Effect of Gut Microbiota and PNPLA3 rs738409 Variant on Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Youth

Ayesha Monga Kravetz, Todd Testerman, Brittany Galuppo, Joerg Graf, Bridget Pierpont, Stephan Siebel, Richard Feinn, Nicola Santoro, Ayesha Monga Kravetz, Todd Testerman, Brittany Galuppo, Joerg Graf, Bridget Pierpont, Stephan Siebel, Richard Feinn, Nicola Santoro

Abstract

Context: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, affecting approximately 3 in 10 obese children worldwide.

Objective: We aimed to investigate the potential relationship between gut microbiota and NAFLD in obese youth, while considering the role of PNPLA3 rs738409, a strong genetic contributor to NAFLD.

Design: In this cross-sectional study, participants completed an abdominal magnetic resonance imaging to measure hepatic fat fraction (HFF), oral glucose tolerance test, and PNPLA3 rs738409 genotyping. Fecal samples were collected to analyze the V4 region of the 16S rRNA gene for intestinal bacteria characterization.

Setting: Yale Pediatric Obesity Clinic.

Participants: Obese youth (body mass index >95th percentile) with NAFLD (HFF ≥5.5%; n = 44) and without NAFLD (HFF <5.5%; n = 29).

Main outcome measure: Shannon-Wiener diversity index values and proportional bacterial abundance by NAFLD status and PNPLA3 genotype.

Results: Subjects with NAFLD had decreased bacterial alpha-diversity compared with those without NAFLD (P = 0.013). Subjects with NAFLD showed a higher Firmicutes to Bacteroidetes (F/B) ratio (P = 0.019) and lower abundance of Bacteroidetes (P = 0.010), Prevotella (P = 0.019), Gemmiger (P = 0.003), and Oscillospira (P = 0.036). F/B ratio, Bacteroidetes, Gemmiger, and Oscillospira were associated with HFF when controlling for group variations. We also observed an additive effect on HFF by PNPLA3 rs738409 and Gemmiger, and PNPLA3 rs738409 and Oscillospira.

Conclusions: Obese youth with NAFLD have a different gut microbiota composition than those without NAFLD. These differences were still statistically significant when controlling for factors associated with NAFLD, including PNPLA3 rs738409.

Trial registration: ClinicalTrials.gov NCT04101045 NCT03454828.

Keywords: NAFLD; gut microbiota; obesity; pediatrics.

© Endocrine Society 2020.

Figures

Figure 1.
Figure 1.
Alpha diversity in NAFLD absent and present groups. The figure shows a significant difference (P = 0.013) in Shannon diversity index values between the group without NAFLD, in blue, and the group with NAFLD, in red. Boxplots are presented in Tukey style. The groups were compared using Welch’s t test.
Figure 2.
Figure 2.
Difference in phylum/genus abundance in HFF groups. The figure shows the mean with SD in Firmicutes/Bacteroidetes (F/B) ratio (A), Bacteroidetes abundance (B), Prevotella abundance (C), Gemmiger abundance (D), and Oscillospira abundance (E) observed in the 2 HFF groups. The group without NAFLD is shown in blue and the group with NAFLD is shown in red. The 2 groups were compared using Mann-Whitney U test.
Figure 3.
Figure 3.
Effect of PNPLA3 variant and bacteria on HFF. The figure shows the additive effect of PNPLA3 rs738409 genotype and F/B ratio (A), Bacteroidetes (B), Gemmiger (C), and Oscillospira (D) on hepatic fat fraction (HFF). Bacterial abundance was categorized in tertiles, from smallest (blue) to largest (green) abundance, T1 to T3. Data are shown as mean and SD.

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Source: PubMed

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