Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut

Abstract

Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. 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. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. 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.

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

“…Secretory immunoglobulin A binds to luminal bacteria and prevents microbial translocation across the epithelial barrier (Macpherson et al, 2005). It also plays a role in influencing the balance of immune and metabolic pathways in the intestinal epithelium through a microbiotadependent mechanism (Shulzhenko et al, 2011). In the absence of IgA, a shift towards the expression of genes involved in host defense emerges, with excessive production of antimicrobial proteins and pro-inflammatory responses to compensate for the deficiency in microbial compartmentalization via the sIgA.…”

Investigating a holobiont: Microbiota perturbations and transkingdom networks

“…2A). 25 This result demonstrated the essential role of microbiota in BcKO phenotype. However, the antibiotics cocktail protocol that has successfully mimicked germfree mice in other studies did not revert host alterations in the intestine of B cell deficient mice (Fig.…”

“…1 Indeed, we have faced the common problem that there is evidence of a microbiota effect on a host phenotype, but it was unclear which microbe was responsible. Building on our previous experience with gene networks, 25,48,50 we developed a new approach that models host-microbiota interaction that we called transkingdom network. 1,49 To build this model, microbial gene abundances and mouse transcriptome data were integrated into one network.…”

“…24 Furthermore, it has been shown that the gut microbiota can mediate molecular cross-talk between host immune and metabolic functions. 25,26 Additionally, derivation of specific genetically modified mouse models under germ free conditions has been used to investigate gene-specific interactions between host and microbiota. 27 Although gnotobiotic technologies for germfree animals have existed since the 1950s, 28 our ability to derive and work with germ-free mice is still a limiting factor for investigation.…”

“…2) as their phenotype was IgA-dependent. 25 An additional, non-mutually exclusive, explanation is that microbiota members insensitive to antibiotics (such as viruses) are responsible for alterations in intestines of B cell deficient mice. Indeed, this hypothesis is supported by other studies demonstrating outgrowth of diverse viruses in immunodeficient animals.…”