A model of functional dysbiosis in the human gut microbiome during initiation and progression of complex disease. Although many current studies focus on microbial composition shifts that occur subsequent to disease establishment, it is critical to differentiate functional from structural changes in the microbiome and their distinct patterns in early versus late disease. (a) An illustration of microbial community structural changes during complex disease progression. Ordinations such as principle coordinate analysis and multidimensional scaling are commonly used to qualitatively visualize microbial community structure among multiple samples (for example, cases and controls). Ordinations project distance measures such as beta diversity among samples into fewer dimensions in such a way that the patterns of greatest change occur on the primary axes (here, x and y). However, particularly in early disease, case/control status is frequently not among the factors with most influence on inter-subject microbial variation. Conversely, later-stage inflammation can have a very large effect on microbial structure, causing other sources of variation to become visually less apparent. (b) Functional profiles of gut microbial communities remain more stable among individuals in health than do microbial profiles, and they can likewise show more concerted differential responses in early and late disease stages. In this illustration, 'case' subject samples exhibit expansion of specific metagenomically encoded functions in their microbial communities during progressive phases of inflammation, as reported in . (c) Representative host histology in different phases of the inflammatory response in Crohn's colitis. Colonic crypts (ring structures) are gradually destroyed by immune infiltration as colitis progresses. Images show transverse sections of human colonic mucosa stained with hematoxylin and eosin; 100 µm scale bars are included for reference (images provided by WSG). CDAC, Clostridium difficile-associated diarrhea; PC, principal coordinate.