota, which in, turn fuel metabolic imbalances.
In tackling the obesity pandemic, considerable efforts are devoted to the development of effective weight reduction strategies, yet many dieting individuals fail to maintain a long-term weight ...reduction, and instead undergo excessive weight regain cycles. The mechanisms driving recurrent post-dieting obesity remain largely elusive. Here we identify an intestinal microbiome signature that persists after successful dieting of obese mice and contributes to faster weight regain and metabolic aberrations upon re-exposure to obesity-promoting conditions. Faecal transfer experiments show that the accelerated weight regain phenotype can be transmitted to germ-free mice. We develop a machine-learning algorithm that enables personalized microbiome-based prediction of the extent of post-dieting weight regain. Additionally, we find that the microbiome contributes to diminished post-dieting flavonoid levels and reduced energy expenditure, and demonstrate that flavonoid-based 'post-biotic' intervention ameliorates excessive secondary weight gain. Together, our data highlight a possible microbiome contribution to accelerated post-dieting weight regain, and suggest that microbiome-targeting approaches may help to diagnose and treat this common disorder.
mRNA is thought to predominantly reside in the cytoplasm, where it is translated and eventually degraded. Although nuclear retention of mRNA has a regulatory potential, it is considered extremely ...rare in mammals. Here, to explore the extent of mRNA retention in metabolic tissues, we combine deep sequencing of nuclear and cytoplasmic RNA fractions with single-molecule transcript imaging in mouse beta cells, liver, and gut. We identify a wide range of protein-coding genes for which the levels of spliced polyadenylated mRNA are higher in the nucleus than in the cytoplasm. These include genes such as the transcription factor ChREBP, Nlrp6, Glucokinase, and Glucagon receptor. We demonstrate that nuclear retention of mRNA can efficiently buffer cytoplasmic transcript levels from noise that emanates from transcriptional bursts. Our study challenges the view that transcripts predominantly reside in the cytoplasm and reveals a role of the nucleus in dampening gene expression noise.
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•Genome-wide catalog of nuclear and cytoplasmic mRNA in mouse tissues•Spliced, polyadenylated mRNA is retained in the nucleus for many protein-coding genes•Retained genes include ChREBP and liver Nlrp6, co-localized with nuclear speckles•Nuclear retention of mRNA reduces cytoplasmic gene expression noise
Bahar Halpern et al. combine whole-transcriptome and single-molecule approaches to demonstrate that a substantial fraction of genes have higher levels of spliced, polyadenylated mRNA in the nucleus compared to the cytoplasm in mammalian tissues. This nuclear retention reduces cytoplasmic gene expression noise created by transcriptional bursts.
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