Valeric Acid as a Harmful Metabolite Generated by the Aged Gut Microbiome
The balance of microbial populations making up the gut microbiome shifts with age. The research community has developed a good list of contributing causes, ranging from lifestyle changes to aspects of degenerative aging that affect immune function and the state of the intestinal lining, but the degree to which any given contribution is important relative to the others remains a question mark. The immune system is responsible for gardening the gut microbiome, suppressing the population growth of problem microbes, but immune aging likely reduces this activity. In turn, growing populations of problem microbes can help to provoke chronic inflammation that further harms immune function, and beyond that tissue function throughout the body.
With an increased attention given to the aging of the gut microbiome, researchers are beginning to identify specific mechanisms by which it can provoke inflammation and tissue dysfunction. Today's open access paper is an example of this sort of work, in which the authors identify valeric acid as a problem metabolite, produced in greater amounts by the aged gut microbiome, and which stimulates harmful inflammatory signaling. This is one of many reasons for a greater focus on ways to rejuvenate the gut microbiome, restoring the youthful balance of populations. Practical approaches do exist, including fecal microbiota transplantation, flagellin immunization, and others. Making these approaches more available to the public would likely provide meaningful benefits to late life health.
Studies have shown that gut microbiota can modulate inflammatory responses in the brain after brain ischemia. Antibiotics-induced changes in the gut flora provide neuroprotection against brain ischemia in mice. A recent study has shown that aging-related changes in gut microbiota may influence the outcome of experimental stroke in mice. However, the mechanisms for this effect are not defined. Consistent with these experimental stroke findings, stroke patients with significant gut dysbiosis may have a worsened neurological outcome, suggesting a potential role of gut microbiota in determining stroke outcome in humans.
Gut microbiota can produce multiple metabolites. Among them, short-chain fatty acids (SCFA) are one of the major types of metabolites and can regulate inflammatory responses, a process that affects neurological outcome after brain ischemia. Previous studies have shown that SCFAs are decreased with aging in the feces. A recent study has shown that stroke patients have changes in SCFA concentrations in their feces. However, whether SCFAs are involved in aging-related changes in brain ischemic tolerance and how SCFAs affect stroke outcome is not known.
Interleukin (IL)-17 is a proinflammatory cytokine. It is produced from a group of T helper cells and can induce the production of chemokines that recruit immune cells to the site of inflammation and facilitate the production of other proinflammatory cytokines, such as IL-6 and IL-1β. A previous study has shown that the decrease of IL-17-positive T helper cells may contribute to the neuroprotection induced by antibiotics-caused gut floral changes.
Old C57BL/6J male mice (18 to 20 months old) had a poorer neurological outcome and more severe inflammation after transient focal brain ischemia than 8-week-old C57BL/6J male mice (young mice). Young mice with transplantation of old mouse gut microbiota had a worse neurological outcome, poorer survival curve, and more severe inflammation than young mice receiving young mouse gut microbiota transplantation.
Old mice and young mice transplanted with old mouse gut microbiota had an increased level of blood valeric acid. Valeric acid worsened neurological outcome and heightened inflammatory response including blood interleukin-17 levels after brain ischemia. The increase of interleukin-17 caused by valeric acid was inhibited by a free fatty acid receptor 2 (FFAR-2) antagonist. Neutralizing interleukin-17 in the blood by its antibody improved neurological outcome and attenuated inflammatory response in mice with brain ischemia and receiving valeric acid. Old mice transplanted with young mouse feces had less body weight loss and better survival curve after brain ischemia than old mice transplanted with old mouse feces or old mice without fecal transplantation.
Our results suggest that a novel pathway linking gut microbiota, valeric acid, FFAR 2, and IL-17 mediates increased inflammatory response to brain ischemia and worsened neurological outcome after ischemic stroke in old mice.
The core consideration here is the interleukin IL17.
It is a really nasty entity heavily implicated in inflammaging and arthritis
( both inflammatory arthritis eg RA and so-called non-inflammatory arthritis ie OA or osteoarthritis),
also any skin inflammation eg psoriasis, asthma , inflammatory bowel disease, and brain deterioration.
Not to mention innapropriate fibrosis ( cardiac fibrosis and vascular fibrosis - fibrosis of the vascular media/ smooth muscle cell layer ) and stabilsation and reinforcement of the integrity of BBB, endothelium and gut monocellular layers.
Purple berries eg blueberries, elderberries, aronia and maqui are very heavy in cyanidin and delphinidin which are hugely antiinflammatory probably by blocking IL17A connecting with IL17RA and thus preventing the triggering of an inflammatory pathway.
In the case of asthma, IL17F, which with IL17A, is blocked.
This is also achieved with Cosentyx( sekuminumab) sold by Novartis for a mere £500 per weekly injection.
Price of purple berries eg elderberries is circa £10 per 1kg.( Large bowl twice per day with ice cream ! )
It goes without saying therefore, that a certain sort of person will automatically opt for the Novartis offering thus to enhance their suffering.
This study concludes the opposite concerning valeric acid
https://www.perstorp.com/en/news_center/news/2022/october/valeric_and_butyric_acid_-_keys_to_unlocking_superior_gut_health_and_performance
As do many others. Even suggesting supplementing with it.
https://www.metabolon.com/metabolites/valeric-acid/#:~:text=Valeric%20Acid%20and%20Gastrointestinal%20Health&text=Valeric%20acid%20exerts%20strong%20GI,health%2C%20and%20enhanced%20tissue%20integrity.