Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD

Stavroula Kanoni, Satish Kumar, Charalampia Amerikanou, Mary Jo Kurth, Maria G Stathopoulou, Stephane Bourgeois, Christine Masson, Aimo Kannt, Lucia Cesarini, Maria-Spyridoula Kontoe, Maja Milanović, Francisco J Roig, Mirjana Beribaka, Jonica Campolo, Nuria Jiménez-Hernández, Nataša Milošević, Carlos Llorens, Ilias Smyrnioudis, M Pilar Francino, Nataša Milić, Andriana C Kaliora, Maria Giovanna Trivella, Mark W Ruddock, Milica Medić-Stojanoska, Amalia Gastaldelli, John Lamont, Panos Deloukas, George V Dedoussis, Sophie Visvikis-Siest, Stavroula Kanoni, Satish Kumar, Charalampia Amerikanou, Mary Jo Kurth, Maria G Stathopoulou, Stephane Bourgeois, Christine Masson, Aimo Kannt, Lucia Cesarini, Maria-Spyridoula Kontoe, Maja Milanović, Francisco J Roig, Mirjana Beribaka, Jonica Campolo, Nuria Jiménez-Hernández, Nataša Milošević, Carlos Llorens, Ilias Smyrnioudis, M Pilar Francino, Nataša Milić, Andriana C Kaliora, Maria Giovanna Trivella, Mark W Ruddock, Milica Medić-Stojanoska, Amalia Gastaldelli, John Lamont, Panos Deloukas, George V Dedoussis, Sophie Visvikis-Siest

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with no therapeutic consensus. Oxidation and inflammation are hallmarks in the progression of this complex disease, which also involves interactions between the genetic background and the environment. Mastiha is a natural nutritional supplement known to possess antioxidant and anti-inflammatory properties. This study investigated how a 6-month Mastiha supplementation (2.1 g/day) could impact the antioxidant and inflammatory status of patients with NAFLD, and whether genetic variants significantly mediate these effects. We recruited 98 patients with obesity (BMI ≥ 30 kg/m2) and NAFLD and randomly allocated them to either the Mastiha or the placebo group for 6 months. The anti-oxidative and inflammatory status was assessed at baseline and post-treatment. Genome-wide genetic data was also obtained from all participants, to investigate gene-by-Mastiha interactions. NAFLD patients with severe obesity (BMI > 35kg/m2) taking the Mastiha had significantly higher total antioxidant status (TAS) compared to the corresponding placebo group (P value=0.008). We did not observe any other significant change in the investigated biomarkers as a result of Mastiha supplementation alone. We identified several novel gene-by-Mastiha interaction associations with levels of cytokines and antioxidant biomarkers. Some of the identified genetic loci are implicated in the pathological pathways of NAFLD, including the lanosterol synthase gene (LSS) associated with glutathione peroxidase activity (Gpx) levels, the mitochondrial pyruvate carrier-1 gene (MPC1) and the sphingolipid transporter-1 gene (SPNS1) associated with hemoglobin levels, the transforming growth factor-beta-induced gene (TGFBI) and the micro-RNA 129-1 (MIR129-1) associated with IL-6 and the granzyme B gene (GZMB) associated with IL-10 levels. Within the MAST4HEALTH randomized clinical trial (NCT03135873, www.clinicaltrials.gov) Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity. We identified several novel genome-wide significant nutrigenetic interactions, influencing the antioxidant and inflammatory status in NAFLD.

Clinical trial registration: ClinicalTrials.gov, identifier NCT03135873.

Keywords: MAST4HEALTH; Mastiha; inflammation; non-alcoholic fatty liver disease; nutrigenetics; oxidative stress; randomized clinical trial.

Conflict of interest statement

Authors MK, MR, and JL were employed by the company Randox Laboratories Ltd (RANDOX), author AK was employed by the company Fraunhofer Institute of Translational Medicine and Pharmacology, author IS was employed by the company Chios Mastic Gum Growers Association, and authors FR and CL were employed by the company Biotechvana. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Kanoni, Kumar, Amerikanou, Kurth, Stathopoulou, Bourgeois, Masson, Kannt, Cesarini, Kontoe, Milanović, Roig, Beribaka, Campolo, Jiménez-Hernández, Milošević, Llorens, Smyrnioudis, Francino, Milić, Kaliora, Trivella, Ruddock, Medić-Stojanoska, Gastaldelli, Lamont, Deloukas, Dedoussis and Visvikis-Siest.

Figures

Figure 1
Figure 1
Differences in adjusted means for post-treatment TAS, between the Mastiha and placebo groups, stratified by BMI category. Adjustments were performed for baseline levels of TAS, age, sex and center.
Figure 2
Figure 2
Boxplots of selected post-treatment levels (adjusted for the baseline levels, age, sex, center and the first 5 genetic principal components) between the Mastiha and placebo groups, stratified by genotype, for the significant gene-by-Mastiha interactions (outliers are presented as dots: (A) Gpx levels by the rs12004915 genotypes, (B) HB by rs12211694, (C) IL-6 by rs4731418, (D) IL-6 by rs9651127, (E) TNF-α by rs10928182 and (F) IL-10 by rs8021058.

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