Understanding the interoceptive pathway controlling dietary protein intake during recovery from catabolic states.

• Applicant: Dr. Nikolai Pirmin Jaschke, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Nutritional Sciences
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570662403

The definition of a healthy diet across populations and physiological states remains a matter of debate. Although nutritional support has long been assumed to promote restoration of health in individuals recovering from injury or critical illness, recent clinical trials have shown that excessive exposure to certain nutrients can be harmful to such patients. Why ingestion of certain nutrients can be dangerous in some, but not other settings, and whether mechanisms exist that would otherwise prevent such harmful exposure to occur, remains unknown. This proposal seeks to systematically dissect the mechanistic basis of an interoceptive pathway controlling protein appetite during recovery from catabolic states. The applicant’s data show that mice recovering from catabolic states, which accompany most acute illnesses, tightly defend their upper limit of protein consumption. This remarkably potent control of protein intake does not require canonical modes of appetite regulation. Instead, three amino acids (AA) with increased ammonia generating properties were identified, which are necessary and sufficient for protein aversion during recovery. A pathway was discovered, in which the wasabi receptor TRPA1 is required for sensing of ammoniagenesis and appetite restriction in response to protein ingestion. Activation of TRPA1 by these cues is transduced to a subset of neurons in the brainstem. Yet, it remains unclear which TRPA1-expressing cell type relays these effects, where ammoniagenesis occurs anatomically, how sensing of ammonia is relayed to the brain, which neurons integrate these signals, why ammonia handling is impaired during recovery and whether voluntary protein restriction also occurs in recovering humans. The goals of this project are thus to 1.) identify the anatomical location and cellular substrate of TRPA1 sensing of dietary ammoniagenesis, 2.) delineate the molecular identity and function of protein and ammonia-responsive neurons controlling protein ingestion and 3.) decipher the unique physiology of ammonia generation and handling in the recovering mice and 4.) explore whether volunatry restriction of protein intake is conserved between rodents and humans. The applicant’s hypothesis suggests that enterochromaffin cells of the gut sense AA-derived ammonia in TRAP1-dependent manner, which triggers serotonin release. These peripheral events are transduced to brainstem neurons via a neuronal pathway, which restricts further AA ingestion when ammonia levels have already reached a critical threshold. This unique mechanism of appetite control synchronizes dietary AA intake with the host’s ammonia detoxifiction capacity, which becomes saturated during recovery states. Together, these studies will delineate a novel, potentially druggable gut-to-brain pathway controlling appetite and also provide foundational insights into recovery physiology for the rational clinical design of recovery diets.

• DFG Programme: Emmy Noether Independent Research Groups
• Major Instrumentation: Climatic chambers