Recurrent salmonella infections can cause colitis

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Recurrent infections of Salmonella, a common pathogen for human food poisoning, can cause colitis. Credit: Sanford Burnham Prebys Medical Discovery Institute

An international research group, led by Jamey Marth, Ph.D., a professor at Sanford Burnham Prebys, has shown that the enzyme Neuraminidase 3 (Neu3) is responsible for the onset and progression of colitis, a chronic digestive disease caused by by inflammation the colon. The study, recently published in Proceedings of the National Academy of Sciences, was performed in a model of recurrent human food poisoning previously related to the disease. The findings represent a scientific breakthrough toward specific therapy to help the millions of people affected by the disorder worldwide.

“Our new research shows how Neu3: an activity increases which is in the gut: it triggers an inflammatory cascade that leads to disease, “says Marth.” Prior to this study, we knew that a neuraminidase enzyme was involved, but we did not know the origin of the enzyme.

“This study identifies Neu3 as the protein that triggers the onset and progression of colitis,” adds Marth. “In the absence of Neu3, the onset and progression of the disease does not occur, indicating that the enzyme may be a valuable therapeutic target.”

Previously, the Marth Laboratory developed a unique model of colitis based on recurrent human food poisoning, which can identify environmental sources of disease. The (mouse) model reflects how humans can contract colitis after repeated and mild infections of Salmonella enterica Typhimurium (ST), a common pathogen for human food poisoning.

“We are now studying an intrinsic mechanism of protein aging and rotation that is being modified by a food-borne pathogen,” says Marth. “The pathogen targets the aging process of proteins in the , thus decreasing the expression of a key anti-inflammatory enzyme that would normally prevent the onset of colitis and inflammatory bowel disease (IBD).

“This enzyme is intestinal alkaline phosphatase (IAP), which detoxifies , and its increase is also the foundation of current clinical trials in the treatment of colitis and sepsis.

“The problem begins when the pathogen ST is ingested and causes our immune system to‘ amplify ’the expression of Neur3 neuraminidase,” adds Marth. “Increased Neu3 activity leads to a reduced shelf life of PAI and this affects the ability to detoxify a harmful endotoxin that is normally found among gut bacteria, and this causes chronic inflammation of the intestine “.

Inhibition of Neu3 with the antiviral drug Relenza (used to treat the flu) broke this chain, reduced inflammatory cytokine expression, and prevented severe colitis. However, current neuraminidase inhibitors such as Relenza and Tamiflu are optimized for viral and bacterial neuraminidases and would need further development to be clinically effective against the human form of Neu3.

“We had to increase the oral dose of Relenza well above the recommended one for use in humans,” says Marth. “It worked without apparent side effects; however, a new generation of mammalian enzyme-targeted neuraminidase inhibitors is needed. Several research groups are now focusing on the development of clinically relevant inhibitors.

“We were surprised that the culprit was Neu3, as many gut bacteria are able to synthesize their own enzymes, “Marth points out.” Based on the genetic test of our study, Neu3 inhibition is expected to have a positive therapeutic impact. But there is also another option: increasing the PAI seems to be just as beneficial. Perhaps a dual approach that simultaneously includes oral inhibition of Neu3 and oral increase in PAI could be even more effective in reducing inflammation and preventing the onset of colitis. ”


Intestinal reaction: Repeated food poisoning triggers chronic diseases


More information:
Won Ho Yang et al, Neur3 neuraminidase induction triggers intestinal inflammation and colitis in a recurrent human food poisoning model. Proceedings of the National Academy of Sciences (2021). DOI: 10.1073 / pnas.2100937118

Citation: Recurrent Salmonella Infections May Cause Colitis (2021, July 16) Retrieved July 16, 2021 at https://medicalxpress.com/news/2021-07-recurrent-salmonella-collitis-infections.html

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