C. Difficile toxins Found to Cause Inflammation by Targeting Nerves and Cells in the Gut: Implications for New Treatments

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Tiefgreifende Entzündungen des Darms durch Clostridioides difficile Infektion (CDI) stellen eine bedeutende Ursache für Infektionen des Magen-Darm-Trakts im Gesundheitswesen dar. Die Exposition gegenüber Toxinen wie Toxin B (TcdB) von Clostridioides difficile führt zu einer verstärkten Entzündung des Kolons, welches Gewebe schädigt und die Besiedlung von Clostridioides difficile begünstigt. Bisher war jedoch unklar, wie genau TcdB Entzündungen hervorruft. Eine neue Studie hat nun gezeigt, dass TcdB neurogene Entzündungen auslöst, indem es auf afferente Neuronen und Perizyten im Darm wirkt. Neuronen exprimieren dabei Rezeptoren wie Frizzled 1/2/7 (FZD1/2/7), während Perizyten den Chondroitin-Sulfat-Proteoglykan 4 (CSPG4) als Rezeptor nutzen. TcdB stimuliert die Ausschüttung von …
In-depth inflammation of the intestine by Clostridioides Difficile infection (CDI) is an important cause of infections of the gastrointestinal tract in the healthcare system. Exposure to toxins such as toxin B (TCDB) from Clostridioides Difficile leads to increased inflammation of the colon, which damages tissue and the settlement of Clostridioides Difficile favored. So far, however, it was unclear how exactly TCDB causes inflammation. A new study has now shown that TCDB triggers neurogenic inflammation by acting on afferent neurons and perizytes in the intestine. Neurons express receptors such as Frizzled 1/2/7 (FZD1/2/7), while perizytes use the chondroitin sulfate-protoglykan 4 (CSPG4) as a receptor. TCDB stimulates the distribution of ... (Symbolbild/natur.wiki)

Deep inflammation of the intestine by Clostridioides Difficile infection (CDI) are an important cause of the gastrointestinal tract infections. Exposure to toxins such as toxin B (TCDB) of Clostridioides Difficile leads to increased inflammation of the colon, which damages tissue and the settlement of Clostridioides favored difficile. So far, however, it was unclear how exactly TCDB causes inflammation.

A new study has now shown that TCDB triggers neurogenic inflammation by acting on afferent neurons and perity in the intestine. Neurons express receptors such as Frizzled 1/2/7 (FZD1/2/7), while perizytes use the chondroitin sulfate-protoglykan 4 (CSPG4) as a receptor. TCDB stimulates the distribution of neuropeptides such as substance P (SP) and the calcitonin-gene-related peptides (CGRP) by neurons and pro-inflammatory cytokines.

In order to take a closer look at the role of neurogenic inflammation at CDI, new approaches were used. Through the targeted delivery of the enzymatic domain of TCDB using the detoxified diphtheria toxin (DT), especially to peptidergic sensorotor neurons, which express the exogenous DT receptor (an approach called "toxogenetics"), a neurogenic inflammation could be induced. This corresponds to the essential colorectal histopathologies associated with CDI.

In experimental models, it was shown that mice that substance P, CGRP or the substance-P receptor (NK1R) did not express, had a lower tissue damage both after the injection of TCDB into the appendix and CDI. By blocking the signals from substance P or CGRP, the tissue damage and the load with Clostridioides Difficile in mice that were infected with a standard strain or a hypervirulent variant of Clostridioides Difficile.

These findings indicate that the targeted treatment of neurogenic inflammation could offer a therapeutic approach to the treatment of CDI. A promising path opens for host -oriented therapy that aims to reduce inflammation in the intestine.

source:
https://www.nature.com/articles/s41586-023-06607-2