Dysbiotic Proteobacteria expansion: a microbial signature of epithelial dysfunction.
TL;DR: Observations suggest a dysbiotic expansion of Proteobacteria is a potential diagnostic microbial signature of epithelial dysfunction, a hypothesis that could spawn novel preventative or therapeutic strategies for a broad spectrum of human diseases.
About: This article is published in Current Opinion in Microbiology.The article was published on 2017-10-01. It has received 350 citations till now. The article focuses on the topics: Dysbiosis & Gut flora.
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TL;DR: This review highlights the latest findings on the role of Proteobacteria not only in intestinal but also in extraintestinal diseases, and demonstrates an increased abundance of members belonging to this phylum in such conditions.
Abstract: Microbiota represents the entire microbial community present in the gut host. It serves several functions establishing a mutualistic relation with the host. Latest years have seen a burst in the number of studies focusing on this topic, in particular on intestinal diseases. In this scenario, Proteobacteria are one of the most abundant phyla, comprising several known human pathogens. This review highlights the latest findings on the role of Proteobacteria not only in intestinal but also in extraintestinal diseases. Indeed, an increasing amount of data identifies Proteobacteria as a possible microbial signature of disease. Several studies demonstrate an increased abundance of members belonging to this phylum in such conditions. Major evidences currently involve metabolic disorders and inflammatory bowel disease. However, more recent studies suggest a role also in lung diseases, such as asthma and chronic obstructive pulmonary disease, but evidences are still scant. Notably, all these conditions are sustained by various degree of inflammation, which thus represents a core aspect of Proteobacteria-related diseases.
560 citations
TL;DR: Preliminary evidence from two cases suggests that fecal microbiota transplantation may provide a viable treatment option for a severe adverse effect of immune checkpoint blockade therapy in patients with cancer.
Abstract: We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
453 citations
TL;DR: The central role of colonic epithelial cells (colonocytes) in maintaining homeostasis by shaping the colonic microbiota to provide benefit is now beginning to be appreciated, and the metabolism of colonocytes functions as a control switch of the gut microbiota, mediating a shift between homeostatic and dysbiotic communities.
Abstract: An imbalance in the colonic microbiota might underlie many human diseases, but the mechanisms that maintain homeostasis remain elusive. Recent insights suggest that colonocyte metabolism functions as a control switch, mediating a shift between homeostatic and dysbiotic communities. During homeostasis, colonocyte metabolism is directed toward oxidative phosphorylation, resulting in high epithelial oxygen consumption. The consequent epithelial hypoxia helps to maintain a microbial community dominated by obligate anaerobic bacteria, which provide benefit by converting fiber into fermentation products absorbed by the host. Conditions that alter the metabolism of the colonic epithelium increase epithelial oxygenation, thereby driving an expansion of facultative anaerobic bacteria, a hallmark of dysbiosis in the colon. Enteric pathogens subvert colonocyte metabolism to escape niche protection conferred by the gut microbiota. The reverse strategy, a metabolic reprogramming to restore colonocyte hypoxia, represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases.
357 citations
TL;DR: Understanding the complexity and the molecular aspects linking gut microbes to health will help to set the basis for novel therapies that are already being developed, according to a critical evaluation of the current understanding.
Abstract: The gut microbiota is now considered as one of the key elements contributing to the regulation of host health. Virtually all our body sites are colonised by microbes suggesting different types of crosstalk with our organs. Because of the development of molecular tools and techniques (ie, metagenomic, metabolomic, lipidomic, metatranscriptomic), the complex interactions occurring between the host and the different microorganisms are progressively being deciphered. Nowadays, gut microbiota deviations are linked with many diseases including obesity, type 2 diabetes, hepatic steatosis, intestinal bowel diseases (IBDs) and several types of cancer. Thus, suggesting that various pathways involved in immunity, energy, lipid and glucose metabolism are affected. In this review, specific attention is given to provide a critical evaluation of the current understanding in this field. Numerous molecular mechanisms explaining how gut bacteria might be causally linked with the protection or the onset of diseases are discussed. We examine well-established metabolites (ie, short-chain fatty acids, bile acids, trimethylamine N-oxide) and extend this to more recently identified molecular actors (ie, endocannabinoids, bioactive lipids, phenolic-derived compounds, advanced glycation end products and enterosynes) and their specific receptors such as peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ), aryl hydrocarbon receptor (AhR), and G protein-coupled receptors (ie, GPR41, GPR43, GPR119, Takeda G protein-coupled receptor 5). Altogether, understanding the complexity and the molecular aspects linking gut microbes to health will help to set the basis for novel therapies that are already being developed.
345 citations
01 Feb 2021
TL;DR: The mechanisms and the impact of SCFA on gut functions and host immunity and consequently on human health are discussed.
