scholarly journals Development of a self-limiting model of Methotrexate-induced mucositis reinforces butyrate as a potential therapy

2020 ◽  
Author(s):  
Ana Rita da Silva Ferreira ◽  
Stijn A.J. van der Aa ◽  
Tjalling Wehkamp ◽  
Hannah R. Wardill ◽  
Jean Paul Ten Klooster ◽  
...  
Keyword(s):  
Folinic Acid ◽  
Metabolic Activity ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Optimal Dosage ◽  
Protective Effects ◽  
Clinical Practices ◽  
Chemokine Production ◽  
The Impact

Abstract Background: Gastrointestinal mucositis remains a significant complication of anticancer treatment, with limited anti-mucositis interventions. Currently, there are few validated in vitro systems suitable to study the mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Methods: Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX), ranging from 0-1000 ng/ml. Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. To link the model to clinical practices, the protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005-50 µg/mL) folinic acid. Given the impact of microbial-derived short-chain fatty acids in epithelial health, we also evaluated the impact of short-chain fatty acid supplementation on MTX toxicity in the organoid model. Results: MTX treatment caused a dose-dependent reduction in cell metabolic activity and citrulline production. Folinic acid treatment reduced MTX toxicity when applied simultaneously or up to 24 hours after treatment. Supplementation of the growth medium with butyrate reduced MTX toxicity. Analysis of organoid gene expression suggests that butyrate may reduce intracellular MTX concentrations by increasing the expression of MTX transporters, including the ABCC1 transporter.Conclusion: MTX causes significant organoid damage, which can be reversed upon removal of MTX. The specific readouts and the protective effects of folinic acid suggest that the model is clinically relevant, and can be used in the future to study mucositis, diminishing the need for animal models. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

scholarly journals Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. R. da Silva Ferreira ◽  
S. A. J. van der Aa ◽  
T. Wehkamp ◽  
H. R. Wardill ◽  
J. P. ten Klooster ◽  
...  
Keyword(s):  
Folinic Acid ◽  
Metabolic Activity ◽  
Mucosal Injury ◽  
Short Chain Fatty Acids ◽  
Optimal Dosage ◽  
Protective Effects ◽  
Chemokine Production ◽  
In Vitro Systems ◽  
The Impact

AbstractGastrointestinal mucositis is a complication of anticancer treatment, with few validated in vitro systems suitable to study the complex mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX). Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. The protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005–50 µg/mL) folinic acid. The impact of microbial-derived short-chain fatty acids was evaluated by supplementation with butyrate in the organoid model. MTX caused a dose-dependent reduction in cell metabolic activity and citrulline production that was salvaged by folinic acid treatment. Overall, MTX causes significant organoid damage, which can be reversed upon removal of MTX. The protective effect of folinic acid suggest that the organoids respond in a clinical relevant manner. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

scholarly journals Short Chain Fatty Acids Modulate the Growth and Virulence of Pathosymbiont Escherichia coli and Host Response

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 462
Author(s):  
Shiying Zhang ◽  
Belgin Dogan ◽  
Cindy Guo ◽  
Deepali Herlekar ◽  
Katrina Stewart ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Virulence Gene ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Host Responses ◽  
Virulence Gene Expression ◽  
E Coli ◽  
The Impact ◽  
Chain Fatty Acids

Short chain fatty acids (SCFA), principally acetate, propionate, and butyrate, are produced by fermentation of dietary fibers by the gut microbiota. SCFA regulate the growth and virulence of enteric pathogens, such as enterohemorrhagic E. coli (EHEC), Klebsiella and Salmonella. We sought to investigate the impact of SCFA on growth and virulence of pathosymbiont E. coli associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC), and their role in regulating host responses to bacterial infection in vitro. We found that under ileal conditions (pH = 7.4; 12 mM total SCFA), SCFA significantly (p < 0.05) potentiate the growth and motility of pathosymbiont E. coli. However, under colonic conditions (pH = 6.5; 65 to 123 mM total SCFA), SCFA significantly (p < 0.05) inhibit growth in a pH dependent fashion (up to 60%), and down-regulate virulence gene expression (e.g., fliC, fimH, htrA, chuA, pks). Functional analysis reveals that colonic SCFA significantly (p < 0.05) inhibit E. coli motility (up to 95%), infectivity (up to 60%), and type 1 fimbria-mediated agglutination (up to 50%). In addition, SCFA significantly (p < 0.05) inhibit the activation of NF-kB, and IL-8 production by epithelial cells. Our findings provide novel insights on the role of the regional chemical microenvironment in regulating the growth and virulence of pathosymbiont E. coli and opportunities for therapeutic intervention.

