Dietary Habits and Intestinal Immunity: From Food Intake to CD4+ T H Cells

Abstract

Dietary habits have a profound impact on intestinal homeostasis and in general on human health. In Western countries, high intake of calories derived from fried products, butter and processed meat is favored over dietary regimens rich in fruits and vegetables. This type of diet is usually referred to as Western-type diet (WTD) and it has been associated with several metabolic and chronic inflammatory conditions of the gastrointestinal tract. In this review, we describe how WTD promotes intestinal and extra-intestinal inflammation and alters mucosal immunity acting on CD4⁺ T cells in a microbiota-dependent or -independent fashion, ultimately leading to higher susceptibility to infectious and autoimmune diseases. Moreover, summarizing recent findings, we propose how dietary supplementation with fiber and vitamins could be used as a tool to modulate CD4⁺ T cell phenotype and function, ameliorating inflammation and restoring mucosal homeostasis.

Keywords: CD4 T cells; fat; fiber; inflammation; microbiota; mucosal immunity; salt; western diet.

Figure 1

Impact of dietary habits on local and systemic homeostasis and immunity. Graphical abstract summarizing the main findings that this review will discuss. Western-type diets, rich in fat, cholesterol, sugar, and salt are reported to drive intestinal and extra-intestinal inflammation by causing microbial dysbiosis and alteration of the balance of pro- and anti-inflammatory T cells in the intestine, ultimately dampening intestinal immunity and affecting intestinal homeostasis. In contrast, diets enriched in fiber, indoles and vitamins implement beneficial effects on intestinal homeostasis by increasing microbial variety and inducing a regulatory environment.

Figure 2

Lipids, cholesterol and salt shape the intestinal CD4⁺ T cell phenotype in a microbiota-dependent or independent-manner. (A) High intake of lipids induces dysbiosis, shifting the composition of the intestinal microbiota toward a higher ratio of Proteobacteria and Firmicutes to Bacteroidetes. This can lead to higher susceptibility to pathobiont infections, e.g. from invasive E. coli or Bilophila wadsworthia (BW). The mucus layers of both small intestine and colon get thinned, leading to higher gut permeability, which in turn favors the invasion of Gram-negative bacteria, and exacerbates intestinal inflammation. Furthermore, diets rich in saturated fatty acids increase the levels of pro-inflammatory cytokines, such as IL-1β, IL-6, TNF-α, within the gastrointestinal (GI) tract, contributing to the inflammatory state. (B) Diets rich in cholesterol alter the composition of bile acids and increase the levels of IL-1β in the small intestine, creating an inflammatory environment, which can lead to higher susceptibility to infections with BW, a pathogen known to require bile acids to outgrow. Cholesterol metabolites can also modulate intestinal inflammation inhibiting or promoting T_H17 cell development through interaction with LXR or RORγt, respectively. (C) Within the WTD-driven intestinal inflammation, salt can alter the phenotype of CD4⁺ T_H17 and T_reg cells either directly or indirectly, worsening mucosal homeostasis. Via triggering of serum glucocorticoid kinase-1 (SGK1), salt drives the expression of IL-23R on T_H17 cells, inducing their pathogenicity, and it promotes IFN-γ secretion from T_reg cells, attenuating their suppressive capacities. Furthermore, high intake of salt can increase the frequencies of pathogenic T_H17 cells reducing the amount of Lactobacillus spp. within the GI tract.

Figure 3

Fiber, indoles and vitamins act in a synergistic fashion promoting intestinal homeostasis. (A) Diets rich in fiber promote bacterial species diversity and short chain fatty acid (SCFA)-producing bacteria, which in turn limit pathogen growth, e.g. Clostridium difficile, and promote barrier integrity. SCFAs also support intestinal homeostasis upon engagement of GPR43 expressed on intestinal epithelial cells. Furthermore, SCFAs can directly interact with intestinal CD4⁺ T cells, shifting the balance of T_reg/T_H17 cells toward T_reg cells, thus inducing a regulatory microenvironment. (B) Within the lumen of the GI tract, the conversion of indoles to biologically active ligands of AhR contributes to maintain intestinal homeostasis acting on innate and adaptive immune cells. On the one hand, engagement of AhR by its ligands induces secretion of IL-22 from ILC3s, which in turn promotes the production of antimicrobial peptides (AMPs) from Paneth cells. On the other hand, triggering of AhR axis on T_H17 cells mediates their conversion into IL-10-secreting T_R1 cells, which are in turn able to terminate immune responses. (C) The biologically active form all-trans retinoic acid (ATRA) of vitamin A induces the expression of the gut homing receptors CCR9 and α4β7 integrin on T_reg cells, contributing to create a regulatory microenvironment within the GI tract, which is further augmented by the reduction of intestinal T_H17 cells. Similarly, engagement of VDR by active vitamin D metabolites dampens IL-17 secretion by T_H17 cells.