Increased production of an anti-inflammatory molecule called interleukin (IL)-10, and suppression of a subtype of immune T-cells, may mean that a fatty acid called pentanoate is effective against inflammatory and autoimmune diseases such as multiple sclerosis (MS), according to new research in mice.
The study, “The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes,” was published in the journal Nature Communications.
Short-chain fatty acids (SCFAs) — fatty acids with less than six carbon atoms — are the major nutrients produced by bacterial fermentation in the gut. They have been shown to induce the differentiation of a subtype of immune cells called regulatory T-cells, and improve the gut’s barrier function, which may protect from inflammation and ease autoimmunity.
Work in mice suggested that food containing SCFAs may effectively treat severe immunological defects. However, they also may carry adverse side effects, such as tissue-specific inflammation and bacterial colonization of the gut epithelium (the gut’s surface layer) by Escherichia coli.
Now, a team from Germany, the U.S., and Israel evaluated whether the SCFA pentanoate may be a viable therapy for autoimmune and inflammatory diseases. For this purpose, the investigators used the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, along with a range of molecular biology and imaging techniques.
Results first showed that, similar to SCFAs acetate, propionate, and butyrate, pentanoate was present in the gut of wild-type (normal) mice, but not of germ-free animals — a model to study the effects of gut microbes on gastrointestinal health.
The team observed that pentanoate blocked the proliferation of T helper (Th) 17 lymphocytes — key cells in tissue inflammation and destruction — and their production of IL-17A, a molecule implicated in chronic inflammation. This was associated with increased expression of the Il10 gene, which codes for IL-10, and suppression of most of Th17-associated genes.
In mice, pentanoate eased EAE severity, and reduced the number of immune T-cells expressing the cell surface markers CD4 and CD8 in the central nervous system (CNS) — brain and spinal cord. Pentanoate also lowered the levels of cells containing IL-17A and interferon (IFN)-gamma, an immune molecule implicated in MS.
In the CNS of germ-free mice, pentanoate eased inflammation induced by bacteria, and reduced the number and frequency of Th17 cells. Pentanoate also blocked the generation of gut Th17 cells in these mice.
Researchers then showed that pentanoate effectively inhibited the activity of enzymes called histone deacetylases (HDACs), a mechanism used by other SCFAs to induce epigenetic changes — referring to changers in gene expression, rather than in the gene itself — in immune cells.
The effects of pentanoate were explored in the presence of 2-DG, which blocks the breakdown of glucose, to evaluate whether metabolic changes might regulate the balance between pro- and anti-inflammatory molecules. This led to a complete blockade of pentanoate-induced production of IL-10.
When analyzing molecular mechanisms, investigators found that pentanoate activated the mTOR pathway, which regulates the growth, survival, and proliferation of immune T- and B-cells. Pentanoate also increased the levels of ATP — the molecular “currency” of energy — and further boosted IL-10 production in the presence of glucose in Th17 cells.
These results indicated that glucose breakdown controls the increased levels of IL-10, the team noted. Also, the findings showed that pentanoate is converted into acetyl-CoA, a key molecule in cellular metabolism and energy production.
In regulatory B-cells (Bregs) of the spleen, pentanoate also increased the production of IL-10. The fatty acid decreased the expression of genes related to cell death and, in contrast, increased the expression of those implicated in cell survival. Treatment with pentanoate also boosted glucose breakdown and activated the mTOR pathway.
Mice transferred with Bregs after treatment with pentanoate showed prevention of weight loss, lessened disease-related immune changes, and lower numbers of CD4-containing T-cells in the gut and in lymph nodes. These mice also revealed no symptoms of autoimmune disease due to the lack of infiltrating, disease-related lymphocytes in the CNS.
The team showed that blockers of the mTOR pathway markedly reduced the benefits of pentanoate in EAE.
“Taken together, by enhancing IL-10 production and suppressing Th17 cells, the SCFA pentanoate might be of therapeutic relevance for inflammatory and autoimmune diseases,” the researchers wrote.
According to the team, pentanoate may become a low-cost and well-tolerated therapy in patients with MS and other Th17-mediated autoimmune disorders.