Promoting butyrate in the gut may prevent diabetes, study shows
Healthier metabolism seen in FA mice given butyrate supplement in food
Supplementation with butyrate, a short-chain fatty acid produced in the gut by good bacteria, reversed many diabetes-like metabolic defects found in fat tissue from a mouse model of Friedreich’s ataxia, a study reported.
In addition to its effects on metabolism, butyrate lowered signs of ongoing inflammation observed in FA fat tissue.
“Our work emphasizes the role of [fat tissue] in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management,” the researchers wrote in the study, “Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich’s ataxia mouse model,” published in the journal iScience.
Potential add-on Friedreich’s ataxia treatment seen in dietary supplement
FA is caused by mutations in the FXN gene, which carries instructions for making a protein called frataxin. This protein is important for the proper functioning of mitochondria, the structures within cells that supply them with energy. A lack of frataxin in people with FA results in impaired cell function, particularly those of the nervous system and muscles.
Beyond hallmark disease motor symptoms, FA patients can develop diabetes, when sugar levels in the body are very high. Accumulation of visceral white adipose tissue (vWAT), the energy-storing fat tissue around the abdomen, alongside chronic and low-grade inflammation that increases the risk of diabetes, also has been noted in FA patients.
Using an FA mouse model, scientists in Italy investigated vWAT and its role in FA-related metabolic complications. This model has reduced frataxin levels, subtle behavioral symptoms, evident diabetes-like metabolic defects, and starts to gain weight at 8 months of age.
“This model provides valuable insights that can guide the development of therapeutic approaches targeting metabolic dysfunction in FA,” the team wrote.
Genetic tests of visceral white adipose tissue in these mice found 97 genes with different activity, or differentially expressed, compared with healthy mice. Functional analysis found these altered genes were associated with inflammation, the growth of blood vessels (angiogenesis), and scar tissue formation (fibrosis).
Cells isolated and cultured from the adipose tissue in FA mice showed increased levels of lactate, which is typical of type 2 diabetes conditions. Other diabetes-like traits included larger-than-normal fat cells, called adipocytes, and the presence of elevated numbers of immune cells.
Consistent with the increased inflammatory processes within vWAT, genes that encode pro-inflammatory signaling proteins showed increased activity, while anti-inflammatory immune protein genes had lower activity.
Bacteria producing butyrate largely absent in gut of FA mouse model
Because vWAT and microbes in the digestive tract interact to maintain a balanced metabolism, the team examined fecal samples from FA mice. They discovered a near complete absence of bacteria that produce butyrate — a short-chain fatty acid mainly generated by the breakdown of dietary fiber. It is known to have anti-inflammatory and neuroprotective effects.
“We show that our FA mouse model has an altered gut microbiota composition compared to healthy mice, with a reduction in the abundance of butyrate-producing bacteria,” the scientists wrote.
Based on these findings, researchers supplemented FA mice with sodium butyrate by adding it to food pellets starting at 4 months of age until they were 8 months old, when metabolic symptoms arise.
Butyrate supplementation restored certain butyrate-producing bacteria in fecal samples from both FA and healthy mice, and lowered the blood levels of triglycerides, a type of fat. Treatment also restrained glucose intolerance, a sign of diabetes, with a significant return to normal glucose levels within two hours after glucose dosing.
Notably, butyrate reduced the size of adipocytes in the visceral white adipose tissue of FA mice, comparable to those of healthy mice. Markers of fat accumulation and lower blood vessel growth also were restored to healthy values after butyrate treatment.
At the same time, butyrate dampened pro-inflammatory genes, reset the production on an anti-inflammatory molecule, and prevented the influx of immune cells into vWAT.
Lastly, butyrate shifted cellular metabolism from glycolysis, an alternative energy production pathway that generates lactate, to mitochondrial energy metabolism. Consistently, lactate production of FA mice eased following butyrate treatment.
“Our results suggest that vWAT is dysfunctional and microbiota altered in FA,” the researchers wrote. “Butyrate supplementation prevents vWAT expansion and inflammation as well as the development of [type 2 diabetes]-like features in FA animals.”
Further studies are needed, they added, as “the identification of the molecular mechanisms underlying the butyrate-mediated beneficial effects will hopefully pave the way for its safe usage as an adjuvant for treating [type 2 diabetes]-related symptoms in FA.”
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