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Transcriptional responses of Bacteroides fragilis to linoleoyl ethanolamide (LEA) and arachidonoyl ethanolamine (AEA) a, Differential gene expression between three independent exponential cultures treated for 10 minutes with a sub-inhibitory concentration (25 µM) of LEA or AEA and controls (0.04% DMSO). Differential expression was determined with edgeR, and gene functions were defined using InterPro (EMBL), the NCBI Conserved Domain Database (CDD) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Selected significantly differentially expressed genes (|log2 fold-change (treated/control)|>0.5, FDR<0.05; Benjamini-Hochberg FDR values were derived from p-values calculated using the likelihood-ratio test) are shown in color. b, Genomic environment of the differentially expressed genes using colors that correspond with (a). Genes in white were not significantly differentially expressed. Coordinate maps refer to the genome of strain B. fragilis ATCC 25285. Gene products that have been experimentally shown to be associated with the outer membrane by LC-MS/MS analysis are in bold (Wilson, M. M., Anderson, D. E. & Bernstein, H. D. Analysis of the outer membrane proteome and secretome of Bacteroides fragilis reveals a multiplicity of secretion mechanisms. PLoS ONE10, e0117732 (2015)).
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
... The NAE class of metabolites represents a broad family of lipid messengers that play a well-established role in energy metabolism and feeding behavior (84)(85)(86), as well as inflammation (85), and prior work has established a relationship between the gut microbiome and NAEs (87)(88)(89), so we next tested if the abundance of these metabolites is related to microbiome composition and antibiotic exposure. Strikingly, we observed a robust association between the abundance of these NAE compounds and gut represents an individual fish. ...
... Our multi-omic analysis reveals substantial alterations in NAEs and NAE precursors between parasitic infected and uninfected hosts, with a potential route of control by the gut microbiome. Given that NAEs play in a broad range of physiological functions such as immune regulation as well as energy metabolism and feeding behavior (84)(85)(86)108), IHPs are capable of modulating NAEs to enhance infection (90), and their alteration is associated with changes in the gut microbiome (87), these compounds represent a potentially rich area to understand the intersection of parasite infection with the gut microbiome and host immune regulation. Our results demonstrate that alteration of the gut microbiome by antibiotic exposure appears to drive changes in NAE abundance that are sustained in the profile of several NAE compounds several weeks after initial antibiotic exposure. ...
Intestinal helminth parasite (IHP) infection induces alterations in the composition of microbial communities across vertebrates, although how gut microbiota may facilitate or hinder parasite infection remains poorly defined. In this work, we utilized a zebrafish model to investigate the relationship between gut microbiota, gut metabolites, and IHP infection. We found that extreme disparity in zebrafish parasite infection burden is linked to the composition of the gut microbiome and that changes in the gut microbiome are associated with variation in a class of endogenously produced signaling compounds, N-acylethanolamines, that are known to be involved in parasite infection. Using a statistical mediation analysis, we uncovered a set of gut microbes whose relative abundance explains the association between gut metabolites and infection outcomes. Experimental investigation of one of the compounds in this analysis reveals salicylaldehyde, which is putatively produced by the gut microbe Pelomonas, as a potent anthelmintic with activity against Pseudocapillaria tomentosa egg hatching, both in vitro and in vivo. Collectively, our findings underscore the importance of the gut microbiome as a mediating agent in parasitic infection and highlight specific gut metabolites as tools for the advancement of novel therapeutic interventions against IHP infection.
