Pathogens Are Picky Eaters and Their Choices Impact Our Health

Growing up in Santiago, Chile, Sebastián Riquelme, daydreamed of playing in a progressive rock band or on a professional soccer team. But those fantasies would eventually give way to a third passion: biology.

“I was particularly taken with the discoveries of Watson and Crick and how the structure of molecules is so critical to life,” he remembers.

With no other scientists in his middle-class family, he didn’t grasp what kind of career his passion could lead to. But at this stage, it didn’t matter. “I just wanted to learn everything about biological processes in the cell,” he says. Riquelme enrolled at the Pontifical Catholic University of Valparaiso to study biochemistry and later continued to graduate school at Pontifical Catholic University of Chile to study immunology, finishing his PhD at INSERM (France’s renowned biomedical research institute).

During graduate school, he became especially intrigued with an emerging idea that metabolic processes not only energize our cells and our microbial pathogens, but also shape the immune response—a growing field now known as immunometabolism.

Immunometabolism and pneumonia

After completing his PhD, Riquelme landed a postdoctoral fellowship in Columbia’s Department of Pediatrics in 2015, working in the lab of Alice Prince, MD, who studies how bacteria cause pneumonia.

Pneumonia is an abrupt inflammatory response aimed at eradicating pulmonary pathogens. However, certain sophisticated bugs exploit this inflammatory milieu to thrive. The mechanism of how this process occurs remains poorly understood, but during his postdoc, Riquelme built a compelling case that immunometabolic alterations play a major role in the persistence of pathogens during pneumonia, especially in the lungs of people with cystic fibrosis.

In one study, he discovered how the much-feared bacterium Pseudomonas aeruginosa colonizes the lungs by feasting on succinate, a byproduct of metabolism of inflammatory cells that are abundant in the lungs of people with cystic fibrosis. Another of his studies showed how Pseudomonas can dodge an antibacterial substance in the lungs by using it as food to fuel its own growth. “By identifying the mechanisms by which these organisms adapt and exploit our defenses,” Riquelme says, “we may be able to target these very adaptations to combat infectious agents.”

Calming superbugs with ketones

When Riquelme started his own lab at Columbia in 2021, he expanded his studies at the intersection of immunology and metabolism to explore why some superbug infections are benign, with a goal of finding ways to tamp down infections in patients. His most recent paper shows how lung cells reach a healthy détente with Pseudomonas. When this bacterium invades the lungs, it often triggers a brisk inflammatory reaction, sometimes to the host’s own detriment. However, in some cases, the lungs restrain the immune reaction and the superbug calms down.

“It’s as if the bacteria are saying, ‘since you aren’t attacking me, I won’t attack you,’” Riquelme says. “It’s an evolutionary conserved defense strategy called disease tolerance, but it’s not well understood how this happens in the context of pulmonary disease.”

In studies of mice, Riquelme found that the truce is brokered by a surprising mediator: the liver. In response to pulmonary infection, the liver generates energy-rich ketone bodies that travel to the lungs. Once they arrive, the ketone bodies reshape the surface architecture of Pseudomonas, selecting for less virulent strains that enable airway cells to produce energy in mitochondria. This favorable environment limits inflammation, establishing a host-pathogen tradeoff that makes both happy.

The findings suggest that patients infected with Pseudomonas could benefit by eating a ketogenic diet (which is high in fats and low in carbohydrates), at least temporarily.

“We know that ketogenesis is good because it can suppress inflammation,” Riquelme says. “But you have to be careful because excess ketones can lead to ketonemia, harmful concentration of ketone bodies in blood, among other complications.” The controlled utilization of ketogenic diets has already showed promising results in other inflammatory pathologies, including cancer where it limits the growth of tumors that feed off carbohydrates.

The language of metabolism

Riquelme’s growing research portfolio now includes an NIH grant to study how metabolites called nucleotides (best known as the building blocks of DNA and RNA) may modulate inflammation in lung infections. “Although the immunoregulatory role of nucleotides is well appreciated in cancer and autoimmune diseases, it’s not clear how they contribute to pneumonia and other inflammatory pathologies in the lung,” Riquelme says. “In this project, we hope to understand how the host’s nucleotide metabolism regulates opportunistic superbugs like Pseudomonas and Staphylococcus, which should reveal ways we can prevent or clear these dangerous infections.”

Thanks to the work of Riquelme and others, immunometabolism is gaining traction in the larger medical community. “When the field started, research was limited to studies at the cellular level,” he says. “Now, we’re also looking at immunometabolism in the whole body, showing how the host changes its metabolic program to fight infection and how pathogens change in response.

"Hosts and pathogens talk the same language, and that language is metabolism.”