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Validation of metabolite screen results in dose assays Growth curves are shown for three strains using seven metabolites in multiple concentrations. Growth was monitored over time in a volume of 40 µL per well in 384-well plates. The final concentration of DMSO per treated and control well was 0.25%. Growth curves representative of three independent tests are shown and error bars in controls represent the standard deviation of the mean of six technical replicates.
Source publication
Inflammatory bowel diseases (IBD) are associated with alterations in gut microbial abundances and lumenal metabolite concentrations, but the effects of specific metabolites on the gut microbiota in health and disease remain largely unknown. Here, we analysed the influences of metabolites that are differentially abundant in IBD on the growth and phy...
Citations
... These commensal bacteria utilize host lipids as an energy source and metabolize some lipids to new isoforms to enhance mucosal barrier function. Conversely, gut bacteria have also been associated with detrimental changes to dietary lipids, as demonstrated by studies of the microbiome associated with irritable bowel syndrome (69,70). These studies begin to shed light on the potential circular relationship between dietary lipids, changes in the local host environment, and selection for bacteria that metabolize those same nutrients and benefit from changes to the environment (71). ...
Periodontitis is a chronic inflammatory disease induced by dysbiotic dental biofilms. Management of periodontitis is primarily anti-bacterial via mechanical removal of bacterial biofilm. The successful resolution requires wound healing and tissue regeneration, which are not always achieved with these traditional methods. The discovery of specialized pro-resolving mediators (SPMs), a class of lipid mediators that induce the resolution of inflammation and promote local tissue homeostasis, creates another option for the treatment of periodontitis and other diseases of chronic inflammation. In this mini-review, we discuss the host-modulatory effects of SPMs on periodontal tissues and changes in the taxonomic composition of the gut and oral microbiome in the presence of SPMs and SPM precursor lipids. Further research into the relationship between host SPM production and microbiome-SPM modification has the potential to unveil new diagnostic markers of inflammation and wound healing. Expanding this field may drive the discovery of microbial-derived bioactive therapeutics to modulate immune responses.
... Molecularly complex regulation of abundance, composition, structure and function of gut microbiota requires exact understanding of the role of a designated molecule, but most of our previous understandings are limited in short-chain fatty acids (SCFAs) 37 , glycans 6 , sugar 38 and other molecules 39,40 . Increasing evidence has revealed the important roles of dietary long-chain unsaturated fatty acids in regulating inflammatory responses 13 . ...
Magnitude and diversity of gut microbiota and metabolic systems are critical in shaping human health and diseases, but it remains largely unclear how complex metabolites may selectively regulate gut microbiota and determine health and diseases. Here, we show that failures or compromised effects of anti-TNF-α therapy in inflammatory bowel diseases (IBD) patients were correlated with intestinal dysbacteriosis with more pro-inflammatory bacteria, extensive unresolved inflammation, failed mucosal repairment, and aberrant lipid metabolism, particularly lower levels of palmitoleic acid (POA). Dietary POA repaired gut mucosal barriers, reduced inflammatory cell infiltrations and expressions of TNF-α and IL-6, and improved efficacy of anti-TNF-α therapy in both acute and chronic IBD mouse models. Ex vivo treatment with POA in cultured inflamed colon tissues derived from Crohn's disease (CD) patients reduced pro-inflammatory signaling/cytokines and conferred appreciable tissue repairment. Mechanistically, POA significantly upregulated the transcriptional signatures of cell division and biosynthetic process of Akkermansia muciniphila, selectively increased the growth and abundance of Akkermansia muciniphila in gut microbiota, and further reprogrammed the composition and structures of gut microbiota. Oral transfer of such POA-reprogrammed, but not control, gut microbiota induced better protection against colitis in anti-TNF-α mAb-treated recipient mice, and co-administration of POA with Akkermansia muciniphila showed significant synergistic protections against colitis in mice. Collectively, this work not only reveals the critical importance of POA as a polyfunctional molecular force to shape the magnitude and diversity of gut microbiota and therefore promote the intestinal homeostasis, but also implicates a new potential therapeutic strategy against intestinal or abenteric inflammatory diseases.
... The original LC-MS data were processed by software Progenesis QI V2.3 (Nonlinear Dynamics, Newcastle, UK) for baseline filtering, peak identification, integral, retention time correction, peak alignment, and normalization (Fornelos et al., 2020). The main parameters of 5 ppm precursor tolerance, 10 ppm product tolerance, and a 5% production threshold were applied. ...
