Abstract

Long-term fasting has become a promising research subject for its potential of treating and preventing metabolic diseases. However, little is known about its impact on the functional capacity of the gut microbiome and the combined effect on the serum metabolome. Here, we demonstrate extensive remodelling of the gut microbial ecosystem in humans (n=92) after an average of 9.8 days of fasting (~250 kcal / day). Fasting transiently affected the relative abundance of the majority of bacterial species (306 decreased and 210 increased out of 772). Species changes could largely be explained by their genomic repertoire of carbohydrate-active enzymes (CAZymes), which were investigated here for the first time. Fasting induced extensive abundance changes in CAZyme families, depleting families with dietary fibre substrates and increasing families with host-derived glycan substrates. Likewise, we observed extensive changes in the serum metabolome, with 382 out of 721 metabolites significantly affected (246 increased and 136 decreased). In-depth metagenome-metabolome co-variation analysis suggested Oscillibacter species to be key producers of indole-3-propionic acid, a crucial metabolite for cardiometabolic health. Together, our results provide an unprecedented view on the impact of long-term fasting on gut microbiome composition and function.