Abstract: In recent years, the importance of the gut microbiota in human health has been revealed and many publications have highlighted its role as a key component of human physiology. Owing to the use of modern sequencing approaches, the characterisation of the microbiome in healthy individuals and in disease has demonstrated a disturbance of the microbiota, or dysbiosis, associated with pathological conditions. The microbiota establishes a symbiotic crosstalk with their host: commensal microbes benefit from the nutrient-rich environment provided by the gut and the microbiota produces hundreds of proteins and metabolites that modulate key functions of the host, including nutrient processing, maintenance of energy homoeostasis and immune system development. Many bacteria-derived metabolites originate from dietary sources. Among them, an important role has been attributed to the metabolites derived from the bacterial fermentation of dietary fibres, namely SCFA linking host nutrition to intestinal homoeostasis maintenance. SCFA are important fuels for intestinal epithelial cells (IEC) and regulate IEC functions through different mechanisms to modulate their proliferation, differentiation as well as functions of subpopulations such as enteroendocrine cells, to impact gut motility and to strengthen the gut barrier functions as well as host metabolism. Recent findings show that SCFA, and in particular butyrate, also have important intestinal and immuno-modulatory functions. In this review, we discuss the mechanisms and the impact of SCFA on gut functions and host immunity and consequently on human health.
320 citations
References
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TL;DR: A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms, and significant intersubject variability and differences between stool and mucosa community composition were discovered.
Abstract: The human endogenous intestinal microflora is an essential “organ” in providing nourishment, regulating epithelial development, and instructing innate immunity; yet, surprisingly, basic features remain poorly described. We examined 13,355 prokaryotic ribosomal RNA gene sequences from multiple colonic mucosal sites and feces of healthy subjects to improve our understanding of gut microbial diversity. A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms. We discovered significant intersubject variability and differences between stool and mucosa community composition. Characterization of this immensely diverse ecosystem is the first step in elucidating its role in health and disease.
7,049 citations
"Dysbiotic Proteobacteria expansion:..." refers background in this paper
...Proteobacteria are a minor constituent within a balanced gut-associated microbial community [2]....
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...Minor constituents commonly found within a balanced gut microbiota include obligate anaerobic bacteria belonging to the phyla Actinobacteria and Fusobacteria [2]. www.sciencedirect.com The dominance of obligate anaerobic bacteria in the large bowel is likely a consequence of the severe oxygen limitation that characterizes this host environment, which in turn has important consequences for the catabolic pathways used to break down nutrients....
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...Minor constituents commonly found within a balanced gut microbiota include obligate anaerobic bacteria belonging to the phyla Actinobacteria and Fusobacteria [2]....
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TL;DR: This review summarizes the role of SCFAs in host energy metabolism, starting from the production by the gut microbiota to the uptake by the host and ending with the effects on host metabolism.
3,040 citations
"Dysbiotic Proteobacteria expansion:..." refers background in this paper
...The host absorbs an estimated 95–99% of microbially produced short-chain fatty acids (reviewed in [3,4]), which reach the blood stream to impact immune development (summarized in [5])....
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TL;DR: The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways, and the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis are provided.
Abstract: Background: The inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status. Results: Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn’s disease was notable for increases in virulence and secretion pathways.
2,189 citations
TL;DR: This work reviews studies that explored the association between an abnormal expansion of Proteobacteria and a compromised ability to maintain a balanced gut microbial community and proposes that an increased prevalence of ProTeobacteria is a potential diagnostic signature of dysbiosis and risk of disease.
2,019 citations
"Dysbiotic Proteobacteria expansion:..." refers background in this paper
...Based on these observations it has been proposed that an expansion of Proteobacteria is a microbial signature of gut dysbiosis [7]....
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...Perhaps the most consistent and robust ecological pattern observed during gut dysbiosis is an expansion of facultative anaerobic bacteria belonging to the phylum Proteobacteria (reviewed in [6,7]) (Figure 1)....
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TL;DR: This review provides an overview of the current knowledge of the diversity, metabolism and microbial ecology of this functionally important group of bacteria and suggests that mechanisms proposed recently in non-gut Clostridium spp.
Abstract: Butyrate-producing bacteria play a key role in colonic health in humans. This review provides an overview of the current knowledge of the diversity, metabolism and microbial ecology of this functionally important group of bacteria. Human colonic butyrate producers are Gram-positive firmicutes, but are phylogenetically diverse, with the two most abundant groups related to Eubacterium rectale/Roseburia spp. and to Faecalibacterium prausnitzii. Five different arrangements have been identified for the genes of the central pathway involved in butyrate synthesis, while in most cases butyryl-CoA : acetate CoA-transferase, rather than butyrate kinase, appears to perform the final step in butyrate synthesis. Mechanisms have been proposed recently in non-gut Clostridium spp. whereby butyrate synthesis can result in energy generation via both substrate-level phosphorylation and proton gradients. Here we suggest that these mechanisms also apply to the majority of butyrate producers from the human colon. The roles of these bacteria in the gut community and their influence on health are now being uncovered, taking advantage of the availability of cultured isolates and molecular methodologies. Populations of F. prausnitzii are reported to be decreased in Crohn's disease, for example, while populations of Roseburia relatives appear to be particularly sensitive to the diet composition in human volunteer studies.
1,529 citations
"Dysbiotic Proteobacteria expansion:..." refers background in this paper
...While a migration of neutrophils into the intestinal lumen is a source of tetrathionate [33], it also causes a depletion of Clostridia [52,53], the taxon containing the lion’s share of butyrate-producing bacteria in the gut-associated microbial community [54,55]....
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