Researchers Find That a Common Nutrient in Food Is Linked to Depression

Proline, an amino acid abundant in many foods, has been linked to depression through its interaction with gut bacteria and brain chemistry.

The findings reveal that controlling proline levels or its transport to the brain could help prevent or treat depression.

A Surprising Link Between Proline and Depression

Researchers at the Girona Biomedical Research Institute (IDIBGI) and Pompeu Fabra University (UPF) in Barcelona, Spain, have identified a surprising connection between an amino acid and depression in humans, mice, and fruit flies. The compound, called proline, is found in many common foods, including gelatin, grass-fed beef, and wild-caught fish. Their research, published in Cell Metabolism, suggests that diets rich in proline may raise the likelihood of developing depressive symptoms.

Dr. José Manuel Fernández-Real and Dr. Jordi Mayneris-Perxachs from the IDIBGI and CIBEROBN research groups on Nutrition, Eumetabolism, and Health led the investigation, along with Dr. Rafael Maldonado of UPF’s Neuropharmacology-Neurophar research group, which is linked to the Hospital de la Mar Medical Research Institute (IMIM).

Measuring Mood and Metabolism

To explore the relationship between diet and mood, the team examined both the type and amount of amino acids consumed by participants. Each participant also completed a survey to evaluate their level of depression.

“We were surprised that what was most associated with depression, evaluated through this questionnaire, was the consumption of proline,” explains Dr. Fernández-Real, who is also head of Endocrinology at Hospital Dr. Josep Trueta in Girona and director of the Department of Medical Sciences at the University of Girona.

Further analysis of participants’ blood confirmed this association, showing that higher plasma proline levels were among the strongest metabolic indicators linked to depression.

However, not everyone with high proline intake experienced more depressive symptoms. When researchers examined participants’ gut microbiota, they discovered that bacterial composition also played an important role. Depression was associated not only with certain bacteria but also with microbial genes involved in proline metabolism. In other words, an individual’s gut bacteria appeared to influence how much proline circulated in their bloodstream.

“The microbiota of patients with high proline consumption but low plasma levels of proline was similar to the microbiota associated with low levels of depression and was enriched in bacterial genes involved in the transport and metabolism of proline,” notes Dr. Mayneris-Perxachs, a Miguel Servet researcher at IDIBGI.

Transferring Depression Through the Microbiota

To determine whether proline’s presence causes depression or is merely a byproduct, the team transplanted human microbiota into mice. The animals that received microbiota from participants with higher proline levels or greater depressive symptoms showed more depression-like behavior. The researchers also identified differences in the mice’s brain genes linked to proline transport.

“The possibility of transferring the depression phenotype from humans to mice through microbiota transplantation and the demonstration that such transplantation generates alterations in proline transport reveals that this proline may be associated causally with depression” says Dr. Maldonado of UPF.

The team performed additional experiments in fruit flies (Drosophila melanogaster), which can also display depression-like behaviors. They introduced two bacterial strains linked to proline metabolism into the flies’ sterilized food. Those fed Lactobacillus, which was associated with lower depression in mice, showed greater persistence when faced with challenges. Flies that consumed Enterobacter, linked to depression in humans, exhibited more depressive traits.

Finally, researchers tested genetically modified flies that lacked the channels responsible for transporting proline to the brain. In these flies, proline could not reach brain tissue, and they displayed a remarkable resistance to depression-like behavior.

The Importance of Proline in Future Treatments

“These results demonstrate the importance of proline and its influence on people’s depressive mood, which so far had not been taken into account,” highlights Dr. Fernández-Real. The study also opens the way for new studies to find possible diet-based treatments for depression.

Reference: “Microbiota alterations in proline metabolism impact depression” by Jordi Mayneris-Perxachs, Anna Castells-Nobau, María Arnoriaga-Rodríguez, Miquel Martin, Lisset de la Vega-Correa, Cristina Zapata, Aurelijus Burokas, Gerard Blasco, Clàudia Coll, Anira Escrichs, Carles Biarnés, José María Moreno-Navarrete, Josep Puig, Josep Garre-Olmo, Rafel Ramos, Salvador Pedraza, Ramón Brugada, Joan Carles Vilanova, Joaquín Serena, Jordi Gich, Lluís Ramió-Torrentà, Vicente Pérez-Brocal, Andrés Moya, Reinald Pamplona, Joaquim Sol, Mariona Jové, Wifredo Ricart, Manuel Portero-Otin, Gustavo Deco, Rafael Maldonado and José Manuel Fernández-Real, 3 May 2022, Cell Metabolism.
DOI: 10.1016/j.cmet.2022.04.001

This study has also enjoyed the collaboration of researchers from the FISABIO Foundation, the Lleida Biomedical Research Institute (IRBLleida), and the Institute for Integrative Systems Biology (I2SysBio) of the University of Valencia and the CSIC.

A version of this article was originally published in June 2022.

Editor’s Note (October 16, 2025):

This story examines a 2022 study investigating the relationship between proline and depression. The findings, particularly the gut-microbiome-metabolite pathway, have proven influential in shaping subsequent research, though causality in humans has not been established.

Since 2022, the field has advanced considerably. Researchers have employed more sophisticated multi-omics approaches and identified broader connections between the microbiome and mood disorders. However, no clinical guidelines currently recommend modifying proline intake for mental health purposes. These results should be interpreted as a promising research avenue requiring further investigation rather than a definitive conclusion, and individuals should consult healthcare professionals regarding personal medical decisions.

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