Short-chain fatty acids

Get short-chain fatty acids the ordinary way, by eating plenty of varied plant fibre. The only trial of the acids themselves was in Parkinson's disease and did not test aging; there is no evidence that supplementing them helps healthy aging.

What they are and what they do in the gut

When commensal bacteria in the colon ferment dietary fibre they produce short-chain fatty acids, chiefly acetate, propionate and butyrate. Butyrate is the main fuel of the cells lining the colon. In germ-free mice, which have no gut bacteria to make it, colon cells fall short on energy, and adding butyrate rescues them.^[1] In cultured human intestinal cells, butyrate also helps assemble the tight-junction proteins that seal the gut wall.^[2] The case that losing butyrate makes the gut leak, and what that does with age, is on leaky gut.

Older guts often have fewer of the makers

The changes reported most often in older guts include a relative loss of Faecalibacterium and the Lachnospiraceae family, both major producers of short-chain fatty acids. A systematic review of 27 human studies found the specific changes varied from study to study, and every study was a snapshot rather than people followed over time.^[3]

Centenarians don't settle it. A very small Italian study found centenarians' microbes carried fewer genes for making short-chain fatty acids.^[4] A larger cross-sectional study of 19 Sardinian centenarians found the opposite on this point: a high capacity for central metabolism, especially glycolysis and fermentation to short-chain fatty acids.^[5]

The brain: where "more" may backfire, so far in mice

In a healthy state, short-chain fatty acids and other bacterial products that reach the brain are thought to help keep its resident immune cells in check. But three mouse studies point the other way, all in germ-free or genetically engineered animals:

• In germ-free mice engineered to overproduce tau and to carry the human ApoE4 risk variant, adding short-chain fatty acids to drinking water increased brain inflammation and the tangle-forming form of tau in older animals.^[6]
• In a separate mouse model that builds amyloid plaques, supplementation raised plaque load in germ-free mice to the level of normally colonised mice, and raised it further still in normally colonised ones.^[7]
• In germ-free mice that overproduce alpha-synuclein, the protein that clumps in Parkinson's disease, feeding these bacterial products promoted brain inflammation and worsened movement problems.^[8]

People with Parkinson's disease look different. Pooled across 9 studies of 485 patients and 338 healthy controls, patients' stool held less acetate, propionate and butyrate, while blood levels of propionate, butyrate and isobutyrate ran modestly higher.^[9] In one study of 95 patients and 33 controls, lower stool levels went with more severe disease, and so did higher blood levels, which the authors read as a leakier gut wall letting the acids through rather than the gut making too much.^[10] The one trial so far gave 72 people with Parkinson's a prebiotic, short-chain fatty acids or both for 6 months; the prebiotic alone or combined with the acids eased constipation, but the trial had no placebo group and did not test effects on the disease itself.^[11]

So the warning that more short-chain fatty acid can do harm comes from germ-free and genetically engineered mice. In people with Parkinson's, the evidence so far points to too little made in the gut plus a leaky barrier, not too much.

Muscle: associations in people, mechanism in mice

In 88 Taiwanese adults over 65, those with low muscle mass had less butyrate in their stool, and the amount tracked with their muscle mass.^[12] In 823 Japanese adults aged 60 and over who started with normal grip strength and were followed for about eight years, those who ate more short-chain fatty acids were less likely to develop weak grip: about 23% lower odds for every extra 268 milligrams a day.^[13] Both are observational. The step from there to muscle growth is so far mouse work: a short-chain fatty acid mix given to fast-ageing mice with muscle loss increased muscle mass and grip strength by switching on the mTOR growth pathway.^[14]

The body clock

Short-chain fatty acids are among the bacterial products, with secondary bile acids and indoles, that feed back to set the clock genes in the liver and gut lining, part of a two-way loop between the microbiome and the body clock.^[15]

What to do

1. Eat varied plant fibre. It is the fuel the producing bacteria need, and it is the only route on this page with no warning attached.
2. Don't buy short-chain fatty acid or butyrate supplements for aging. The only trial of the acids themselves described here was in Parkinson's, for constipation, and the mouse data raise a question mark over "more is better".
3. For the whole picture of the aging gut, see Dysbiosis; for fibre itself, see fibre.

Further reading

• Donohoe DR, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 2011.^[16]
• Seo DO, et al. ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science 2023.^[17]
• Colombo AV, et al. Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition. Elife 2021.^[18]
• An K, et al. Associations of diet-derived short chain fatty acids with Parkinson's disease: a systematic review and meta-analysis. Nutr Neurosci 2026.^[19]
• Yang X, et al. Parkinson's Disease Is Associated with Impaired Gut-Blood Barrier for Short-Chain Fatty Acids. Mov Disord 2022.^[20]
• Otsuka R, et al. Association between short-chain fatty acid intake and development of muscle strength loss among community-dwelling older Japanese adults. Exp Gerontol 2023.^[21]