Normocaloric Low Cholesterol Diet Modulates Th17/Treg Balance in Patients with Chronic Hepatitis C Virus Infection

Abstract

Hepatitis C virus (HCV) infection is associated with hepatic and extrahepatic manifestations, including immunological disorders. Chronic Hepatitis C (CHC) is often characterized by cholesterol and lipid metabolism alterations, leading to hepatic steatosis. Cholesterol metabolism, in fact, is crucial for the viral life cycle. Recent works described that a higher dietary cholesterol intake is associated with the progression of HCV-related liver disease. CHC patients have increased levels of T helper 17 (Th17)-cells, a lymphocytic population involved in the pathogenesis of liver inflammation and autoimmune hepatitis. The balance between Th17 and regulatory T (Treg) cells is crucial for chronic inflammation and autoimmunity. Th17-cell differentiation is deeply influenced by the activation LXRs, nuclear receptors modulating cholesterol homeostasis. Moreover, HCV may affect these nuclear receptors, and cholesterol metabolism, through both direct and indirect mechanisms. On these bases, we hypothesized that modulation of cholesterol levels through Normocaloric Low Cholesterol Diet (NLCD) may represent an innovative strategy to reduce the progression of HCV infection, through the modulation of peripheral Th17/Treg balance. To this end, we performed a pilot study to investigate whether a Normocaloric Low Cholesterol Diet may be able to modulate Th17/Treg balance in patients affected by chronic HCV infection. After 30 days of NLCD CHC patients showed a significant reduction in Th17 cells frequency, which correlated with strong reduction of IL-17 and IL-22 serum levels. At the same time, we appreciated an increase in the percentage of Treg cells, thus improving Treg/Th17balance. Moreover, we observed an increased expression of LXRs and their target genes: SREBP-1c and ABCA-1. In conclusion, NLCD finely regulates Th17/Treg balance, improving immune system response in CHC patients. This study could pave the way for new treatments of CHC patients, suggesting that change in lifestyle could support the management of these patients, promoting well-being and possibly hindering disease progression.Trial RegistrationClinicalTrials.gov NCT02038387

Chronic hepatitis C liver microenvironment: role of the Th17/Treg interplay related to fibrogenesis

“…On the other side, most studies focus on peripheral immune cell population but the results are somewhat controversial, with some authors reporting elevated Treg 30 , 32 and Th17 16 , 33 while others describing low frequencies 20 . These contradictory results probably reflect differences in the design of immune assay, the sample tested (i.e.…”

Regulatory T cells and T helper 17 cells in viral infection

“…In addition, HCV could directly or indirectly affect the expression and activity of liver X receptors (LXRs). LXR‐induced sterol‐regulatory element binding protein 1 (Srebp‐1) inhibited IL‐17 transcript to bind to IL‐17 promoter, by which Th17 cell proliferation and differentiation were regulated …”

Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

“…For example, an increase in Th17 cells and IL-17A under hypercholesterolemic conditions might at least in part be due to an increase in endogenous sterol levels and their subsequent activation of ROR γ t, while low cholesterol diet might do the inverse. This hypothesis is supported by a study reporting that patients with chronic hepatitis C, which is associated with increased levels of Th17 cells, when placed on a normocaloric, low cholesterol diet showed a significant reduction in Th17 cells and IL-17 levels [ 252 ]. Furthermore, treatment with statins, inhibitors of cholesterol synthesis, lead to a reduction in Th17 differentiation and IL-17 production [ 253 ].…”