IMPORTANCE
Intestinal helminth parasites (IHPs) impact human health globally and interfere with animal health and agricultural productivity. While anthelmintics are critical to controlling parasite infections, their efficacy is increasingly compromised by drug resistance. Recent investigations suggest the gut microbiome might mediate helminth infection dynamics. So, identifying how gut microbes interact with parasites could yield new therapeutic targets for infection prevention and management. We conducted a study using a zebrafish model of parasitic infection to identify routes by which gut microbes might impact helminth infection outcomes. Our research linked the gut microbiome to both parasite infection and to metabolites in the gut to understand how microbes could alter parasite infection. We identified a metabolite in the gut, salicylaldehyde, that is putatively produced by a gut microbe and that inhibits parasitic egg growth. Our results also point to a class of compounds, N-acyl-ethanolamines, which are affected by changes in the gut microbiome and are linked to parasite infection. Collectively, our results indicate the gut microbiome may be a source of novel anthelmintics that can be harnessed to control IHPs.
... Firmicutes, Bacteroidota, and Actinobacteriota transferred less efficiently to inflamed than uninflamed recipient hosts, while Proteobacteria transferred as efficiently to inflamed and uninflamed hosts. Gut inflammation induces host-derived metabolites, such as nitrate, lactate, and ethanolamine, that enhance fitness, abundance, and virulence of Proteobacteria such as resident adherent-invasive E. coli and promotes ectopic gut colonization of inflammation-associated Veillonella species [62][63][64][65][66][67]. Adherent and invasive E. coli and other inflammation-associated aggressive resident bacteria drive intestinal inflammation in murine colitis models [1,18,19,21]. ...
Background
Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis.
Results
Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10−/− mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10−/− mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10−/− host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10−/− mice than the distinct microbiota reassembled in non-inflamed WT hosts.
Conclusions
Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.
9-8iLEe2BorBmu_z2q_8UWVideo Abstract
... The inclusion of Rausch et al. [53], with a mean participant age of 42.07 years and a standard deviation of 17.14 for their study, indicated a broad age range within this study, reflecting its diverse participant pool. study, the percentage of male participants in each study, the percentage of female participants in each study, and the age characteristics (mean age ± SD) of participants in each study [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. ...
... Table 2 consolidates data to highlight consistent patterns, such as the decrease in beneficial bacteria like Faecalibacterium prausnitzii, Roseburia, Bacteroides, Ruminococcaceae, and Lachnospiraceae in IBD patients, which are important for their anti-inflammatory properties and role in maintaining gut health (Vich Vila et al. [37], Ananthakrishnan et al. [38], Franzosa et al. [39], Olaisen et al. [46], Pittayanon et al. [49]). . Four subplots showing the number of participants in each study, the percentage of male participants in each study, the percentage of female participants in each study, and the age characteristics (mean age ± SD) of participants in each study [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. ...
... The bottom left bar chart shows the female participant percentages, highlighting that most studies maintained a near-equal gender balance, further emphasizing inclusivity. Studies such as those by Fornelos et al. [52], Nikolaus et al. [51], and Forbes et al. [50] achieved a perfect 50/50 gender split, emphasizing the commitment to demographic diversity. ...
Recent research indicates that the microbiome has a significant impact on the progression of inflammatory bowel disease (IBD) and that creating therapies that change its composition could positively impact the outcomes of IBD treatment. This review summarizes the results of extensive studies that examined IBD patients undergoing several therapies, including anti-TNF medication, vedolizumab, ustekinumab, probiotics, and fecal microbiota transplantation (FMT), and the alterations in their gut microbiota's composition and function. The objective was to investigate the variety and effectiveness of microbial species in order to discover new biomarkers or therapeutic targets that could improve the outcome of treatment for these patients. This research aimed to offer useful insights into personalized medicine techniques for managing IBD. Beneficial bacteria such as Faecalibacterium prausnitzii and Roseburia have been consistently linked to favorable clinical outcomes, whereas pathogenic bacteria such as Escherichia coli and Clostridioides difficile are associated with worsening disease conditions. Although many studies have examined the role of gut microbiota in IBD, there is still a need for more targeted research on the connection between specific microbial communities and treatment outcomes. This study sought to address this gap by exploring the intricate relationship between the gut microbiota composition and the effectiveness of IBD medications.
