Heterogeneity across the murine small and large intestine

Abstract

The small and large intestine of the gastrointestinal tract (GIT) have evolved to have discrete functions with distinct anatomies and immune cell composition. The importance of these differences is underlined when considering that different pathogens have uniquely adapted to live in each region of the gut. Furthermore, different regions of the GIT are also associated with differences in susceptibility to diseases such as cancer and chronic inflammation. The large and small intestine, given their anatomical and functional differences, should be seen as two separate immunological sites. However, this distinction is often ignored with findings from one area of the GIT being inappropriately extrapolated to the other. Focussing largely on the murine small and large intestine, this review addresses the literature relating to the immunology and biology of the two sites, drawing comparisons between them and clarifying similarities and differences. We also highlight the gaps in our understanding and where further research is needed.

Keywords: Epithelial; Immune; Large intestine; Microbial; Small intestine.

Figure 1

Schematic representation of the structural and cellular heterogeneity within the small and large intestine during homeostatic conditions. The small (A and C) and large (B and D) intestine differ greatly in their structure and cellular composition. The small intestinal epithelium is folded to create crypts of Lieberkühn, has finger-like projections called villi and epithelial cell possess striated microvilli (A) whereas the large intestine (B) has crypts and lacks villi. The small intestine has Peyer’s patches, the main site of Microfold or “M” cells that transcytose luminal particulate antigens that are rare in the larger intestine. Both the small and large intestine are covered by mucus, which is much thicker in the large intestine (B) than in the small intestine (A). The large intestine houses the largest and most diverse microbial populations of the two sites (B). Anti-microbial peptides are also differentially expressed along the gastrointestinal tract. The distribution of immune cells also differ in the small and large intestine (inset C and D) with Natural killer T cells, Intraepithelial lymphocytes (IEL), eosinophils and dendritic cells found in the highest numbers in the small intestinal epithelium under steady state conditions. Cell populations are defined in the key.

Figure 2

Schematic representation of the distribution of dendritic cell and macrophage subset in the small and large intestine under homeostatic conditions and upon inflammation. In homeostasis dendritic cells (DCs) and macrophages are found in close contact with the epithelium in the small intestine (A) whereas in the large intestine they are rare and in the LP (B) and are recruited in response to inflammatory stimuli. Within the small intestine lymphoid resident DC (CD11c^high, MHCII^high CD64^-) can be grouped into CD8α⁺, CD11b⁺ and CD8α^-CD11b^- DCs, which are located in Peyer’s patches. In the lamina propria (LP) of the small intestine CD11b⁺CD8α^- DCs predominate. CD8α^-CD11b^- DCs have been identified in regions of the large intestine, including the ILFs, but CD11b^-CD8α⁺ DCs are rarely found during homeostasis. Plasmacytoid B220⁺ CD11c^intermediate DC are present in very low numbers in the LP of the small intestine and ILFs of the large intestine. In the small intestine CX3CR1⁺ cells can produce transepithelial dendrites that extend through the epithelium to directly sample luminal contents. This has not been demonstrated in the large intestine during homeostasis. In addition to CX3CR1, macrophages can be further defined by expression of CD11b, F4/80 and CD64. Upon inflammation, Gr1⁺ monocyte-derived inflammatory DCs accumulate in both the small and large intestine.