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Long-time evolution has shaped a harmonious host-microbiota symbiosis consisting of intestinal microbiota in conjunction with the host immune system. Inflammatory bowel disease (IBD) is a result of the dysbiotic microbial composition together with aberrant mucosal immune responses, while the underlying mechanism is far from clear. In this report, we creatively proposed that when correlating with the host metabolism, functional microbial communities matter more than individual bacteria. Based on this assumption, we performed a systematic analysis to characterize the co-metabolism of host and gut microbiota established on a set of newly diagnosed Crohn’s disease (CD) samples and healthy controls. From the host side, we applied gene set enrichment analysis on host mucosal proteome data to identify those host pathways associated with CD. At the same time, we applied community detection analysis on the metagenomic data of mucosal microbiota to identify those microbial communities, which were assembled for a functional purpose. Then, the correlation analysis between host pathways and microbial communities was conducted. We discovered two microbial communities negatively correlated with IBD enriched host pathways. The dominant genera for these two microbial communities are known as health-benefits and could serve as a reference for designing complex beneficial microorganisms for IBD treatment. The correlated host pathways are all relevant to MHC antigen presentation pathways, which hints toward a possible mechanism of immune-microbiota cross talk underlying IBD.