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Assessing microbial identity, diversity, and community structure could be a valuable tool for monitoring the impact of xenobiotics and anthropogenic inputs in rivers, especially in urban and industrial settings. Here, we characterize the Nile River microbial community in water and sediments in summer and winter at five locations that span its natural flow through the Cairo metropolis. 16S rRNA gene datasets were analyzed to identify the role played by sample type (sediment versus water), season, and location in shaping the community, as well as to predict functional potential of the Nile River microbiome. Microbial communities were mostly influenced by sampling type (sediments versus water), while seasonal effects were only observed in water samples. Spatial differences did not represent a significant factor in shaping the community in either summer or winter seasons. Proteobacteria was the most abundant phylum in both water and sediment samples, with the order Betaproteobacteriales being the abundant one. Chloroflexi and Bacteroidetes were also prevalent in sediment samples, while Cyanobacteria and Actinobacteria were abundant in water samples. The linear discriminative analysis effect size (LEfSe) identified the cyanobacterial genus Cyanobium PCC-6307 as the main variable between summer and winter water. Sequences representing human and animal potential pathogens, as well as toxin-producing Cyanobacteria, were identified in low abundance within the Nile microbiome. Functionally predicted metabolic pathways predicted the presence of antibiotic biosynthesis, as well as aerobic xenobiotic degradation pathways in the river microbiome. [ABSTRACT FROM AUTHOR]