Reconciling host-microbiota metabolic incompatibility safeguards male fertility

The symbiotic relationship between the host and microbiota is widely acknowledged as mutually beneficial. However, due to significant differences in metabolic substrates and products between prokaryotic bacteria and mammalian cells, mechanisms must exist to reconcile the metabolic incompatibility between the host and microbiota. We report that host enzymes are required to detoxify gut microbiota-derived acetate to maintain male fertility in mice. The combined deletion of acetyl-CoA synthetase short-chain family member 1 and 2 (ACSS1 and ACSS2), two enzymes consuming acetate in mammals, leads to excessive accumulation of acetate in circulation. This accumulation causes metabolic acidosis, blocking spermatogenesis and rendering male mice infertile. ACSS1/2-deficient germ cells exhibit comprehensive metabolic alterations with nicotinamide adenine dinucleotide (NAD⁺) deficiency that impairs betaine production. Supplementation with betaine restores spermatogenesis and fertility in ACSS1/2-deficient mice. Thus, the inevitable production of acetate by gut bacteria and its reproductive toxicity to the host represents an unappreciated metabolic incompatibility between the host and microbiota, which is reconciled by ACSS1/2.