Abstract: Shrimp Litopenaeus vannamei is the most widely cultured species globally in terms of scale, production, and economic value. However, its aquaculture is plagued by frequent outbreak of diseases, and the subsequent rapid and massive mortality. Given that etiological study lags behind newly emerged diseases, the causal agents of some shrimp diseases are unknown and are named based on typical symptoms, especially co- and polymicrobial pathogens. Comprehensive information on the status of shrimp diseases remains elusive. Thus, we briefly summarize the knowledge on shrimp diseases, and their effect on the gut microbiome. Integrating the features of primary colonizers, ‘drivers’ taxa in the gut networks from healthy to diseased shrimp, disease-discriminatory taxa, and encoding virulence genes, we advocate a workflow to identify potential polymicrobial pathogens. We review abiotic and biotic factors (e.g., external and internal sources, specific-disease effect) governing the shrimp gut microbiota, with emphases on the ‘holobiome’ concept and common features of gut microbiota in response to diverse diseases. After ruling out the effects of confounded factors, we construct a diagnosis model for quantitatively predicting shrimp disease incidence by using disease common-discriminatory taxa, irrespective causal agents. Owing to the conservation of functional gene for designing specific primers, a practical strategy is proposed, which applies qPCR-assayed abundances of disease common-discriminatory functional genes. This review provides updated roles of the gut microbiota in exploring shrimp etiology, polymicrobial pathogens, and disease incidence.