Bloom-forming algae Phaeocystis globosa is one of the most successful blooming algae in the oceans due to its capacity to sense grazer-associated chemical cues and respond adaptively to these grazer-specific cues with opposing shifts in phenotype. P. globosa produces toxic and deterrent compounds as chemical defenses. However, the origin of the signals and underlying mechanisms that triggered the morphological and chemical defenses remain enigmatic. Rotifer was chosen to establish an herbivore-phytoplankton interaction with P. globosa. The influences of rotifer kairomone and conspecific-grazed cue on morphological and chemical defenses in P. globosa were investigated. As a result, rotifer kairomones elicited morphological defenses and broad-spectrum chemical defenses, whereas algae-grazed cues elicited morphological defenses and consumer-specific chemical defenses. According to multi-omics findings, the difference in hemolytic toxicity caused by different stimuli may be related to the upregulation of lipid metabolism pathways and increased lipid metabolite content, while the inhibition of colonial formation and development of P. globosa may be caused by the downscaled production and secretion of glycosaminoglycans. The study demonstrated that zooplankton consumption cues were recognized by intraspecific prey and elicited consumer-specific chemical defenses, highlighting the chemical ecology of herbivore-phytoplankton interactions in the marine ecosystem.
... High-fat diets induce severe disruptions in colonic microbial communities. Fornelos et al. [59] observed that with the increased ratio of omega-6: omega-3 fatty acid in the diet (such as the HF diet), the symbiotic bacteria that maintain host immunological equilibrium are affected, whereas the growth of pathogenic bacteria favoring inflammatory diseases is favored. Our results showed that incorporating VFPE (0.5%, 1%, and 2%) reduced the abundance of Erysipelotrichales, Chloroplast, Mollicutes, and Mycoplasmatales genus of the group of Firmicutes. ...
Obesity causes systemic inflammation, hepatic and renal damage, as well as gut microbiota dysbiosis. Alternative vegetable sources rich in polyphenols are known to prevent or delay the progression of metabolic abnormalities during obesity. Vachellia farnesiana (VF) is a potent source of polyphenols with antioxidant and anti-inflammatory activities with potential anti-obesity effects. We performed an in vivo preventive or an interventional experimental study in mice and in vitro experiments with different cell types. In the preventive study, male C57BL/6 mice were fed with a Control diet, a high-fat diet, or a high-fat diet containing either 0.1% methyl gallate, 10% powdered VFP, or 0.5%, 1%, or 2% of a polyphenolic extract (PE) derived from VFP (Vachellia farnesiana pods) for 14 weeks. In the intervention study, two groups of mice were fed for 14 weeks with a high-fat diet and then one switched to a high-fat diet with 10% powdered VFP for ten additional weeks. In the in vitro studies, we evaluated the effect of a VFPE (Vachellia farnesiana polyphenolic extract) on glucose-stimulated insulin secretion in INS-1E cells or of naringenin or methyl gallate on mitochondrial activity in primary hepatocytes and C2C12 myotubes. VFP or a VFPE increased whole-body energy expenditure and mitochondrial activity in skeletal muscle; prevented insulin resistance, hepatic steatosis, and kidney damage; exerted immunomodulatory effects; and reshaped fecal gut microbiota composition in mice fed a high-fat diet. VFPE decreased insulin secretion in INS-1E cells, and its isolated compounds naringenin and methyl gallate increased mitochondrial activity in primary hepatocytes and C2C12 myotubes. In conclusion VFP or a VFPE prevented systemic inflammation, insulin resistance, and hepatic and renal damage in mice fed a high-fat diet associated with increased energy expenditure, improved mitochondrial function, and reduction in insulin secretion.
... For example, N-arachidonoyl ethanolamine (anandamide, AEA) was found to have anti-microbial and anti-biofilm activities against methicillin-sensitive and methicillin-resistant Staphylococcus aureus [10][11][12][13]. Fornelos et al. [14] observed that AEA prevented the growth of Streptococcus salivarius and Enterococcus faecalis when applying 17-35 µg/mL (50-100 µM) AEA. Additionally, the endocannabinoids have been found to have anti-fungal activities [15]. ...
... In recent years, the endocannabinoid anandamide (AEA) has been tested alone and in combination with other anti-microbial agents in relation to the growth of different microbes. In Fornelos et al. [14], among the strains tested, the most susceptible bacteria to AEA included Streptococcus salivarius, Bacteroides fragilis and Enterococcus faecalis. AEA was also found to act on multidrug-resistant bacterium Staphylococcus aureus (MDRSA) [11], suggesting that its mechanism of action is unaffected by drug-resistant mechanisms. ...
Streptococcus mutans is a cariogenic bacterium in the oral cavity involved in plaque formation and dental caries. The endocannabinoid anandamide (AEA), a naturally occurring bioactive lipid, has been shown to have anti-bacterial and anti-biofilm activities against Staphylococcus aureus. We aimed here to study its effects on S. mutans viability, biofilm formation and extracellular polysaccharide substance (EPS) production. S. mutans were cultivated in the absence or presence of various concentrations of AEA, and the planktonic growth was followed by changes in optical density (OD) and colony-forming units (CFU). The resulting biofilms were examined by MTT metabolic assay, Crystal Violet (CV) staining, spinning disk confocal microscopy (SDCM) and high-resolution scanning electron microscopy (HR-SEM). The EPS production was determined by Congo Red and fluorescent dextran staining. Membrane potential and membrane permeability were determined by diethyloxacarbocyanine iodide (DiOC2(3)) and SYTO 9/propidium iodide (PI) staining, respectively, using flow cytometry. We observed that AEA was bactericidal to S. mutans at 12.5 µg/mL and prevented biofilm formation at the same concentration. AEA reduced the biofilm thickness and biomass with concomitant reduction in total EPS production, although there was a net increase in EPS per bacterium. Preformed biofilms were significantly affected at 50 µg/mL AEA. We further show that AEA increased the membrane permeability and induced membrane hyperpolarization of these bacteria. AEA caused S. mutans to become elongated at the minimum inhibitory concentration (MIC). Gene expression studies showed a significant increase in the cell division gene ftsZ. The concentrations of AEA needed for the anti-bacterial effects were below the cytotoxic concentration for normal Vero epithelial cells. Altogether, our data show that AEA has anti-bacterial and anti-biofilm activities against S. mutans and may have a potential role in preventing biofilms as a therapeutic measure.
