scholarly journals Depletion of microbiome-derived molecules in the host using Clostridium genetics

2018 ◽  
Author(s):  
Chun-Jun Guo ◽  
Breanna M. Allen ◽  
Kamir J. Hiam ◽  
Dylan Dodd ◽  
Will van Treuren ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Gut Microbiota ◽  
Metabolic Pathways ◽  
General System ◽  
Short Chain Fatty Acids ◽  
Wild Type ◽  
Bacterial Strains ◽  
High Concentrations ◽  
Host Tissues ◽  
Molecule Production

ABSTRACTThe gut microbiota produce hundreds of molecules that are present at high concentrations in circulation and whose levels vary widely among humans. In most cases, molecule production has not been linked to specific bacterial strains or metabolic pathways, and unraveling the contribution of each molecule to host biology remains difficult. A general system to ‘toggle’ molecules in this pool on/off in the host would enable interrogation of the mechanisms by which they modulate host biology and disease processes. Such a system has been elusive due to limitations in the genetic manipulability of Clostridium and its relatives, the source of many molecules in this pool. Here, we describe a method for reliably constructing clean deletions in a model commensal Clostridium, C. sporogenes (Cs), including multiply mutated strains. We demonstrate the utility of this method by using it to ‘toggle’ off the production of ten Cs-derived molecules that accumulate in host tissues. By comparing mice colonized by wild-type Cs versus a mutant deficient in the production of branched short-chain fatty acids, we discover a previously unknown IgA-modulatory activity of these abundant microbiome-derived molecules. Our method opens the door to interrogating and sculpting a highly concentrated pool of chemicals from the microbiome.

scholarly journals Depletion of microbiome-derived molecules in the host using Clostridium genetics

Science ◽  
2019 ◽  
Vol 366 (6471) ◽  
pp. eaav1282 ◽  
Author(s):  
Chun-Jun Guo ◽  
Breanna M. Allen ◽  
Kamir J. Hiam ◽  
Dylan Dodd ◽  
Will Van Treuren ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Immunoglobulin A ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Clostridium Sporogenes ◽  
Microbial Products ◽  
High Concentrations ◽  
Host Tissues

The gut microbiota produce hundreds of molecules that are present at high concentrations in the host circulation. Unraveling the contribution of each molecule to host biology remains difficult. We developed a system for constructing clean deletions in Clostridium spp., the source of many molecules from the gut microbiome. By applying this method to the model commensal organism Clostridium sporogenes, we knocked out genes for 10 C. sporogenes–derived molecules that accumulate in host tissues. In mice colonized by a C. sporogenes for which the production of branched short-chain fatty acids was knocked out, we discovered that these microbial products have immunoglobulin A–modulatory activity.

scholarly journals Short chain fatty acids and methylamines produced by gut microbiota as mediators and markers in the circulatory system

2020 ◽  
Vol 245 (2) ◽  
pp. 166-175 ◽  
Author(s):  
Maksymilian Onyszkiewicz ◽  
Kinga Jaworska ◽  
Marcin Ufnal
Keyword(s):  
Fatty Acids ◽  
Cardiovascular Diseases ◽  
Gut Microbiota ◽  
Therapeutic Targets ◽  
Circulatory System ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Bacterial Strains ◽  
Ample Evidence ◽  
Chain Fatty Acids

Ample evidence suggests that gut microbiota-derived products affect the circulatory system functions. For instance, short chain fatty acids, that are the products of dietary fiber bacterial fermentation, have been found to dilate blood vessels and lower blood pressure. Trimethylamine, a gut bacteria metabolite of carnitine and choline, has recently emerged as a potentially toxic molecule for the circulatory system. To enter the bloodstream, microbiota products cross the gut–blood barrier, a multilayer system of the intestinal wall. Notably, experimental and clinical studies show that cardiovascular diseases may compromise function of the gut–blood barrier and increase gut-to-blood penetration of microbiota-derived molecules. Hence, the bacteria products and the gut–blood barrier may be potential diagnostic and therapeutic targets in cardiovascular diseases. In this paper, we review research on the cardiovascular effects of microbiota-produced short chain fatty acids and methylamines. Impact statement Despite a progress in the diagnosis and treatment of cardiovascular diseases, there are still significant gaps in understanding complex mechanisms underlying cardiovascular pathology. Increasing evidence suggests that gut microbiota products such as short chain fatty acids or methylamines may affect the circulatory system in health and disease. Hence, the microbiota-derived molecules are potential diagnostic and therapeutic targets in cardiovascular diseases. Therapeutic options may include administration of selected bacterial strains (probiotics) producing desired metabolites or administration of direct gut microbiota products.