... 6,7 Indeed, PWH typically exhibit systemic inflammation characterized by constant immune cell activation, resulting in persistent elevated levels of circulating pro-inflammatory and profibrotic cytokines such as interleukin (IL)-1b, IL-6, tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-g), soluble TNF receptor family (sTNFR), monocyte chemotactic factor (CCL2), soluble cluster of differentiation (sCD163 and sCD14), and intercellular adhesion molecule 1 (ICAM-1). 6 This chronic inflammatory state contributes to the dysfunction of vascular endothelial cells, abnormal lipid metabolism, hypercoagulation, inflammation, and fibrosis of vascular coronary tissues that promote the development of Ex-smoker 58 (37) 21 (40) 42 (39) 37 (37) 33 (38) 25 (36) 9 (41) 12 (40) Never smoked 48 (31) 24 (46) 27 (25) 45 (45) 19 (22) 29 (42) 8 (36) 16 ( Tables 2 and 3. Overall, we observed a peculiar pattern with an inverse relationship in plasma levels between NAEs and MAGs (including the two eCBs AEA and 2-AG), with NAEs being most significantly elevated in HIVÀ individuals as well as in CADÀ participants and MAGs being most significantly elevated in HIV+ and in individuals with CAD ( Table 2). ...
Chronic HIV infection is associated with accelerated coronary artery disease (CAD) due to chronic inflammation. The expanded endocannabinoid system (eCBome) and gut microbiota modulate each other and are key regulators of cardiovascular functions and inflammation. We herein investigated the interplay between plasma eCBome mediators and gut microbiota in people with HIV (PWH) and/or subclinical CAD versus HIV-uninfected individuals. CAD was determined by coronary computed tomography (CT) angiography performed on all participants. Plasma eCBome mediator and fecal microbiota composition were assessed by tandem mass spectrometry and 16S rDNA sequencing, respectively. HIV infection was associated with perturbed plasma eCBome mediators characterized by an inverse relationship between anandamide and N-acyl-ethanolamines (NAEs) versus 2-AG and 2-monoacylglycerols (MAGs). Plasma triglyceride levels were positively associated with MAGs. Several fecal bacterial taxa were altered in HIV−CAD+ versus controls and correlated with plasma eCBome mediators. CAD-associated taxonomic alterations in fecal bacterial taxa were not found in PWH.
... Microbiome science overall and as it is related to IBD has grown tremendously since the Challenges in IBD Research report was published in May 2019 1,[31][32][33][34] . Developments in microbiome studies are driven by expansion of well-curated human cohorts with a gut microbiome focus, advancements in microbiome data generation and analysis tools (especially regarding metabolomics) applied to IBD, and innovations in preclinical models [2][3][4][35][36][37][38][39][40][41][42][43][44][45][46][47][48] . In this gap section, we highlight recent impactful discoveries, existing knowledge gaps, and calls to action regarding IBD and the microbiome and provide ideas and concepts for how the microbiome can be approached using preclinical models, first for IBD interception and then for IBD remission and restoration. ...
Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.
... Feces collection was performed as described in a previous study (Fornelos et al., 2020). Mouse feces were collected into sterilized tubes (1.5 mL) using forceps, and forceps were sterilized before and after use. ...
Lactiplantibacillus plantarum is selective for carbohydrate utilization, which is primarily regulated by the catabolic control protein A (ccpA). To investigate the impact of carbohydrate metabolism on the in vivo colonization of L. plantarum AR113, we constructed a ccpA knockout strain (AR113ΔccpA). In vitro assays showed that AR113ΔccpA had a 0.34 decrease in maximum biomass, and a 2.63 h increase in hysteresis time compared to AR113. In a single administration, there was no significant difference in the number of AR113 and AR113ΔccpA in the mucus layers, and the number of AR113 was approximately 34‐times higher than AR113ΔccpA at 48 h in the intestinal lumen. Notably, the knockout of the ccpA gene did not affect the colonization time of AR113 in the intestine during continuous administration. Therefore, the present work demonstrated that the ccpA did not play a crucial role in the in vivo colonization time of AR113 and provided valuable insights into the role of carbohydrate metabolism in bacterial colonization time in vivo.
