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Advances in high-throughput technologies in the past decade have helped delineate the important role of gut microbiota on human health. Changes in gut microbiota composition have consistently been observed in various health conditions, including colorectal cancer (CRC). Studies show that the microbiota fills in a variety of niche metabolic pathways that the host does not possess. For example, the microbiota produces butyrate, which provides the colon’s epithelial cells with about 70% of their energy needs. The typically fast proliferation of tumor cells in CRC patients drastically alters the tumor’s nutrient microenvironment. Those alterations correspond to changes in the microbiota composition and function. Yet, it is not entirely clear how the gut microbiota interacts with the host cells. In the present dissertation, we took a systems biology approach to map various interactions between the microbiota and the host. We presented comprehensive interaction networks between the tissue-associated microbiota, gene expression, metabolites, and immune cell infiltration.First, we performed an integrated analysis between the mucosa-associated microbiota and the mucosa metabolome in healthy, nonhuman primates to investigate the metabolic interactions between the microbiota with its host. We found the microbiota composition was distinct at each tissue location, with variation by host individual also observed. Additionally, the microbiota-metabolome dynamics were primarily driven by interactions in the distal colon. More importantly, we found that the interaction network in the large intestines is sparse compared to the network in the small intestines. We postulate that the sparse interaction is due to a specialized role of microbiota in the large intestines and may explain the associations between altered microbiota and CRC. We then investigated the interaction between the microbiota and host in CRC tissues. Previous studies have shown that microRNAs (miRNAs) regulate gene expression and have important roles in cancer development and overall metabolism. In addition, recent studies suggested that host miRNAs can also regulate bacterial growth and influence the composition of the gut microbiome. Here, we investigated the link between the gut microbiota and the expression of miRNA in CRC. We found that dozens of miRNAs are differentially regulated in CRC tumors and adjacent normal colonic tissues and that these miRNAs are correlated with the abundance of microbes in the tumor microenvironment. Moreover, we found that microbes that have been previously associated with CRC were correlated with miRNAs that regulate genes related to interactions with microbes. Notably, these miRNAs likely regulate glycan production, which is important for the recruitment of pathogenic microbial taxa to the tumor. This work characterized a global relationship between microbial community composition and miRNA expression in human CRC tissues. Finally, we investigated a network interaction between the microbiota, metabolites, and immune cell infiltrations in CRC tissues. We first found metabolic pathways related to essential amino acids enriched in the tumors. Further investigations through network analysis suggest that metabolites potentially mediated the interactions between the microbiota and the host, including the immune cells. Overall, using a multi-omics and systems biology approach, we provide comprehensive interaction networks of host-microbiota interactions. The network suggests a shortlist of interactions that contribute to a better understanding of the complex relationship and informs additional hypotheses for future validations and developing strategies for modulating microbiota in the intestines to improve host health.