P165 INFLUENCE OF THE GUT MICROBIOTA ON COLONIC HISTONE MODIFICATIONS THROUGH BUTYRATE METABOLISM UNDER HEALTHY AND INFLAMMATORY CONDITIONS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S40-S41
Author(s):  
Peder Lund ◽  
Sarah Smith ◽  
Johayra Simithy ◽  
Lillian Chau ◽  
Elliot Friedman ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Epithelial Cells ◽  
Gut Microbiota ◽  
Histone Acetylation ◽  
Metabolic Pathways ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Isotope Tracing ◽  
Colonic Epithelial Cells ◽  
Germ Free

Abstract Inflammatory bowel disease (IBD) is often associated with a disruption in the composition and activity of the gut microbiota, referred to as dysbiosis. Since the microbiota has the potential to interact with host epithelial cells through small molecules generated from microbial metabolism, knowledge of how inflammation alters the microbial metabolome and how epithelial cells react is important for a better understanding of how IBD develops and persists. Butyrate, a short chain fatty acid produced through fermentation of dietary polysaccharides, has long been known to inhibit histone deacetylases (HDACs), which represent one of the many types of enzymes responsible for the epigenetic control of gene expression through the post-translational modification of histone proteins. We and others have observed that colonic epithelial cells from germ-free mice have reduced levels of acetylation on histone H4, which appears to be distributed throughout the genome based on sequencing analysis. The decreased levels of H4 acetylation may stem from a lack of butyrate, and therefore uninhibited HDAC activity, in germ-free mice. However, since colonic epithelial cells utilize short chain fatty acids as an energy source, an alternative explanation is that the germ-free condition results in less oxidation of butyrate to acetyl-CoA, which is the donor substrate for histone acetylation reactions. Isotope tracing experiments, in which cultured cells were incubated with labeled butyrate, demonstrated that the acetyl groups of histones contained carbon derived from butyrate. We have also performed isotope tracing experiments in mice using labeled inulin, a plant polysaccharide that presumably undergoes fermentation into short chain fatty acids. In this more physiologically relevant model, we detected isotope incorporation into the acetylated histones of colonic epithelial cells at rates of 5–20%, which appears dependent on the microbiota since labeling is sensitive to antibiotic treatment. To identify the metabolic pathways that link inulin to histone acetylation, we are investigating which metabolites become isotopically labeled using untargeted metabolomics. We will apply the same approach to the DSS-induced model of colitis to investigate how inflammation modulates the gut metabolome as well as the metabolic connections between the microbiota and the host. Our studies may uncover metabolic pathways that become dysregulated during inflammation, which may contribute to the pathogenesis of diseases such as IBD.

The Consumption of Galactomannan Effervescent Drinks made from Coconut Pulp Waste and Colonic Microbiota in Wistar Rats

2020 ◽  
Vol 15 (1) ◽  
pp. 52-56
Author(s):  
Sri Winarti ◽  
Agung Pasetyo
Keyword(s):  
Fatty Acids ◽  
Gut Microbiota ◽  
Wistar Rats ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
E Coli ◽  
Colonic Microbiota ◽  
Male Wistar Rats ◽  
Lactobacillus Spp ◽  
Chain Fatty Acids

The consumption of prebiotics is known to affect the balance of gut microbiota. The purpose of this study was to explore how a galactomannan-rich effervescent drink can affect the population of Lactobacillus, Bifidobacterium, E. coli, and the concentration of short-chain fatty acids in the cecum of rats. Twenty-eight male Wistar rats (aged 2 months) were divided equally into 7 groups and treated orally each day for 15 days with 2 mL effervescent drinks with increasing levels of prebiotic galactomannan. The dosage of 500 mg galactomannan increased the growth of Lactobacillus spp. and Bifidobacterium spp. with inhibition of the growth of E.coli with increased formation of short-chain fatty acids such as acetate, propionate, and butyrate in the cecum of rats.

