Methods of diagnosing Clostridium difficile infection and compounds used in the methods are provided. The diagnostic methods are specific and sensitive methods for detecting a host cell response and, in some aspects, a target response, i.e. a Clostridium difficile toxin, in an individual infected with Clostridium difficile. The methods comprise detecting in a stool specimen or fluid exposed to the stool specimen a Clostridium difficile toxin, or a fragment thereof, and an increase in a colonic epithelial cell protein exemplified by a non-muscle tropomyosin. Also provided are kits comprising reagents for detecting host cell proteins and Clostridium difficile toxins.