Neonatal necrotizing enterocolitis (NEC) is a life-threatening gut condition in premature infants, but current treatments manage symptoms rather than causes. Now, researchers have found that boosting the gut metabolite indoleacrylic acid (IA)—either directly or through the probiotic Bifidobacterium longum subsp. infantis—help protect the gut and prevent NEC.

The findings, published in Cell Reports Medicine, suggest that Bifidobacterium longum subsp. infantis and its metabolite IA could be promising therapies for NEC.

In NEC, a key driver of damage is necroptosis—a form of cell death that worsens inflammation. Previous studies showed that specific microbial compounds help protect the gut, but it’s unclear whether, and how, these metabolites control necroptosis.

So, researchers led by Xiaoliang Dong at Jiangnan University in Wuxi, China, analyzed microbial metabolites in stool samples from infants and rodents with NEC.

Reducing necroptosis

The team found that the levels of a microbial compound called indoleacrylic acid (IA) was much lower than normal in infants and rodents with NEC. When IA was given as a supplement to rodents, it improved survival, reduced gut damage, and prevented weight loss. 

Further experiments showed that IA protects the gut by blocking necroptosis. In both animals and cultured gut cells, IA reduced the activation of proteins involved in necroptosis, keeping the gut barrier intact and lowering inflammation.

IA appears to counter necroptosis by activating a receptor in intestinal cells, which in turn boosts a protein that binds to and inhibits the STAT1 signaling pathway. This signaling pathway is typically overactive in intestinal cells during necroptosis. 

Metabolite-based interventions 

The researchers also found that the probiotic Bifidobacterium longum subsp. Infantis, which produces IA, can help protect premature infants from NEC. This microbe increased IA in the guts of mice and reduced NEC severity, preventing necroptosis.

The probiotic B. longum is particularly suited for preterm infants because it produces IA without needing certain milk sugars. Overall, the results suggest that IA is a key microbial metabolite for maintaining gut health, the researchers say.

Although human studies are still needed to confirm the safety and effectiveness of B. longum and IA, they add,  “these findings […] provide a mechanistic foundation for developing metabolite-based interventions against NEC and related intestinal inflammatory disorders.”