Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in the gut microbial metagenome and the host genome, but they could not adequately represent the protein-level variants. Single amino-acid polymorphisms (SAP) derived from nonsynonymous SNPs can cause functional changes of proteins and are important forces of adaption. However, SAP remains quite unexplored for the human gut microbiome. Here, we present a comprehensive large-scale analysis of SAP in the gut ecosystem, introducing a rigorous computational pipeline for detecting such protein variation from 992 published human metaproteomes. We find varied yet elaborate SAP patterns, capturing both known and novel functions and adaptive strategies of gut microbes. Microbial SAP is enriched in the outermost shell, motility devices, and ribosomes. Generally, gut microbial SAP is more convergent in metabolic subpathway regions and is enriched in the initial steps of carbohydrate metabolism pathways that catalyze the formation and isomerization of phosphorylated sugars. Furthermore, microbial and host mutant peptide patterns were altered and exhibited significant correlations in both inflammatory bowel disease and type 1 diabetes. Our results highlight the functional and clinically relevant implications and potential host-microbial interactions of gut ecosystem SAP.