... Enrichment of ethanolamines was also observed under various pathological conditions such as in the serum of healthy humans after acute stress, in inflammatory bowel disease (IBD) stool samples, and in colitis model of T-cell transfer. 55,56 Bacterial species harboring ethanolamine utilization (Eut B/C) genes can utilize ethanolamine provided by dead cells as a carbon and nitrogen source, thus providing a growth advantage, 57-60 and Eut B/C genes have been implicated in pathogenesis and colonization of E. coli in urinary tract infections and CD. 59,61 Our metagenomic data indicate an increased abundance of EutC gene in E. faecalis, thus might provide it with a competitive advantage over commensal microbiota. ...
... Also, N-acylethanolamines (NEAs) augmentation led to the expansion of pathogenic E. coli, E. faecalis, and Ruminococcus gnavus and resulted in the shift of complex ex-vivo microbial cultures to a more IBD like microbiome. 55 Our integration results are in tandem with this, and NAEs had strong positive correlations to P. excrementihominis, B. bacterium 1_1_47, E. faecalis, E. caecimuris and A. municiphila, and DEGs involved in inflammatory response thereby implicating NEAs in the expansion of certain pathogenic bacterial taxa and inflammation. ...
Opioid crisis is an ongoing epidemic since the past several decades in the United States. Opioid use-associated microbial dysbiosis is emerging as a key regulator of intestinal homeostasis and behavioral responses to opioid. However, the mechanistic insight into the role of microbial community in modulating host response is unavailable. To uncover the role of opioid-induced dysbiosis in disrupting intestinal homeostasis we utilized whole genome sequencing, untargeted metabolomics, and mRNA sequencing to identify changes in microbiome, metabolome, and host transcriptome respectively. Morphine treatment resulted in significant expansion of Parasuterella excrementihominis, Burkholderiales bacterium 1_1_47, Enterococcus faecalis, Enterorhabdus caecimuris and depletion of Lactobacillus johnsonii. These changes correlated with alterations in lipid metabolites and flavonoids. Significant alteration in microbial metabolism (metabolism of lipids, amino acids, vitamins and cofactors) and increased expression of virulence factors and biosynthesis of lipopolysaccharides (LPS) and lipoteichoic acid (LTA) were observed in microbiome of morphine-treated animals. In concurrence with changes in microbiome and metabolome extensive changes in innate and adaptive immune response, lipid metabolism, and gut barrier dysfunction were observed in the host transcriptome. Microbiome depleted mice displayed lower levels of inflammation, immune response and tissue destruction compared to mice harboring a dysbiotic microbiome in response to morphine treatment, thus establishing dysbiotic microbiome as mediator of morphine gut pathophysiology. Integrative analysis of multi-omics data highlighted the associations between Parasutterella excrementihominis, Burkholderiales bacterium 1_1_47, Enterococcus faecalis, Enterorhabdus caecimuris and altered levels of riboflavin, flavonoids, and lipid metabolites including phosphocholines, carnitines, bile acids, and ethanolamines with host gene expression changes involved in inflammation and barrier integrity of intestine. Omic analysis also highlighted the role of probiotic bacteria Lactobacillus johnsonii, metabolites flavonoids and riboflavin that were depleted with morphine as important factors for intestinal homeostasis. This study presents for the first time ever an interactive view of morphine-induced changes in microbial metabolism, strain level gut microbiome analysis and comprehensive view of changes in gut transcriptome. We also identified areas of potential therapeutic interventions to limit microbial dysbiosis and present a unique resource to the opioid research community.
... 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.
