![]() ![]() ![]() To identify robust gene profiles, we used large sample sizes (27 mice per group, see Supplementary Fig. To exclude effects of particular mutations or of unique background genes, we included mice carrying two different mutations preventing B cell development (μMT: carrying a deletion in the transmembrane domain of the IgM heavy chain and JhKO: carrying a deletion in the J segment of the immunoglobulin heavy chain locus on two different strain backgrounds (B10.A and BALB/c). We started studying their role in intestinal homeostasis by examining gene expression in the jejunum of B cell–deficient (BcKO) mice. Gene expression in the gut of B cell–deficient miceī cells are among the most prominent populations of immune cells in the small intestine’s lamina propria, presumably because of their role in protection from pathogens. This is also the first example, to our knowledge, of a trialogue (in mice and humans) in which the adaptive immune system, the intestine and the microbiota govern a homeostatic metabolic function. However, if the immune system is dysfunctional, the epithelium takes on some of the missing immune functions at the expense of its metabolic activity. When the immune system functions optimally, the intestinal epithelium can concentrate on its metabolic functions. These data support our previous suggestion that tissues take an active role in their own defense 16, 17. The molecular features of the malabsorption found in the B cell–deficient mice were also present in IgA-deficient mice, humans with common variable immunodeficiency (CVID) and humans with HIV infection. This created a defect in fat absorption resulting in decreased body fat and leptin levels. In the presence of the microbiota, the intestinal epithelium in these mice launched its own defense mechanisms, activating innate immune genes at the expense of metabolic ones primarily regulated by the transcription factor Gata4. To begin deciphering the immune system’s effect on the homeostatic functions of the gut epithelium, we studied global gene expression in the jejunum of B cell–deficient mice. Normally, immune protection in the gut results from a partnership between the immune system (supplying B cells, T cells and innate immune cells) and the epithelium (supplying antimicrobial peptides and a mucosal layer that hinders bacterial invasion 2, 15). A defect in adaptive immunity indirectly influences the balance between metabolic and immune functions of the gut epithelium via a three-way conversation between the two host systems and the intestinal microbiota. Here we show that a trialogue does indeed exist. It has been proposed that trialogues may also govern gut metabolism 14, but there has been no direct evidence for this idea. Between the commensals and the intestinal epithelium, some dialogues induce the epithelium to produce specific fucosylated glycans 11, 12, whereas others increase energy harvest from food 13. Conversely, hosts that lack T and B cells, that make only IgM antibodies or that have defective innate immune sensors show changes in intestinal microbiota 8– 10 that sometimes lead to metabolic abnormalities and obesity 8. The microbiota, for example, are essential for the emergence of T cell subsets and the differentiation of gut B cells into IgA-producing plasma cells 1– 7. These components have several bidirectional interactions. The mammalian gut is a complex ecosystem with three main interacting components: the intestinal epithelium with its neuronal connections, the gut-associated immune tissue and the commensal microbiota. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV that also have intestinal malabsorption were very similar to those of the B cell–deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. ![]()
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