Sindre Dahl Mediaas ^1,2 Markus Haug ^1,2 Claire Louet ¹ Sissel Gyrid Freim Wahl ^3,4 Alexandre Gidon ¹ Trude Helen Flo ^1,2*

• ¹ Dept Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
• ² Department of Infection, Clinic of Medicine, St. Olavs Hospital, Trondheim, Norway
• ³ Department of Pathology, Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim, Norway
• ⁴ Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway

The incidence and prevalence of infections with non-tuberculous mycobacteria such as Mycobacterium avium (Mav) are increasing. Prolonged drug regimens, inherent antibiotic resistance, and low cure rates underscore the need for improved treatment, which may be achieved by combining standard chemotherapy with drugs targeting the host immune system. Here, we show that the diabetes type 2 drug metformin improved the control of Mav-infection in mice, mainly by strengthening antimicrobial defenses in macrophage. Three weeks of metformin treatment significantly reduced the lung mycobacterial burden in mice infected intranasally with Mav without major changes in the overall lung pathology or immune cell composition. Metformin treatment had no significant impact on tissue inflammation except for a tendency of increased lung IFN and infiltration of Mav-specific IFN-secreting T cells. Metformin did, however, boost the antimicrobial capacity of infected macrophages directly by modulating metabolism/activating AMPK, increasing mitochondrial ROS and phagosome maturation, and indirectly by bolstering type I immunity. Our data thus suggest that metformin has potential as an adjunct treatment of Mav infections.