scholarly journals Honeybee gut microbiota promotes host weight gain via bacterial metabolism and hormonal signaling

2017 ◽  
Vol 114 (18) ◽  
pp. 4775-4780 ◽  
Author(s):  
Hao Zheng ◽  
J. Elijah Powell ◽  
Margaret I. Steele ◽  
Carsten Dietrich ◽  
Nancy A. Moran
Keyword(s):  
Weight Gain ◽  
Gut Microbiota ◽  
Microbial Metabolism ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Whole Body ◽  
Social Bees ◽  
Host Microbe Interactions ◽  
The Impact

Social bees harbor a simple and specialized microbiota that is spatially organized into different gut compartments. Recent results on the potential involvement of bee gut communities in pathogen protection and nutritional function have drawn attention to the impact of the microbiota on bee health. However, the contributions of gut microbiota to host physiology have yet to be investigated. Here we show that the gut microbiota promotes weight gain of both whole body and the gut in individual honey bees. This effect is likely mediated by changes in host vitellogenin, insulin signaling, and gustatory response. We found that microbial metabolism markedly reduces gut pH and redox potential through the production of short-chain fatty acids and that the bacteria adjacent to the gut wall form an oxygen gradient within the intestine. The short-chain fatty acid profile contributed by dominant gut species was confirmed in vitro. Furthermore, metabolomic analyses revealed that the gut community has striking impacts on the metabolic profiles of the gut compartments and the hemolymph, suggesting that gut bacteria degrade plant polymers from pollen and that the resulting metabolites contribute to host nutrition. Our results demonstrate how microbial metabolism affects bee growth, hormonal signaling, behavior, and gut physicochemical conditions. These findings indicate that the bee gut microbiota has basic roles similar to those found in some other animals and thus provides a model in studies of host–microbe interactions.

scholarly journals Taxonomic Characterization and Short-Chain Fatty Acids Production of the Obese Microbiota

2021 ◽  
Vol 11 ◽  
Author(s):  
M. Carmen Martínez-Cuesta ◽  
Rosa del Campo ◽  
María Garriga-García ◽  
Carmen Peláez ◽  
Teresa Requena
Keyword(s):  
Fatty Acids ◽  
Metabolic Activity ◽  
Energy Content ◽  
Short Chain Fatty Acids ◽  
The Body ◽  
Short Chain ◽  
Rrna Gene ◽  
Fecal Microbiome ◽  
The Impact ◽  
Chain Fatty Acids

Intestinal microbiota seems to play a key role in obesity. The impact of the composition and/or functionality of the obesity-associated microbiota have yet to be fully characterized. This work assessed the significance of the taxonomic composition and/or metabolic activity of obese- microbiota by massive 16S rRNA gene sequencing of the fecal microbiome of obese and normoweight individuals. The obese metabolic activity was also assessed by in vitro incubation of obese and normoweight microbiotas in nutritive mediums with different energy content. We found that the microbiome richness and diversity of the two groups did not differ significantly, except for Chao1 index, significantly higher in normoweight individuals. At phylum level, neither the abundance of Firmicutes or Bacteroidetes nor their ratio was associated with the body mass index. Besides, the relative proportions in Collinsella, Clostridium XIVa, and Catenibacterium were significantly enriched in obese participants, while Alistipes, Clostridium sensu stricto, Romboutsia, and Oscillibacter were significantly diminished. In regard to metabolic activity, short-chain fatty acids content was significant higher in obese individuals, with acetate being the most abundant followed by propionate and butyrate. Acetate and butyrate production was also higher when incubating obese microbiota in mediums mimicking diets with different energy content; interestingly, a reduced capability of propionate production was associated to the obese microbiome. In spite of the large interindividual variability, the obese phenotype seems to be defined more by the abundance and/or the absence of distinct communities of microorganism rather than by the presence of a specific population.

