Extended Data Fig. 10: Illustration of the major findings from the current study in the context of what has previously been observed in the relevant field.

Recent evidence indicates that parenteral/systemic exposure to vaccine or microbe may lead to centrally induced innate immune memory and trained immunity (TII) via imprinting the myeloid progenitors in the bone marrow and subsequent releasing into the blood stream of trained monocytes. On the other hand, respiratory mucosal exposure to vaccine or microbe may induce mucosal tissue-resident memory macrophages and TII in the lung. There is also evidence that respiratory infection may cause gut microbiota dysbiosis. However, it has remained unclear whether parenteral vaccination could lead to gut dysbiosis and altered gut barrier function and metabolome, thus going on to induce mucosal-tissue resident memory macrophages and TII in a distal mucosal organ, the lung. Indeed, our current study finds that following s.c. BCG vaccination, initially BCG bacilli spread to the gut-associated tissues and lead to a time-dependent remarkable changes in gut microbiota and barrier permeability, and metabolomic changes not only in the gut but also in the serum and lung tissue. Thus, such a widespread immunological alert across a number of tissue sites threaded through a microbial metabolomic pathway ultimately results in a time-dependent induction of trained tissue-resident macrophages and innate immunity in the lung.