Cell Host Microbe: Study finds Achilles heel of Crohn's disease-related bacteria

Adhesive invasive E. coli is used to convert by-products of sugar fermentation to grow in the intestines.
specifically, adhesive invasive E. coli uses 1,2-propylene glycol, a by-product of the breakdown of sugar called algal sugar, which is found in the intestinal wall.
When the adhesive invasive E. coli converts 1,2-propylene glycol, it produces propylate, which has been shown to interact with an immune system cell called monocyclic phagocytosis, which also exists in the inner walls of the intestine and triggers a series of inflammations.
Given the increased expression of propylene glycol dehydrase in viscous invasive E. coli compared to Symbia, the researchers first assessed the correlation between the gene abundance of propylene glycol dehydrase and Ron's disease.
Associate Professor of Gastroenterology and Hepatology, Director of the Will Cornell Medical and New York Generals/Will Cornell Medical Center's Jill Roberts Center for Inflammatory Bowel Disease, senior author Dr. Randy Longman and his colleagues, including Ellen Scherl of the Weill Cornell School of Medicine and Dr. Chun-Jun Guo, as well as Dr. Gretchen Diehl of the Sloan Kettering Memorial and Dr. Kenneth Simpson of Cornell University's Ithaka campus, measured the abundance of propylene glycol dehydrase using macrogenomic data from 24 healthy people and 22 crohn's patients.
compared to the healthy control group, subjects with Crohn's disease had significantly higher propylene glycol dehydrase abundance, which corresponded mainly to the E. coli genus.
In order to test the contribution of propylene glycol metabolism pathways to intestinal inflammation using human-based adhesive invasive E. coli from crohn's disease patients, the researchers genetically engineered the adhesive invasive E. coli to lack a key enzyme called propylene glycol dehydrase in the process, turning it into a defective mutant.
of the defective mutant strain led to a decrease in the number and proportion of immune T cells in the inherent layer of the colon and a decrease in inflammatory factors.
To determine the contribution of propylene glycol dehydrase to the pathogenicity of adhesively invasive E. coli in the T-cell-dependent colitis model, the researchers constructed a model of colitis and colonized the intestines of mice with defective mutants, and found that the defective mutant colonized mice with weight loss, increased survival, histological score, and significant reduction in fecal lipid deposition, indicating that the bacterial colonization of defective mutants was sufficient to restore severe colitis.
il-10 limits adhesive invasive E. coli-induced colitis.
, in the absence of IL-10, the weight loss and mortality of defective mutant colonized mice were significantly reduced compared to the control.
, qPCR of the intestinal intrinsic layer monocytes showed a significant decrease in IL-1 beta expression.
to determine the regulation of the secretion of IL-1 beta proteins, the researchers cultured colon implants overnight.
IL-1 beta ELISA, which secretes proteins from supersalts, showed that THE-1 beta protein secretion required propylene glycol dehydrase, and that the induction of IL-1 beta was not caused by another Glollabyte-negative symbic bacillus.
to determine whether IL-1 beta was involved in AIEC-induced intestinal inflammation, the researchers used a meliothic antibody to block IL-1 beta in mice with colitis.
Compared to the same control group, blocking IL-1 beta reduces weight, improves survival, and lowers fecal lipid deposition protein levels, and these findings highlight the synergetic regulation of IL-10 and propylene glycol dehydrase-induced in adhesive invasive E. coli-induced intestinal inflammation.
"Changing a metabolic pathway of a bacterium can have a big impact on intestinal inflammation," said study co-lead researcher Dr. Monica Viladomiu, M.D., M.D., of the Department of Gastroenterology and Hepatology and the Jill Roberts Institute of Inflammatory Bowel Disease at the Weill Cornell School of Medicine.
Maeva Metz is a doctoral student in medical science at Weill Cornell University's Graduate School of Medicine and a doctoral student in Dr. Longman's lab, and co-author of the paper.
findings could lead to better treatments for Crohn's disease, a chronic inflammatory intestinal disease that affects more than 4 million people worldwide.
there is no cure for Crohn's disease, and despite medication, nearly half of the patients in need of treatment develop incurable diseases.
Crohn's disease is associated with characteristic changes in the gut microbiome, including the expansion of pathologically adhered invasive E. coli, to the intestinal and systemic inflammatory load of Crohn's disease, and adhesion to invasive E. coli in preclinical models sufficient to promote inflammation of intestinal and systemic T-cells.
, Crohn's patients are often treated with antibiotics, which can kill beneficial and harmful bacteria and cause unnecessary side effects.
, Dr Longman and colleagues have found that treatments for inflammatory cascading reactions may help reduce inflammation while preserving beneficial bacteria.
Dr Longman, who is also a member of the Jill Roberts Institute for Inflammation, said: "If we can develop small molecule drugs that inhibit propylene glycol dehydrase, or reduce the availability of algal sugars by changing our diet, we may be able to reduce intestinal inflammation and have fewer side effects in patients with Crohn's disease."
”。
Intestinal mucous membrane is a unique nutritional space, including algal sugar fermentation product 1,2-propylene glycol, because the secondary restriction of intestinal algal glycosylation during the inflammatory process may functionally regulate adhesive invasive E. coli-induced propylene acids and subsequent effects on intestinal inflammation, adhesive invasive E. coli metabolic targeting and/or limiting the availability of specific nutrients during inflammation can be used as a treatment to reduce mucosal inflammation.
team's next step will be to test potential treatments.
also plan to study the potential role of an enzyme called algal glycosyl transferase 2 in protecting the gut from this inflammatory cascading reaction.
Longman explains that many Crohn's patients have mutations in the genes that code this enzyme, making it ins functioning.
" is interesting from a clinical point of view, as it may help us layer interventions that may be more useful.
" Original Source: 1. Viladomiu M, Metz ML, Lima SF, et al. Adherent-invasive E. coli metabolism of propanediol in Crohn's disease regulates phagocytes to drive intestinal inflammation. Cell Host Microbe. 2021 Feb 2:S1931-3128(21)00032-9. 2.Dogan B, Suzuki H, Herlekar D,et al. Inflammation-associated adherent-invasive Escherichia coli are enriched in pathways for use of propanediol and iron and M-cell translocation. Inflamm Bowel Dis. 2014 Nov; 20(11):1919-32.