Indigenous populations crashed hard after European contact, mostly from diseases to which they had no immunity, but also to outright predation by Europeans- especially the Spanish. Cahokia had long been abandoned before the Spaniards arrived, but De Soto (among others) recorded interactions with what are now understood to have been Mississippian Cultures across what is now the US southeast. Several successor Mississippian cultures survived to encounter the Spanish- and were then depopulated by disease, causing further societal collapse. The main Mississippian culture (which Cahokia was part of ) probably was done in by the Little Ice Age and environmental/climate disruptions afterward. IIRC, the Mississippian Cultures collapsed from a combination of environmental and European factors.
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