Gastrointestinal Interaction between Dietary Amino Acids and Gut Microbiota: With Special Emphasis on Host Nutrition

2020 ◽  
Vol 21 (8) ◽  
pp. 785-798 ◽  
Author(s):  
Abedin Abdallah ◽  
Evera Elemba ◽  
Qingzhen Zhong ◽  
Zewei Sun
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Immune System ◽  
Gut Microbiota ◽  
Short Chain Fatty Acids ◽  
Nutrition And Health ◽  
Nitrogenous Compounds ◽  
Dietary Amino Acids ◽  
Host Nutrition ◽  
Chain Fatty Acids

The gastrointestinal tract (GIT) of humans and animals is host to a complex community of different microorganisms whose activities significantly influence host nutrition and health through enhanced metabolic capabilities, protection against pathogens, and regulation of the gastrointestinal development and immune system. New molecular technologies and concepts have revealed distinct interactions between the gut microbiota and dietary amino acids (AAs) especially in relation to AA metabolism and utilization in resident bacteria in the digestive tract, and these interactions may play significant roles in host nutrition and health as well as the efficiency of dietary AA supplementation. After the protein is digested and AAs and peptides are absorbed in the small intestine, significant levels of endogenous and exogenous nitrogenous compounds enter the large intestine through the ileocaecal junction. Once they move in the colonic lumen, these compounds are not markedly absorbed by the large intestinal mucosa, but undergo intense proteolysis by colonic microbiota leading to the release of peptides and AAs and result in the production of numerous bacterial metabolites such as ammonia, amines, short-chain fatty acids (SCFAs), branched-chain fatty acids (BCFAs), hydrogen sulfide, organic acids, and phenols. These metabolites influence various signaling pathways in epithelial cells, regulate the mucosal immune system in the host, and modulate gene expression of bacteria which results in the synthesis of enzymes associated with AA metabolism. This review aims to summarize the current literature relating to how the interactions between dietary amino acids and gut microbiota may promote host nutrition and health.

Impact of oral COMT-inhibitors on gut microbiota and short chain fatty acids in Parkinson's disease

2020 ◽  
Vol 70 ◽  
pp. 20-22 ◽  
Author(s):  
Daniel Grün ◽  
Valerie C. Zimmer ◽  
Jil Kauffmann ◽  
Jörg Spiegel ◽  
Ulrich Dillmann ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Fatty Acids ◽  
Parkinson's Disease ◽  
Gut Microbiota ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Comt Inhibitors ◽  
Chain Fatty Acids

scholarly journals Glycerol Monocaprylate Modulates Gut Microbiota and Increases Short-Chain Fatty Acids Production without Adverse Effects on Metabolism and Inflammation

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1427
Author(s):  
Junhui Zhang ◽  
Fengqin Feng ◽  
Minjie Zhao
Keyword(s):  
Fatty Acids ◽  
Gut Microbiota ◽  
Dose Group ◽  
Low Dose ◽  
Short Chain Fatty Acids ◽  
Normal Diet ◽  
Short Chain ◽  
High Dose ◽  
Dose Treatment ◽  
Chain Fatty Acids