Short-Chain Fatty Acids Prevent Diabetic Nephropathy In Vivo and In Vitro

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 92-OR ◽  
Author(s):  
WEI HUANG ◽  
YONG XU ◽  
YOUHUA XU ◽  
LUPING ZHOU ◽  
CHENLIN GAO
Keyword(s):  
Fatty Acids ◽  
Diabetic Nephropathy ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Chain Fatty Acids

scholarly journals The impact of indole-3-lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wuyang Huang ◽  
Ky Young Cho ◽  
Di Meng ◽  
W. Allan Walker
Keyword(s):  
Lactic Acid ◽  
Mechanistic Model ◽  
Transcriptomic Analysis ◽  
Dependent Manner ◽  
Protective Effects ◽  
Very Preterm Infants ◽  
Anti Inflammatory ◽  
The Impact

AbstractAn excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Indole-3-lactic acid (ILA) of breastmilk tryptophan was identified as the anti-inflammatory metabolite involved in probiotic conditioned media from Bifidobacteria longum subsp infantis. This study aimed to explore the molecular endocytic pathways involved in the protective ILA effect against inflammation. H4 cells, Caco-2 cells, C57BL/6 pup and adult mice were used to compare the anti-inflammatory mechanisms between immature and mature enterocytes in vitro and in vivo. The results show that ILA has pleiotropic protective effects on immature enterocytes including anti-inflammatory, anti-viral, and developmental regulatory potentials in a region-dependent and an age-dependent manner. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. These studies were validated by real-time RT-qPCR and STAT1 inhibitor experiments. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated. These findings may be helpful in preventing NEC for premature infants.

scholarly journals Exogenous Alginate Protects Staphylococcus aureus from Killing by Pseudomonas aeruginosa

2019 ◽  
Vol 202 (8) ◽  
Author(s):  
Courtney E. Price ◽  
Dustin G. Brown ◽  
Dominique H. Limoli ◽  
Vanessa V. Phelan ◽  
George A. O’Toole
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Physical Space ◽  
Late Time ◽  
Protective Effects ◽  
Content Type ◽  
Alginate Production ◽  
The Impact

ABSTRACT Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are monoinfected with either P. aeruginosa or S. aureus. We showed previously that mucoid strains of P. aeruginosa can coexist with S. aureus in vitro due to the transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here, we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm coculture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to the transcriptional downregulation of pvdA, a gene required for the production of the iron-scavenging siderophore pyoverdine as well as the downregulation of the PQS (Pseudomonas quinolone signal) (2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that coculture of mucoid P. aeruginosa with nonmucoid P. aeruginosa strains can mitigate the killing of S. aureus by the nonmucoid strain of P. aeruginosa, indicating that the mechanism that we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability to kill S. aureus at late time points and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the S. aureus-protective effects of mucoidy in a strain-specific manner. IMPORTANCE CF patients are chronically infected by polymicrobial communities. The two dominant bacterial pathogens that infect the lungs of CF patients are P. aeruginosa and S. aureus, with ∼30% of patients coinfected by both species. Such coinfected individuals have worse outcomes than monoinfected patients, and both species persist within the same physical space. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus coexistence, despite evidence that P. aeruginosa kills S. aureus when these organisms are cocultured in vitro. Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to coexist in proximal physical space, will lead to better-informed treatments for chronic polymicrobial infections.

scholarly journals The impact of long-term dietary pattern of fecal donor on in vitro fecal fermentation properties of inulin

2016 ◽  
Vol 7 (4) ◽  
pp. 1805-1813 ◽  
Author(s):  
Junyi Yang ◽  
Devin J. Rose
Keyword(s):  
Fatty Acids ◽  
Short Chain Fatty Acids ◽  
Processed Meats ◽  
Branched Chain Fatty Acids ◽  
Fiber Plant ◽  
Branched Chain ◽  
The Impact ◽  
Chain Fatty Acids

A diet high in whole grains, dry beans, and certain vegetables that contributed dietary fiber, plant protein, and B vitamins resulted in high short chain fatty acids, while a diet high in diary and processed meats that provided cholesterol and little fiber resulted in high branched chain fatty acids and ammonia during fecal fermentation of inulin.

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