Suche
Mein Konto
C. difficile toxins found to cause inflammation by targeting nerves and cells in the gut: Implications for new treatments
Profound inflammation of the intestine caused by Clostridioides difficile infection (CDI) represents a significant cause of gastrointestinal tract infections in healthcare settings. Exposure to toxins such as Clostridioides difficile toxin B (TcdB) leads to increased inflammation of the colon, which damages tissue and promotes Clostridioides difficile colonization favored. However, it was previously unclear how exactly TcdB causes inflammation. A new study has now shown that TcdB triggers neurogenic inflammation by acting on afferent neurons and pericytes in the intestine. Neurons express receptors such as Frizzled 1/2/7 (FZD1/2/7), while pericytes use chondroitin sulfate proteoglycan 4 (CSPG4) as a receptor. TcdB stimulates the release of...
C. difficile toxins found to cause inflammation by targeting nerves and cells in the gut: Implications for new treatments
Profound inflammation of the intestine caused by Clostridioides difficile infection (CDI) represents a significant cause of gastrointestinal tract infections in healthcare settings. Exposure to toxins such as Clostridioides difficile toxin B (TcdB) leads to increased inflammation of the colon, which damages tissue and promotes Clostridioides difficile colonization favored. However, it was previously unclear how exactly TcdB causes inflammation.
A new study has now shown that TcdB triggers neurogenic inflammation by acting on afferent neurons and pericytes in the intestine. Neurons express receptors such as Frizzled 1/2/7 (FZD1/2/7), while pericytes use chondroitin sulfate proteoglycan 4 (CSPG4) as a receptor. TcdB stimulates the release of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) by neurons as well as pro-inflammatory cytokines by pericytes.
To shed more light on the role of neurogenic inflammation in CDI, new approaches have been used. By specifically delivering the enzymatic domain of TcdB via fusion with the detoxified diphtheria toxin (DT) to peptidergic sensorimotor neurons that express the exogenous DT receptor (an approach the scientists call “toxogenetics”), neurogenic inflammation could be induced. This corresponds to the major colorectal histopathologies associated with CDI.
In experimental models, mice that do not express substance P, CGRP, or the substance P receptor (NK1R) were shown to have less tissue damage both after injection of TcdB into the cecum and in CDI. Blocking substance P or CGRP signaling reduced tissue damage and Clostridioides difficile burden in mice infected with a standard strain or a hypervirulent variant of Clostridioides difficile.
These findings suggest that targeting neurogenic inflammation may provide a therapeutic approach for the treatment of CDI. A promising avenue is opening for host-directed therapy aimed at reducing inflammation in the gut.
Source:
https://www.nature.com/articles/s41586-023-06607-2