Probiotics and prebiotics restore appetite control in mice raised on unhealthy diets

Consuming a diet heavy in fat and sugar during childhood can permanently alter how the brain regulates appetite later in life, even if healthy eating habits are adopted in adulthood. However, supplementing the diet with specific beneficial gut bacteria or dietary fibers can reverse these long-lasting brain changes and restore normal eating habits. These discoveries were recently published in the journal Nature Communications.

The environment a child grows up in heavily influences their physical development. A diet filled with highly processed, sugary, and fatty foods is common in many modern households. Frequent consumption of these energy-dense, nutrient-poor meals can establish unhealthy eating patterns that last well into adulthood.

The digestive system is home to trillions of bacteria and other microscopic organisms, collectively called the gut microbiome. These microbes help digest food, produce vitamins, and send chemical signals to the brain. This biological highway is often called the gut-brain axis.

Through the gut-brain axis, bacteria influence the production of neurotransmitters, which are the chemical messengers of the nervous system. This communication network helps control feelings of hunger, fullness, and even mood. A healthy, diverse microbiome generally sends signals that promote a balanced appetite and stable energy levels.

Prior studies suggest that an unhealthy diet can disrupt this delicate microbial community. When the gut microbiome changes, the chemical messages it sends to the brain also change. Researchers wanted to understand if a poor diet early in life leaves a permanent mark on this communication system.

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They also wanted to see if treating the microbiome could fix any lasting damage to the brain’s appetite control centers. The research team was led by Harriet Schellekens and Cristina Cuesta-Martí. Both scientists conduct research at APC Microbiome, a specialized research institute at University College Cork in Ireland.

To explore these questions, the team fed a group of young mice a diet extremely high in fat and sugar. A separate control group of mice received a standard, balanced diet. The high-fat and high-sugar diet was designed to mimic a modern, highly processed human diet.

After this early developmental period, all the mice were switched to the standard, balanced diet for several weeks. This was done to simulate a transition to healthy eating in adulthood. The researchers then observed the adult mice to see how they interacted with food.

They offered the mice choices between regular food and highly palatable, sweet treats. The adult mice that had eaten the high-fat and high-sugar diet in their youth showed a strong preference for the unhealthy treats. Male mice in particular showed an increased preference for drinking sweetened water compared to plain water, while the results for female mice were not statistically significant.

These adult mice also ate more food overall and displayed a habit of crumbling or playing with their food. This food crumbling behavior is a known sign of altered feeding habits and food reward processing in rodents. These unusual behaviors persisted even though the mice had been eating a healthy diet for weeks and had reached a normal body weight.

“Our findings show that what we eat early in life really matters,” Cuesta-Martí said in a press release. “Early dietary exposure may leave hidden, long-term effects on feeding behavior that are not immediately visible through weight alone.”

The research team then looked inside the brains of the mice, specifically focusing on the hypothalamus. The hypothalamus is a small region near the base of the brain that acts as a control center for appetite and energy balance. It contains specialized cells that detect hormones related to hunger and fullness.

In the mice exposed to the early poor diet, the researchers found a reduced number of these specialized appetite-controlling cells. The brains of these mice literally had fewer receptors available to receive biological signals indicating that the stomach is full. This structural brain change provides a physical explanation for why the mice continued to overeat and crave sugar.

The study also revealed that these effects were distinct between male and female mice. Female mice showed a greater loss of the specific brain cells that respond to fullness hormones like leptin. Male mice showed more disruptions in how their brains sensed bacterial components and processed steroid hormones.

To see if these effects could be prevented or reversed, the scientists introduced two different microbiome-targeted treatments. One group of mice received a prebiotic supplement in their drinking water alongside their early diet. Prebiotics are types of dietary fiber that humans and mice cannot digest, but which serve as food for beneficial gut bacteria.

The specific prebiotics used are naturally found in foods like onions, garlic, and bananas. A second group of mice received a probiotic supplement in their water. Probiotics are live, beneficial bacteria, and the researchers used a specific bacterial strain known as Bifidobacterium longum for this study.

Both the prebiotic fiber and the live probiotic bacteria successfully prevented the long-lasting eating abnormalities. Mice receiving either of these supplements during their early development did not show the same intense cravings for sweets in adulthood. Their brains also maintained normal numbers of appetite-regulating cells in the hypothalamus.

While both treatments worked, they appeared to operate through completely different mechanisms. The prebiotic fibers caused massive shifts in the overall makeup of the gut microbiome, encouraging the growth of many different healthy bacterial families. This widespread bacterial remodeling helped restore normal chemical signaling to the brain.

On the other hand, the live probiotic bacteria did not drastically change the overall composition of the gut microbiome. Instead, this specific bacterial strain seemed to act like a targeted medicine. It directly influenced specific chemical pathways, such as the metabolism of the amino acid tryptophan, to protect the brain from the unhealthy diet.

Schellekens highlighted the practical importance of these discoveries in the press release. “Our findings show that targeting the gut microbiota can mitigate the long-term effects of an unhealthy early-life diet on later feeding behavior,” she said. “Supporting the gut microbiota from birth helps maintain healthier food-related behaviors into later life.”

While these results are promising, it is necessary to recognize the limitations of animal studies. Mice and humans have different metabolic rates, lifespans, and brain structures. A treatment that works in a mouse model does not always translate directly to a human patient.

Despite these differences, animal models remain a necessary tool in biological research. They allow scientists to study brain tissue and genetic expression in ways that are simply not possible in human subjects. Mice share many fundamental biological pathways with humans, making them highly effective for uncovering the basic mechanisms of diet and brain development.

Future research will need to explore exactly when these dietary interventions are most effective. In this study, the mice received the prebiotic and probiotic supplements continuously throughout their lives. Scientists still need to determine if giving these supplements only during adulthood can actively reverse established brain changes.

Alternatively, researchers need to confirm if these treatments must be given early in life to prevent the damage from occurring in the first place. The researchers also plan to investigate other areas of the brain that control the reward and pleasure associated with eating. Understanding the full brain network involved in food cravings will help refine these microbial treatments.

Developing targeted therapies based on gut bacteria could eventually help combat rising global obesity rates. As Cryan noted in the press release, “Studies like this exemplify how fundamental research can lead to potential innovative solutions for major societal challenges.” He added that revealing how early diets shape brain pathways opens new doors for treatments based on gut bacteria.

The study, “Bifidobacterium longum and prebiotic interventions restore early-life high-fat/high-sugar diet-induced alterations in feeding behavior in adult mice,” was authored by Cristina Cuesta-Marti, Eduardo Ponce-España, Friederike Uhlig, Iris Stoltenborg, Luiza A. Wasiewska, Lamiah Kareem, Dara Hedayatpour, Loreto Olavarría-Ramírez, Cristina Rosell-Cardona, Thomaz. F. S. Bastiaanssen, Gabriel. S. S. Tofani, Benjamin Valderrama, Klara Vlckova, Suzanne L. Dickson, Aonghus Lavelle, Catherine Stanton, R. Paul Ross, John F. Cryan, Timothy G. Dinan, Gerard Clarke, Siobhain M. O’Mahony & Harriët Schellekens.