How gut microbes and hormones shape your sweet tooth

Researchers discover a gut-microbe-driven pathway involving pantothenate and GLP-1 that could revolutionize sugar consumption management and metabolic health strategies.

Study: Free fatty acid receptor 4 modulates dietary sugar preference via the gut microbiota. Image Credit: ya_create / Shutterstock

In a recent study published in the journal Nature Microbiology, researchers in China investigated the role of the free fatty acid receptor 4 (Ffar4) in regulating dietary sugar preference. The research uncovered a link between intestinal Ffar4 expression, gut microbiota, and sugar consumption behavior. The findings also suggested potential strategies to manage sugar intake and related metabolic disorders by exploring gut-derived metabolites.

Background

Excessive sugar consumption has been found to contribute significantly to global health challenges, including obesity and type 2 diabetes. Studies indicate that a preference for sugar-rich foods arises from complex interactions between flavor perception and physiological signaling. The gut microbiota is also known to influence host metabolism and dietary behaviors through metabolite production, indicating that the gut–brain axis and liver-to-brain hormonal signaling are critical pathways in regulating nutritional preferences.

Research shows that alterations in gut microbial composition are associated with changes in nutrient absorption and food intake. Free fatty acid receptors, particularly Ffar4, are implicated in dietary preference regulation due to their role in responding to dietary fats. However, the mechanisms linking Ffar4 to sugar preference remain poorly understood. Identifying these mechanisms is crucial for developing interventions to address sugar over-consumption and related metabolic disorders.

About the Study

The present study investigated the relationship between intestinal Ffar4, the gut microbiome, and a preference for dietary sugar through a series of integrated approaches in human and mouse models. The researchers first analyzed intestinal and systemic Ffar4 expression in diabetic patients and multiple diabetic mouse models to establish correlations between Ffar4 levels and sugar preference. Three distinct diabetic mouse models, including one with autoimmune diabetes (NOD−/−), were used to ensure robustness.

They then generated systemic knockout mice and tissue-specific knockout murine models, including intestinal epithelial cell-specific knockouts, to determine the functional role of Ffar4. Conversely, overexpression models were also created using intestine-specific transgenic approaches.

Additionally, behavioral assays, including two-bottle choice tests, were conducted to assess preferences for natural sugars such as sucrose, glucose, dextrin, and artificial sweeteners, enabling the researchers to distinguish between metabolic and sensory regulation of sugar preference.

The researchers used 16S ribosomal ribonucleic acid (rRNA) sequencing for the gut microbiome analysis to identify changes in microbial composition linked to intestinal Ffar4 expression. The study focused on Bacteroides vulgatus, a key gut bacterium, and utilized both fecal microbiota transplantation (FMT) and co-housing experiments to confirm its role in modulating sugar preference.

High-throughput metabolomic profiling was performed to identify the differential metabolites produced by B. vulgatus. Moreover, pantothenate, a metabolite strongly correlated with sugar preference, was further studied using supplementation experiments. Its effects on gut hormone secretion, particularly glucagon-like peptide 1 (GLP-1), were also assessed in vivo and in vitro using enteroendocrine cell lines.

Finally, the study evaluated the downstream effects of GLP-1 on the production of hepatic fibroblast growth factor 21 (FGF21), a major regulator of Ffar4. Recombinant protein and gene knockout models for FGF21 were also used to verify its role in regulating sugar preference.

Key Findings

The researchers observed that reduced Ffar4 expression in diabetic patients and mouse models correlated with an increased preference for dietary sugar. This relationship was further validated in systemic and intestinal-specific Ffar4 knockout mice, which displayed heightened sugar preference. Conversely, mice with intestinal overexpression of Ffar4 exhibited reduced sugar preference, which confirmed the receptor’s regulatory role.

Furthermore, the gut microbiome analysis showed significant changes in bacterial composition associated with intestinal Ffar4 expression. In particular, the abundance of B. vulgatus was reduced in Ffar4-deficient mice but elevated in those with overexpression. The FMT and co-housing experiments demonstrated that restoring B. vulgatus in knockout mice reduced sugar preference.

Pantothenate, identified through metabolomic profiling as a key metabolite of B. vulgatus, emerged as a mediator in sugar preference regulation. The researchers found that supplementing pantothenate reduced sugar preference and fasting blood glucose levels in both Ffar4 knockout and diabetic mice. Further studies revealed that pantothenate promotes the secretion of GLP-1, a gut hormone known to influence feeding behavior.

Additionally, increased GLP-1 levels stimulated hepatic production of FGF21, a hormone critical for reducing sugar preference and improving glucose regulation. GLP-1 administration also reduced sugar preference in Ffar4-deficient mice, while FGF21 knockout mice exhibited a loss of sugar preference modulation. Furthermore, recombinant FGF21 reversed the effects of Ffar4 deletion on sugar preference.

These findings established a mechanistic pathway involving Ffar4, B. vulgatus, pantothenate, GLP-1, and FGF21, which collectively regulate dietary sugar preference. This pathway also highlights the interplay between gut microbiota and host metabolism, offering potential therapeutic targets for managing sugar consumption and related metabolic disorders.

Conclusions

Overall, the study demonstrated that intestinal Ffar4 expression regulates dietary sugar preference by modulating gut microbiota and metabolites. The metabolite pantothenate derived from the gut microbe B. vulgatus was found to be a key mediator of the process, influencing GLP-1 and FGF21 secretion to reduce sugar consumption.

These findings provided new insights into the metabolic control of dietary behavior and suggested potential therapeutic targets for managing sugar-related metabolic disorders.