Immunization Against Flagellin as a Way to Beneficially Alter Aging Gut Microbiota Populations

The microbial populations of the gut make a significant contribution to health via secreted metabolites and interactions with the immune system. Starting in mid-life, these populations alter for the worse, and this is thought to influence the progression of aging - perhaps primarily as a contributing cause of chronic inflammation. How this effect size compares with those resulting from dietary and exercise choices is an open question, but it isn't unreasonable to suggest it to be in the same ballpark as exercise.

What can be done to improve this situation? Supplementation with metabolites produced in larger amounts in youth, perhaps. Known options include tryptophan, indole, butyrate, and propionate, but there are no doubt many others as yet uncatalogued. Fecal microbiota transplants from young animals to old animals have been shown to reverse age-related changes in microbial populations and consequently extend life in short-lived species. This seems the best option of those on the table. There are others, however. As an example, the work here is quite clever, building upon a point of difference between beneficial and harmful gut microbes in order to steer the immune system to preferentially attack those harmful microbes and thus control their population size and impact on health.

The intestinal tract is colonized by billions of bacteria and other microorganisms that play numerous beneficial roles, but improperly controlled microbiota can lead to chronic inflammatory diseases. Previous studies have shown the intestinal microbiota are associated with inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, and diseases characterized by low-grade inflammation of the intestinal tract, such as obesity and metabolic syndrome.

Therapeutic options have focused on lessening the inflammatory response and have often overlooked the contribution of the intestinal microbiota. The researchers wanted to determine if a targeted immune response could be used to beneficially shape the intestinal microbiota and protect against inflammatory diseases. Previously, they found that a common feature of microbiotas associated with inflammation is an increased level of expression of flagellin by select microbiota members, a protein that forms the appendage that enables bacterial mobility, which can drive bacteria to penetrate the intestinal mucosa and disrupt homeostasis.

The researchers immunized mice with flagellin to elicit an adaptative immune response and demonstrated targeted immunization against bacterial flagellin is sufficient to beneficially alter the composition and function of the intestinal microbiota. Anti-flagellin antibodies were produced and affected the microbiota by reducing its pro-inflammatory potential and ability to penetrate its host. These alterations were associated with protection against chronic inflammatory diseases.



This is part of what Andrei Gudkov is doing with his work on LINE1 and age reversal. They are testing reverse transcriptase and endonuclease inhibitors along with Entolimod (salmonella flagellin).

They found the flagellin alone basically stopped the increase of frailty with aging, but only in men.

Posted by: Lee at December 18th, 2019 5:36 AM
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