Linking the microbiota and metabolic disease with lymphotoxin

Abstract

The field of lymphotoxin biology has seen many advances in the past decade. Notably, a role for lymphotoxin as a key effector cytokine has emerged to add to its foundational contribution to lymphoid organogenesis. It is now clear that lymphotoxin contributes to host defense for a wide variety of pathogens, and the lymphotoxin receptor is a defining feature of and regulatory mechanism in both innate and adaptive immunities. Specifically, lymphotoxin contributes to Th education, licensing of IL-22 production from type 3 innate lymphoid cells, and even maintains innate myeloid populations within the fully developed lymph node. Most recently, lymphotoxin has been implicated in regulation of the microbiota and metabolic disease. Early studies revealed that lymphotoxin might influence composition of the commensal microbiota through its regulation of immunological compartmentalization in the gut. Additionally, several epidemiological studies have linked polymorphisms in lymphotoxin to metabolic disease. Studies exploring the role of lymphotoxin in metabolic disease have demonstrated that lymphotoxin may influence metabolism both directly in the liver and indirectly through regulation of gut immune responses. It now appears that lymphotoxin may bridge the gap between altered composition of the commensal microbiota and metabolism.

Keywords: SFB; diabetes; lymphotoxin; metabolism; microbiota; obesity.

Fig. 1.

Gut immunity coordinates diet-induced changes in the microbiota for host growth. (A) Host growth relies on the sum of interactions between diet, immunity and commensal composition. HFD is able to alter microbial community composition independently of the lymphotoxin pathway to some effect (i.e. expansion of Firmicute phyla). This may occur through different bacteria’s individual capacity to utilize the new nutrient source. However, lymphotoxin-dependent regulation of the IL-23 and IL-22 axis appears to facilitate species reduction (i.e. SFB) through the expression of anti-microbial peptides, for example RegIIIγ. Both HFD and immunity are therefore able to change to the commensal microbiota and thus influence weight gain. The lymphotoxin-signaling pathway may be agonized by dietary components, microbial products or even changes in epithelial cells that can agonize the IL-23/IL-22 axis. Cells that produce IL-22 (i.e. type 3 ILCs, T_h22 cells) do not express LTβR but can express membrane-bound lymphotoxin that agonizes IL-23 from local myeloid or stromal populations that may initiate their own IL-22 production. (B) Gaps in the current model for how immunity can coordinate changes to the microbiota and influence host health. Although LTβR is emerging as a paradigm for these interactions, more knowledge is needed about how a range of human diets directly affects both the microbiome and mucosal immunity; how immunity directly affects the microbiome and vice versa; and how interactions between the diet and immunity combine to affect the microbiome and thus affect host health. It is not clear whether LTβR signaling directly influences composition of the microbiome or if instead the lymphotoxin pathway is required to maintain an appropriate immune microenvironment for the effector function of innate lymphoid cells, epithelial cells or even T_h17 cells. Additionally, many factors will influence the outcome of any given model system including composition of diet and starting microbial community composition.