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Supplements that raised colonic levels of the short-chain fatty acid (SCFA) propionate improved insulin sensitivity in non-diabetic overweight people, reported British researchers.

As shown in their small randomized crossover trial, published online in , boosting the SCFA propionate had distinct positive effects on the gut microbiota, plasma metabolome, and systemic inflammatory responses.

"Strategies that promote colonic propionate production may represent a more targeted route to improve glucose homeostasis in individual patients, depending on the underlying mechanisms contributing to the metabolic disorder," wrote Edward S. Chambers, PhD, of Imperial College London, and colleagues.

With the increasing global obesity burden, manipulating gut microbiota-generated SCFAs to protect against energy-dense diets offers a potential avenue for regulating and cardiovascular disease risk. Improved whole-body insulin sensitivity after increased dietary fiber intake has been linked to increased colonic production of the -- acetate, propionate, and butyrate, which are end products of dietary fiber fermentation by the gut bacteria.

"Research has shown that SCFAs produced by the gut microbiota can improve insulin sensitivity," Chambers told 麻豆传媒. "The present work demonstrates that raising the production of one of these SCFAs, propionate, has a distinct impact on the physiological processes that contribute to metabolic health."

In previous research, long-term colonic propionate delivery reduced levels of , a recognized contributor to β-cell dysfunction and peripheral .

The next step, Chambers said, is to determine whether the other major SCFAs, acetate and butyrate, provoke this selective metabolic response. "In the future, this could help with the design of treatments that promote a specific SCFA profile in the gut to target the mechanisms that are contributing to a patient's metabolic disorder," he said.

Study Details

The randomized double-bind trial recruited 12 healthy but overweight volunteers with a mean age of 60 (range of 49-65) and a mean body-mass index of 29.8 (range of 26.2-37.0). Of these, nine were female and 11 were white. All were randomly assigned to receive 20 g daily for 42 days of the following supplements in crossover fashion:

• Inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon

• Inulin, a high-fermentability fiber control

• Cellulose, a low-fermentability fiber control

Metabolic responses, inflammatory markers, and gut bacterial composition were analyzed at the end of each 42-day supplementation period, and there was a washout period of at least 28 days between different supplementations.

Both IPE and inulin supplementation similarly improved indices of insulin resistance compared with cellulose supplementation, although the authors had originally hypothesized that IPE would be superior to inulin in promoting glucose homeostasis, they noted. As measured by glucose homeostatic model assessment, the mean (± standard error of the mean) values were as follows:

• 1.17±0.15 for inulin vs 1.59±0.17 for cellulose (P=0.009)

• 1.23±0.17 for IPE vs 1.59±0.17 for cellulose (P=0.001)

• No difference between IPE and inulin (P=0.272)

According to the Matsuda Insulin Sensitivity Index, the mean values were:

• 4.0±0.7 for inulin vs 3.2±0.5 for cellulose (P=0.014)

• 4.0±0.6 for IPE vs 3.2±0.6 for cellulose (P=0.002)

In addition, IPE supplementation decreased proinflammatory interleukin (IL)-8 levels compared with cellulose, while inulin had no impact on systemic inflammatory markers. In vitro, peripheral blood mononuclear cells isolated from healthy humans secrete were found to lessen IL-8 in media containing sodium propionate compared with both sodium acetate and sodium chloride.

The researchers said that interestingly, despite the positive effects on metabolic markers, both IPE and inulin supplementation decreased the diversity of bacterial species compared with cellulose: "This outcome appears counterintuitive given the commonly accepted association in humans between a lower gut and poor health." the authors wrote.

Fasting insulin level following each supplementation period was associated with different plasma metabolome profiles. A positive association between plasma N-acetyl glycoproteins and fasting insulin was observed after cellulose supplementation but not after inulin or IPE supplementation. These glycoproteins have previously been linked to increased .

Two amino acids were associated with fasting insulin levels only after inulin supplementation: tyrosine (positively) and glycine (negatively). Higher tyrosine is associated with increased and type 2 diabetes risk, while glycine correlates to reduced risk of these, Chambers and co-authors explained. "Our data therefore indicate that the observed improvement in insulin sensitivity following inulin supplementation was related to a favourable modulation of amino acid metabolism."

As for the impact on fecal bacterial populations, compared with cellulose, inulin produced changes both at the class level, increasing Actinobacteria, to which health-promoting Bifidobacterium belongs, while decreasing pathogen-associated Clostridia, and at the order level, decreasing Clostridiales. Small differences between IPE and cellulose emerged at the species level, the researchers reported.

They said the findings suggest that manipulating the colonic fermentation profile of a dietary fiber in favor of propionate promotes selective effects on mechanisms, contributing to metabolic dysregulation. "It would be of interest to establish the individual effects of delivering acetate and butyrate to the colon as, in the future, this would support the development of fermentable carbohydrate that delivers a specific SCFA profile to improve metabolic health and glucose homeostasis," the team wrote.

"This small study does not demonstrate a mechanism of action, but it's a step in the right direction," Thomas Schmidt, PhD, of the University of Michigan in Ann Arbor, told 麻豆传媒.

"It's consistent with other studies showing that if you provide fuel for the gut microbiome, it often has a beneficial effect," added Schmidt, who was not involved with the current research.

Although the authors did not address study limitations, the small study sample and its focus only on the SCFA propionate were obvious constraints.

麻豆传媒 previously reported on research by the Imperial College group showing that IPE was associated with less weight gain than dietary inulin.

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