Nail infections are typically caused by fungi, though bacteria can occasionally be involved. These conditions are widespread, affecting an estimated 4-10% of people worldwide, with rates climbing to nearly 50% among adults aged 70 and older.

These infections can create serious complications in vulnerable groups such as older adults and individuals with diabetes. Despite their prevalence, they remain difficult to eliminate.

Why Current Treatments Often Fall Short

Standard therapies include oral antifungal medications taken as pills and topical products placed on the surface of the nail. Oral medications usually take 2-4 months to show results and are generally effective, but they also pose risks for side effects, particularly in patients with other health conditions.

Topical treatments are considered safer, but they often require very long application periods, sometimes lasting years. Even then, they frequently fail to fully clear the infection or the infection returns.

One major obstacle is that most medications struggle to pass through the dense structure of the nail, preventing them from reaching the fungi or bacteria living beneath it. Even the best topical antifungal options achieve relatively low cure rates, underscoring the need for treatments that can reliably reach microbes deep within the nail.

Hydrogen Sulfide Shows Strong Antimicrobial Potential

A research team from the University of Bath and KCL has identified hydrogen sulfide (H2S) as a promising alternative. This small, naturally occurring gas appears capable of penetrating the nail plate far more effectively than existing topical drugs.

Earlier studies already suggested that H2S travels through nail tissue with ease. The new findings show that it also has powerful antimicrobial activity, killing a broad spectrum of pathogens, including fungal species that do not respond well to common antifungal medications.

In controlled laboratory experiments, the researchers used a compound that releases hydrogen sulfide as it breaks down. They found that the gas disrupts microbial energy production and causes irreversible damage to the cells, ultimately destroying the fungi responsible for infection.

The study is detailed in Scientific Reports.

Researchers See Promise for a Future Topical Therapy

Dr. Albert Bolhuis of the University of Bath's Department of Life Sciences said: "Thanks to its ability to efficiently reach the site of infection and its novel mode of action, we believe that a topically applied medicine containing hydrogen sulfide could become a highly effective new treatment for nail infections, which avoids the limitations of current therapies.

"Our research lays the foundation for a compelling alternative to existing treatments, with the potential to improve outcomes for patients suffering from persistent and drug-resistant fungal nail infections."

Hydrogen sulfide does have a strong smell and some level of toxicity. However, researchers emphasize that the concentrations needed for treatment appear to be far below harmful levels, and the right formulation should greatly reduce any unpleasant odor.

Next Steps Toward Patient Use

So far, the research has been conducted only in vitro. Even so, the team hopes to continue development and create a topical treatment suitable for patients within the next five years.

Professor Stuart Jones, Director of the Centre for Pharmaceutical Medicine Research at KCL, said: "We are looking forward to translating these findings into an innovative topical product that can treat nail infection."

Researchers linked these effects to the action of FGF19 in the hypothalamus, a key brain region that receives information from the rest of the body and the environment to coordinate energy metabolism. They found that when FGF19 signals in the hypothalamus, it boosts the activity of thermogenic adipocytes (i.e., fat cells that burn energy to produce heat), which are specialized fat cells that help the body generate heat instead of storing calories.

New Paths for Obesity and Diabetes Treatments

Because of these findings, the scientists believe that FGF19 could inspire new medications for obesity, diabetes, and other metabolic conditions. The idea is to develop compounds that imitate the behavior of natural substances in the body, mimicking the action of endogenous compounds (i.e. those produced by the body itself).

This strategy resembles the way some of the latest diabetes and obesity drugs work. Ozempic, for example, contains semaglutide, an ingredient that activates receptors mimicking the hormone GLP-1. By doing so, it sends satiety signals to the brain and helps patients feel full with less food.

According to the study, FGF19 did more than change appetite or fat storage. The hormone also lowered peripheral inflammation and improved the animals' tolerance to cold. When the researchers blocked the sympathetic nervous system, however, these benefits disappeared. In further experiments, they observed that exposure to cold increased the expression of FGF19 receptors in the hypothalamus. Because the hypothalamus is crucial for maintaining body temperature, these results suggest that FGF19 may help the body adapt by coordinating energy balance and thermoregulation.

