Early life gut microbiome crucial for immune system development

Antibiotics are powerful treatments that have saved countless lives over the course of decades. New findings from Scripps Research have identified a way to preserve healthy immune development even when infants need antibiotic treatment.

The study, published in the Journal of Experimental Medicine on December 16, 2025, uncovers how gut bacteria help develop and train key immune cells during a specific window of infancy. Known as mucosal-associated invariant T (MAIT) cells, they reside in barrier tissues-such as the lungs, skin and gut-where the body frequently encounters germs. Critically, the researchers found that administering a specific probiotic during antibiotic treatment could preserve healthy MAIT cell development.

"Physiological development is a dynamic process, and events that happen during this early phase can have long-term effects on how the immune system is wired," says Michael Constantinides, associate professor at Scripps Research and senior author of the study.

Our work shows there's a specific window in early life when the gut microbiome is laying the foundation for certain immune defenses-understanding this opens the door to therapies that support optimal immune development."

Michael Constantinides, Associate Professor, Scripps Research

The immune system is a complex network made up of different cells that surveil the body for disease-causing pathogens. This intricate system begins to develop during gestation and continues to mature until about eight years of age. Among its components are MAIT cells, which act as dynamic first responders-capable of recognizing and fighting a broad spectrum of harmful pathogens.

MAIT cells are unusual because they don't recognize specific germs the way most immune cells do. While a typical immune cell might specialize in detecting one kind of pathogen, MAIT cells take a broader approach: they identify a chemical byproduct that many different bacteria and fungi produce when they make riboflavin (an essential nutrient also known as vitamin B2). When a germ producing this byproduct enters the body, other cells display it on their surface like a warning flag. MAIT cells spot this flag and respond by releasing proteins that kill the invader or call in reinforcements from other parts of the immune system. This is what makes MAIT cells such effective first responders: rather than waiting for the immune system to build a tailored response to a specific threat, they can recognize a wide range of dangers-from pneumonia-causing bacteria to common fungal infections-all through the riboflavin signal.

However, MAIT cells need exposure to this riboflavin byproduct during infancy to develop properly. Beneficial gut bacteria that colonize an infant's intestines during weaning naturally produce it-essentially providing the "training signal" that tells MAIT cells to mature. The researchers found that these riboflavin-producing bacteria are especially abundant during a brief developmental window, and that this timing coincides with a critical stage of MAIT cell development.

"MAIT cells are like a multi-pathogen surveillance system-they can recognize many different threats using a single conserved pathway," says Gabrielle LeBlanc, a graduate student in the Skaggs Graduate School of Chemical and Biological Sciences and co-first author of the study. "The challenge is that these cells develop early after birth, right when infants are most likely to need antibiotics."

To understand what happens when this process is interrupted, the team tested common antibiotics and found that several-including ampicillin, vancomycin and metronidazole-reduced the population of healthy gut bacteria. When antibiotics were given during the critical developmental window, MAIT cell numbers dropped significantly, and this reduction persisted into adulthood. Mice with fewer MAIT cells were more vulnerable to pneumonia, while animals that naturally lacked them showed no additional effect from antibiotic treatment-confirming that MAIT cells were the key factor in determining long-term health outcomes.

Crucially, the researchers also found a potential solution. By giving a riboflavin-producing probiotic-a bacterium called Bacteroides thetaiotaomicron that's naturally found in the human gut-alongside antibiotic treatment, the team could restore normal MAIT cell development and maintain healthy immune function.

"This research highlights how important the microbiome is in helping us develop as healthy human beings," says Adam Sobel, a former member of the Constantinides lab and co-first author of the paper. "We hope these findings will help motivate better strategies, like targeted probiotics, to support infants who need antibiotic treatment."

LeBlanc noted that the same healthy gut bacteria found in mice are also plentiful in human infants during the first year of life, suggesting a similar developmental window likely exists in humans. Future research could explore whether probiotic therapies could help protect immune development in human infants receiving necessary antibiotic treatment, potentially reducing the risk of respiratory infections later in life.