Glycerol monocaprylate (GMC) is a glycerol derivative of medium-chain fatty acids (MCFAs) and is widely used as a preservative in food processing. However, GMC and its hydrolytic acid (octylic acid) have antibacterial properties that may affect the physiology and intestinal microecology of the human body. Therefore, in this study, the effects of two different dosages of GMC (150 and 1600 mg kg−1) on glucose, lipid metabolism, inflammation, and intestinal microecology of normal diet-fed C57BL/6 mice were comprehensively investigated. The obtained results showed that the level of triglycerides (TGs) in the low-dose group down-regulated significantly, and the anti-inflammatory cytokine interleukin 10 (IL-10) significantly increased, while the pro-inflammatory cytokines monocyte chemotactic protein 1 (MCP-1) and interleukin 1beta (IL-1β) in the high-dose group were significantly decreased. Importantly, GMC promoted the α-diversity of gut microbiota in normal-diet-fed mice, regardless of dosages. Additionally, it was found that the low-dose treatment of GMC significantly increased the abundance of Lactobacillus, while the high-dose treatment of GMC significantly increased the abundance of SCFA-producers such as Clostridiales, Lachnospiraceae, and Ruminococcus. Moreover, the content of short-chain fatty acids (SCFAs) was significantly increased by GMC supplementation. Thus, our research provides a novel insight into the effects of GMC on gut microbiota and physiological characteristics.

scholarly journals Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Stefano Romano ◽  
George M. Savva ◽  
Janis R. Bedarf ◽  
Ian G. Charles ◽  
Falk Hildebrand ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Fatty Acids ◽  
Parkinson's Disease ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Intestinal Inflammation ◽  
Meta Analysis ◽  
Gastrointestinal Symptoms ◽  
Short Chain Fatty Acids ◽  
Inflammatory Status

AbstractThe gut microbiota is emerging as an important modulator of neurodegenerative diseases, and accumulating evidence has linked gut microbes to Parkinson’s disease (PD) symptomatology and pathophysiology. PD is often preceded by gastrointestinal symptoms and alterations of the enteric nervous system accompany the disease. Several studies have analyzed the gut microbiome in PD, but a consensus on the features of the PD-specific microbiota is missing. Here, we conduct a meta-analysis re-analyzing the ten currently available 16S microbiome datasets to investigate whether common alterations in the gut microbiota of PD patients exist across cohorts. We found significant alterations in the PD-associated microbiome, which are robust to study-specific technical heterogeneities, although differences in microbiome structure between PD and controls are small. Enrichment of the genera Lactobacillus, Akkermansia, and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent PD gut microbiome alterations. This dysbiosis might result in a pro-inflammatory status which could be linked to the recurrent gastrointestinal symptoms affecting PD patients.

scholarly journals Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Velma T. E. Aho ◽  
Madelyn C. Houser ◽  
Pedro A. B. Pereira ◽  
Jianjun Chang ◽  
Knut Rudi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Fatty Acids ◽  
Parkinson's Disease ◽  
Gut Microbiota ◽  
Inflammatory Responses ◽  
Disease Onset ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Dependent Manner ◽  
Chain Fatty Acids

Abstract Background Previous studies have reported that gut microbiota, permeability, short-chain fatty acids (SCFAs), and inflammation are altered in Parkinson’s disease (PD), but how these factors are linked and how they contribute to disease processes and symptoms remains uncertain. This study sought to compare and identify associations among these factors in PD patients and controls to elucidate their interrelations and links to clinical manifestations of PD. Methods Stool and plasma samples and clinical data were collected from 55 PD patients and 56 controls. Levels of stool SCFAs and stool and plasma inflammatory and permeability markers were compared between patients and controls and related to one another and to the gut microbiota. Results Calprotectin was increased and SCFAs decreased in stool in PD in a sex-dependent manner. Inflammatory markers in plasma and stool were neither intercorrelated nor strongly associated with SCFA levels. Age at PD onset was positively correlated with SCFAs and negatively correlated with CXCL8 and IL-1β in stool. Fecal zonulin correlated positively with fecal NGAL and negatively with PD motor and non-motor symptoms. Microbiota diversity and composition were linked to levels of SCFAs, inflammatory factors, and zonulin in stool. Certain relationships differed between patients and controls and by sex. Conclusions Intestinal inflammatory responses and reductions in fecal SCFAs occur in PD, are related to the microbiota and to disease onset, and are not reflected in plasma inflammatory profiles. Some of these relationships are distinct in PD and are sex-dependent. This study revealed potential alterations in microbiota-host interactions and links between earlier PD onset and intestinal inflammatory responses and reduced SCFA levels, highlighting candidate molecules and pathways which may contribute to PD pathogenesis and clinical presentation and which warrant further investigation.

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