FGF19, Thermogenesis, and Brain Control of Energy

"FGF19 had already been linked to a reduction in food intake. Our work broke new ground by showing that it also plays an important role by acting on the hypothalamus and stimulating an increase in energy expenditure in white and brown adipose tissue. In other words, in addition to controlling appetite, it stimulates thermogenesis. So, in terms of therapy associated with obesity, it'd make a lot of sense," explains Professor Helena Cristina de Lima Barbosa, from the Obesity and Comorbidities Research Center (OCRC) at the State University of Campinas (UNICAMP).

The OCRC is a Research, Innovation, and Dissemination Center (RIDC) of FAPESP, which also funded the project through grants to doctoral student Lucas Zangerolamo, the first author of the study, supervised by Barbosa.

The work has been described in detail in an article published in the American Journal of Physiology -- Endocrinology and Metabolism, where it was highlighted as a Top Article in May.

Global Obesity Crisis and Urgent Health Targets

The World Atlas of Obesity 2025 warns that, if current trends continue, global health goals for this year will not be met. These targets include halting the rise in diabetes and obesity and cutting premature deaths from cardiovascular disease, chronic respiratory disease, and cancer by 25%, using 2010 as the reference year.

The Atlas estimates that more than 1 billion people worldwide are currently living with obesity. If effective actions are not put in place, this number could surpass 1.5 billion by 2030. Obesity is already associated with about 1.6 million premature deaths each year from non-communicable diseases.

In Brazil, around 31% of the population has obesity. In addition, between 40% and 50% of adults do not reach the recommended levels of physical activity in terms of frequency or intensity.

Where FGF19 Comes From and How It Works

FGF19, which is involved in the control of energy metabolism, is mainly produced in the small intestine. In the liver, it regulates the production of bile acids and also influences the synthesis of glucose and fats. While its primary roles in the liver have been widely explored in scientific literature, its effects in the brain have received much less attention.

"In the lab, we work with bile acids, which are also the subject of my master's degree, and they regulate the release of FGF-19. Our initial studies led us down this path," Zangerolamo told Agência FAPESP.

At eight weeks of age, the mice used in the study were randomly assigned to two groups. One group received a standard diet (control) and the other was fed a high-fat diet to induce obesity. The researchers then administered FGF19 directly into the brains of the obese animals. All mice were kept in carefully controlled conditions of temperature, lighting, and access to water.

In the article, the scientists report that central FGF19 signaling improved energy homeostasis. It did this by boosting the activity of the sympathetic nervous system and stimulating thermogenesis in adipose tissue, leading the tissue to consume more energy in the form of heat.

"The brain plays an extremely important role in controlling the body's adiposity. At the same time as it receives information from peripheral tissues, it triggers commands. These commands, apparently using the sympathetic nervous system, seem to be an interesting way of thinking about energy expenditure," adds Barbosa.

Digging Deeper Into Brain Cells and FGF19 Receptors

To better understand which brain cells respond to FGF19, the authors compiled and examined public scRNA-seq data from several studies of the hypothalamus. This method makes it possible to sequence RNA from individual cells, revealing which genes are active in each cell type. In total, the team evaluated transcription from more than 50,000 single cells to identify hypothalamic cell populations that express FGF19 receptors.

The researchers note that a key question now is how to encourage the body to produce more FGF19 on its own. They are also working to connect these findings with what is already known about the neural circuits that regulate eating behavior.

"We want to broaden this understanding. We're studying the hypothalamus to evaluate the inflammation commonly observed when a high-fat diet is administered and whether FGF19 plays a role in this area," says Zangerolamo, who did part of the work during an internship at the Joslin Diabetes Center at Harvard Medical School with Professor Yu-Hua Tseng, who is also an author of the article.