Direct suppression of host gluconeogenesis by Trypanosoma brucei

The cause of hypoglycaemia in African trypanosomiasis remains unresolved. We found that infected mice show normal carbohydrate digestion, intestinal glucose absorption, and tissue glucose uptake, but a profound reduction of host glucose production via gluconeogenesis. Liver transcriptomics uncovered coordinated repression of gluconeogenic pathways alongside inflammatory activation. Infection of Rag2⁻/⁻ mice showed that adaptive immunity contributes only minimally to suppression of host gluconeogenesis. In contrast, therapeutic parasite clearance completely restored host glycaemia and gluconeogenesis despite persistent immune activation. These results demonstrate that live parasites directly repress gluconeogenesis in vivo. Using a co-culture assay, we showed that T. brucei is sufficient to directly repress gluconeogenic gene expression in primary hepatocytes in vitro. Finally, we found that providing glycerol in drinking water to infected animals stimulated gluconeogenesis, elevated glycaemia, and improved survival without impacting parasitaemia. This study reveals a previously unrecognised pathogenic strategy in which a eukaryotic parasite directly suppresses host gluconeogenesis.