Although the human genome adapts on slow time scales, there is mounting evidence that industrialized lifestyles have rapidly changed the human gut microbiome (1, 2). Conceptions of health-diminishing biological incompatibility (“mismatch”) arising from the disruption of human-microbe relationships negotiated over evolutionary time have led to proposals that the altered microbiota contributes to high rates of noncommunicable disease (3–6) and related calls to restore aspects of the ancestral gut microbiota through “rewilding” (4). However, appropriate applications of rewilding remain uncertain because the idea does not easily reconcile with present evidence or predictions rooted in evolutionary theory. In particular, high microbial plasticity may underpin an industrialized gut microbiota that is reasonably well adapted to the industrialized environment, even if it is then less well matched with the host. Complex tripartite human-microbiota-environment interactions present an unsolved puzzle for human health: When is it better for the gut microbiota to track versus resist environmental change?

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