Inflammation associated ethanolamine facilitates infection by Crohn's disease-linked adherent-invasive Escherichia coli

Abstract

Background The predominance of specific bacteria such as adherent-invasive Escherichia coli (AIEC) within the Crohn's disease (CD) intestine remains poorly understood with little evidence uncovered to support a selective pressure underlying their presence. Intestinal ethanolamine is however readily accessible during periods of intestinal inflammation, and enables pathogens to outcompete the host microbiota under such circumstances. Methods Quantitative RT-PCR (qRT-PCR) to determine expression of genes central to ethanolamine metabolism; transmission electron microscopy to detect presence of bacterial microcompartments (MCPs); in vitro infections of both murine and human macrophage cell lines examining intracellular replication of the AIEC-type strain LF82 and clinical E. coli isolates in the presence of ethanolamine; determination of E. coli ethanolamine utilization ( eut ) operon transcription in faecal samples from healthy patients, patients with active CD and the same patients in remission following treatment. Results Growth on the intestinal short chain fatty acid propionic acid (PA) stimulates significantly increased transcription of the eut operon (fold change relative to glucose: >16.9; p -value <.01). Additionally ethanolamine was accessible to intra-macrophage AIEC and stimulated significant increases in growth intracellularly when it was added extracellularly at concentrations comparable to those in the human intestine. Finally, qRT-PCR indicated that expression of the E. coli eut operon was increased in children with active CD compared to healthy controls (fold change increase: >4.72; P < .02). After clinical remission post-exclusive enteral nutrition treatment, the same CD patients exhibited significantly reduced eut expression (Pre vs Post fold change decrease: >15.64; P < .01). Interpretation Our data indicates a role for ethanolamine metabolism in selecting for AIEC that are consistently overrepresented in the CD intestine. The increased E. coli metabolism of ethanolamine seen in the intestine during active CD, and its decrease during remission, indicates ethanolamine use may be a key factor in shaping the intestinal microbiome in CD patients, particularly during times of inflammation. Fund This work was funded by Biotechnology and Biological Sciences Research Council (BBSRC) grants BB/K008005/1 & BB/P003281/1 to DMW; by a Tenovus Scotland grant to MJO; by Glasgow Children's Hospital Charity, Nestle Health Sciences, Engineering and Physical Sciences Research Council (EPSRC) and Catherine McEwan Foundation grants awarded to ...

Microbial adaptation to the healthy and inflamed gut environments

“…Typhimurium and AIEC increase transcription of the eut operon to use intestinal ethanolamine, which is secreted from intestinal epithelial cells during inflammation. 61 , 62 This selective use of ethanolamine gives the pathogens a competitive edge over commensal bacteria. As discussed earlier, iron is of critical importance to pathogen fitness in several species of Proteobacteria (e.g., E. coli ).…”

Microbiome-aware Ecotoxicology: Relevance, Pitfalls and Challenges

“…The resulting mucosa degradation allows bacterial encroachment, indirectly leading to a shift in microbiome composition, and triggering inflammatoryassociated diseases (Chassaing et al 2015). Host compounds produced during inflammation may also modify the microbiome (Ormsby et al 2019). Bacterial products can also destabilize the whole community as illustrated in the case of Crohn's disease where propionic acid promotes the growth of a virulent phenotype of Escherichia coli (Ormsby et al 2020).…”

Ethanolamine improves colonic barrier functions and inflammatory immunoreactions via shifting microbiome dysbiosis

“…To date, most EA signaling related researches were focused on bacterial utilization and CDP-EA pathway in PE synthesis 11,17,[19][20] . Our previous study has demonstrated that ethanolamine could promote the proliferation of IPEC-J1 cells by regulating the mTOR signaling pathway and mitochondrial function 44 .…”

“…Lipid-mediated host-microbial interactions in metabolism and immune reactions are implicated in chronic inflammatory diseases like IBD 15 . Ethanolamine has been detected at a relatively high concentration within the inflamed gut of both IBD patients and rodent models as the hydrolysate of PE [16][17] . Ethanolamine can be utilized by both intestinal epithelial cells 11 and bacteria like Enterococcus faecalis 18 that hold the EA utilization (eut) genes via the CDP-EA pathway 10 , which confers it with the potential role in mediating the cross-talk between the intestinal epithelium and gut microbiota.…”

“…A recent study highlighted that EA could promote the mesenchymal-to-epithelial transitions via a CDP-EA-Pebp1 dependent manner that ultimately leads to NF-κB inhibition 11 . Ethanolamine has been associated with the pathogenesis of eut pathogens such as Salmonella 16 and enterohemorrhagic Escherichia coli (EHEC) 17 that have been reported to promote colorectal carcinogenesis and tumor formation [2][3] . For instance, several studies have demonstrated that S. Typhimurium can sidestep nutritional competition with commensal bacteria by utilizing EA in inflamed gut 16,[19][20] .…”