A gut microbe for curbing sugar cravings

Whether in a spoonful of yogurt or a refreshing sip of soda at lunch, sugar’s sweetness is a universal pleasure. But when these cravings go unchecked, they can result in excessive sugar intake, raising the risk of metabolic conditions like diabetes (1).

In a new study published in Nature Microbiology, researchers revealed that sugar cravings are driven in part by the gut microbiota — a vast community of microbes that live within the gastrointestinal tract (2). The study, coauthored by Yong Chen, a molecular biologist at Jiangnan University, found that one gut microbial species produces specific metabolites that trigger the release of hormones that act on the brain to reduce sugar intake. Understanding the role of these microbes could help researchers develop new therapies for metabolic diabetes.

“We often think of microbes as really competitive, and they are to some degree,” said Jeremy Burton, a microbiologist at the University of Western Ontario, who was not involved in the study. However, as Burton explained, microbes in the gut also work together to send signals to the brain that influence mood and behavior. This connection, known as the gut-brain axis, is crucial in regulating appetite and food intake. With this in mind, Chen and his team sought to investigate how gut microbes might influence humans’ preferences for sugary foods.

Molecular biologist Yong Chen studies how the gut microbiome influences sugar cravings.

Credit: Yong Chen, PhD, Jiangnan University

The researchers began by investigating the expression of the free fatty acid receptor 4 (Ffar4) in the blood of people with and without type 2 diabetes. Ffar4 is a receptor for long-chain fatty acids, which are produced during digestion. The receptor’s activation triggers the release of glucagon-like peptide 1 (GLP-1), a hormone that increases circulating insulin and whose synthetic analogs, such as semaglutide (branded as Ozempic and Wegovy), are commonly used to treat obesity and diabetes (3).

Chen and his team observed that Ffar4 expression was significantly lower in diabetic patients. When they examined its expression in mice, the results were consistent: Diabetic mice had lower Ffar4 levels compared to healthy mice. The researchers also found that mice with reduced Ffar4 expression showed a stronger preference for sugar — a link that was also observed in humans, as the presence of Ffar4 mutations correlated with higher sugar intake in human populations.

Knowing that gut microbes influence food preferences through communication with the brain, Chen and his team hypothesized that these microbes might play a role in Ffar4-mediated sugar preference. To test this, they evaluated a range of different gut bacteria to see if their abundance was linked to changes in Ffar4 expression. They observed that the gut microbe Bacteroides vulgatus was most strongly linked to Ffar4 expression, with the bacteria being more abundant in mice overexpressing Ffar4 and less so in mice with reduced Ffar4 levels.

The researchers then analyzed the metabolites released by B. vulgatus in an in vitro culture. They identified 11 compounds of interest, with pantothenate — the precursor molecule to vitamin B5 — standing out as the most abundantly expressed.

This finding piqued Chen’s interest. Previous research from his lab had already established pantothenate as a key regulator of Ffar4 expression (4). When the researchers administered pantothenate to diabetic mice, they found that the metabolite reduced the mice's preference for sugar and increased GLP-1 levels in the gut.

Chen knew from previous studies that GLP-1 activation stimulates the production of the liver hormone fibroblast growth factor 21 (FGF21), which acts directly on the hypothalamus to regulate sugar intake behavior (5). When the researchers administered pantothenate to mice lacking FGF21, they observed that the metabolite did not affect sugar preference in these mice. This suggested that FGF21 acted downstream of GLP-1 and was the key hormone responsible for controlling sugar preference.

Piecing this together, Chen proposed that the gut-brain axis may be part of a broader gut-liver-brain axis that regulates human sugar preferences. This connection could provide “a ‘gut feeling’ of sweetness which adds to the conventional sweet taste sensing by the tongue,” Chen wrote in an email.

He hopes that these findings could help shape future diabetes treatments. “Ffar4 could be a target by using an agonist, the gut could be another [by] using B. vulgatus as a probiotic, and finally, pantothenate can be used for systemic treatment," wrote Chen.

[I hope that] B. vulgatus and pantothenate modulation of sugar cravings is evaluated in large multi-center clinical trials, and can eventually be used for diabetes management.
– Yong Chen, Jiangnan University

Burton echoed these hopes, adding that Ffar4 could serve as a biomarker for the health of the gut microbiome. He sees both benefits and drawbacks to translating the findings into a viable treatment for diabetes. “The pitfalls of delivering Bacteroides vulgatus is that it’s a highly anaerobic bacteria,” he said. “People aren’t set up to commercially produce it and deliver it. It’s a new microbe that would really need to go through safety testing and all that sort of thing.”

Burton also pointed to potential difficulties in using pantothenate as a treatment, noting that it might require delayed-release technology to ensure it reaches the colon, where it could have the desired outcome on diabetes management.

Despite these challenges, Chen remains optimistic for the future development of B. vulgatus and pantothenate. “[I hope that] B. vulgatus and pantothenate modulation of sugar cravings is evaluated in large multi-center clinical trials, and can eventually be used for diabetes management,” he wrote.

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