... Although the mechanism behind the accumulation of these atypical endocannabinoids still needs to be elucidated, current evidence suggests that ethanolamides might shape the gut microbiota during inflammation. 37 Our study found that patients with IBD also have elevated levels of long-chain fatty acids (LCFAs) and PUFAs, such as acylcarnitines and arachidonic acid, in their faeces. Previous research by Smith et al has identified palmitoylcarnitine (C16) as a faecal ...
Objective
Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn’s disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD.
Design
We measured 1684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 patients with IBD and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant’s lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels.
Results
We identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC=0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of Ruminococcus gnavus was positively associated with tryptamine levels. In addition, we found 158 associations between metabolites and dietary patterns, and polymorphisms near NAT2 strongly associated with coffee metabolism.
Conclusion
In this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.
... In our opinion, there is to date enough evidence, coming from several laboratories and the use of multidisciplinary approaches, to support the participation of the gBiome-eCBome axis in the control of energy metabolism, inflammation (including metabolic endotoxaemia) and motivation (Fig. 1). However, most of the molecular mechanisms through which these two complex systems control each other are still unknown, and might include epigenetic as well as biochemical and pharmacological modulations [6][7][8][9][10] . We believe that the gBiome-eCBome axis will be more and more often the focus of studies aimed at understanding the role of small chemical signals in host-microbe communications of key functional importance. ...
... For example, increased availability of oxygen and the release of byproducts of inflammatory reactive oxygen and nitrogen metabolism enhance growth of Enterobacteriaceae in mouse models [23,24]. An overabundance of N-acylethanolamines in IBD patients inhibits the growth of obligate beneficial microbes while promoting the growth of potentially harmful microbes such as Enterobacteriaceae and Enterococcaceae [25]. These studies highlight the importance of metabolism-based host-microbe interactions. ...
Background
Intestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology.
Results
We investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis.
Conclusions
The release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition.
4h64TYW6e28QusiMD-BunNVideo Abstract
... We have shown that endocannabinoids released by P-gp suppress aberrant inflammation via inhibition of neutrophil infiltration (1). Studies are beginning to unravel how endocannabinoids may alter the microbiome community (82). Moreover, these findings identify new mechanisms for the roles for PXR and VDR in intestinal health via induction of P-gp in response to the microbiota. ...
Preventing aberrant inflammation is essential to maintaining homeostasis in the mammalian intestine. Although P-glycoprotein (P-gp) expression in the intestine is critical for protecting the intestinal epithelium from toxins and damage due to neutrophil infiltration, its regulation in the intestine is poorly understood.
... The main manifestation of the dysbiosis of gut microbiota is a reduction in biodiversity (8,9) as well as an imbalance between the putative protective and harmful species in gut microbiota (1,10). For example, a reduction in the relative abundance of dominant phyla in the commensal gut microbiota, including Firmicutes and Bacteroidetes, as well as the abnormal increase in the relative abundance of phylum Proteobacteria have been confirmed as a signature of the dysbiosis of gut microbiota in IBD patients (11,12). Specific opportunistic pathogens, such as Escherichia coli (E. ...
Objective
To investigate the preventive effects of plant oils with different linoleic acid/alpha-linolenic acid (LA/ALA) ratios against colitis symptoms, and dysbiosis of gut microbiota in acute colitis mouse model.
Methods
Sixty male C57BL/6 mice were assigned into six groups ( n = 10): three groups were fed low-fat diets with low, medium, and high LA/ALA ratios; and three groups were fed with high-fat diets with low, medium, and high LA/ALA ratios. After 3 months of diet, the mice were exposed to dextran sodium sulfate solution to induce acute colitis. The severity of colitis was estimated by disease activity index (DAI) and histopathological examination. 16S rRNA gene sequencing was used for the analysis of gut microbiota.
Results
Plant oils with a lower LA/ALA ratio showed higher alleviating effects on the symptoms of colitis, which were accompanied by the better prebiotic characteristics manifested as effectively inhibiting the abnormal expansion of phylum Proteobacteria and genus Escherichia-Shigella in the gut microbiota of colitis mouse models.
Conclusion
A potential IBD prevention strategy of reducing the LA/ALA ratio in the daily consumed plant oils was proposed in this study. Furthermore, based on the optimized LA/ALA ratio, this preventive effect might not be weakened by the high intake of plant oils.
