Abstract
<jats:p>Microbes often generate by-products that inhibit own or consortial growth. Such imposing constraints can be alleviated by symbiotic partnerships where the partner consumes the limiting factor resulting in mutually beneficial cooperation. Theories of mitochondrial origin envisage such metabolic syntrophy of partners as the initial interaction, often coupled with mechanistic membrane gymnastics to trap the alphaproteobacterial symbiont to ensure vertical inheritance and as a prerequisite or vestibule of endosymbiosis. Yet we do not know how this happened. Here, using a mathematical model, we investigate how such metabolic self-inhibition enables and facilitates the evolution of compact physical integration between syntrophic partners. We show that when one species produces a metabolite that is self-inhibitory, selection favors increasingly tight spatial association of a detoxifying partner to mitigate local accumulation of the self-limiting product. Under a broad parameter range, this process drives the emergence of surface-associated configurations promoting morphological adaptations such as membrane protrusions or invaginations that increase inter-partner contact area. Our results prove that such costly host membrane contortions can evolve as a means to improve benefits of inhibition reduction by protective syntrophic ectosymbionts. Additionally, a unilateral syntrophic interaction between parties is sufficient for the transition; a mutualistic (or bilateral) one is not necessary. Our model establishes a direct evolutionary link between metabolic coupling and physical integration, suggesting that the need to alleviate (self-generated) inhibition can be a primary driver of ectosymbiotic attachment and its transition toward more intimate associations. Our findings provide a general theoretical framework for understanding how microbial consortia evolve structural complexity from initially loose metabolic interactions, with implications for the origins of stable symbioses and the early steps toward cellular integration.</jats:p>