Exercise and diet are treatments for nonalcoholic fatty liver disease (NAFLD) and prediabetes, however, how exercise and diet interventions impact gut microbiota in patients is incompletely understood. We previously reported a 8.6-month, four-arm (Aerobic exercise, n = 29; Diet, n = 28; Aerobic exercise + Diet, n = 29; No intervention, n = 29) randomized, singe blinded (for researchers), and controlled intervention in patients with NAFLD and prediabetes to assess the effect of interventions on the primary outcomes of liver fat content and glucose metabolism. Here we report the third primary outcome of the trial—gut microbiota composition—in participants who completed the trial (22 in Aerobic exercise, 22 in Diet, 23 in Aerobic exercise + Diet, 18 in No Intervention). We show that combined aerobic exercise and diet intervention are associated with diversified and stabilized keystone taxa, while exercise and diet interventions alone increase network connectivity and robustness between taxa. No adverse effects were observed with the interventions. In addition, in exploratory ad-hoc analyses we find that not all subjects responded to the intervention in a similar manner, when using differentially altered gut microbe amplicon sequence variants abundance to classify the responders and low/non-responders. A personalized gut microbial network at baseline could predict the individual responses in liver fat to exercise intervention. Our findings suggest an avenue for developing personalized intervention strategies for treatment of NAFLD based on host-gut microbiome ecosystem interactions, however, future studies with large sample size are needed to validate these discoveries. The Trial Registration Number is ISRCTN 42622771.

The aim of this study was to investigate the association between cardiorespiratory fitness and gut microbiota composition in premenopausal women. The participants consisted of 71 premenopausal Finnish women (aged 19–49 years). Gut microbiota were analyzed using flow cytometry, 16S rRNA gene hybridization and DNA-staining. Maximum oxygen uptake (VO_2max) was assessed by respiratory gas analyzer and body composition by Bioimpdance. We found that participants with low VO_2max had lower Bacteroides, but higher Eubacterium rectale-Clostridium coccoides than the high VO_2max group (p < 0.05 for all). VO_2max was inversely associated with EreC (r = −0.309, p = 0.01) but not with other bacteria. VO_2max also negatively correlated with fat% (r = −0.755, p < 0.001), triglycerides (r = −0.274, p = 0.021) and leptin (r = −0.574, p < 0.001). By contrast, EreC was positively associated with fat% (r = 0.382, p = 0.002), dietary fat intake (r = 0.258, p = 0.034), triglycerides (r = 0.390, p = 0.002) and leptin (r = 0.424, p = 0.001), but negatively with carbohydrate intake (r = −0.252, p = 0.034) and HDL (r = −0.26, p = 0.028). After adjusting for age and dietary intake, all the significant associations remained. However, after adjusting for fat%, the associations between VO_2max and EreC disappeared. Our results suggest that cardiorespiratory fitness is associated with gut microbiota composition, independent of age and carbohydrate or fat intake. The association between VO_2max and EreC, however, appears to be mediated by body fatness.

The tumor suppressor p53 as an innate antiviral regulator contributes to restricting Japanese encephalitis virus (JEV) replication, but the mechanism is still unclear. The interferon-induced transmembrane protein 3 (IFITM3) is an intrinsic barrier to a range of virus infection, whether IFITM3 is responsible for the p53-mediated anti-JEV response remains elusive. Here, we found that IFITM3 significantly inhibited JEV replication in a protein-palmitoylation-dependent manner and incorporated into JEV virions to diminish the infectivity of progeny viruses. Palmitoylation was also indispensible for keeping IFITM3 from lysosomal degradation to maintain its protein stability. p53 up-regulated IFITM3 expression at the protein level via enhancing IFITM3 palmitoylation. Screening of palmitoyltransferases revealed that zinc finger DHHC domain-containing protein 1 (ZDHHC1) was transcriptionally up-regulated by p53, and consequently ZDHHC1 interacted with IFITM3 to promote its palmitoylation and stability. Knockdown of IFITM3 significantly impaired the inhibitory role of ZDHHC1 on JEV replication. Meanwhile, knockdown of either ZDHHC1 or IFITM3 expression also compromised the p53-mediated anti-JEV effect. Interestingly, JEV reduced p53 expression to impair ZDHHC1 mediated IFITM3 palmitoylation for viral evasion. Our data suggest the existence of a previously unrecognized p53-ZDHHC1-IFITM3 regulatory pathway with an essential role in restricting JEV infection and provide a novel insight into JEV-host interaction.

This study aimed to assess whether the benefits of exercise on central adiposity and insulin resistance (HOMA-IR) are maintained after discontinuation of intervention in the overweight/obese (OWOB) women. The study subjects were from 2 independent studies with similar aerobic exercise (AE) intervention programs. In study I, 15 OWOB postmenopausal women with pre-diabetes (body mass index, BMI = 24-33 kg/m², aged 52-65 years) completed an 8-month exercise intervention and were followed for 2 years after the intervention. In study II, 12 OWOB (BMI = 25-35 kg/m², aged 30-50 years) premenopausal women participated in a 6-week AE and were followed for 4 years after the intervention. The exercise program consisted of progressive AE with intensity of 60%-75% of initial fitness level, 30-60 min/time and 3-5 times/week. Fat mass (FM) was assessed by Dual Energy X-ray Absorptiometry (DXA Prodigy; study I) or bioelectrical impedance device (Inbody 720; study II). Plasma glucose and insulin were assessed by chemiluminescent immunoassay and HOMA-IR was calculated. Both 8-month and 6-week moderate AE were effective in reducing HOMA-IR (-18.9%, p = 0.012 and -26.7%, p = 0.046, respectively), and 8-month AE reduced FM at upper abdominal region (-6.2%, p = 0.021). However, these improvements were not maintained in either study at the follow-up. The AE program used in these studies was effective to reduce insulin resistance and/or FM in central body region among overweight and obese women. However, when exercise intervention was discontinued, the beneficial effects following both short- and long-term intervention disappeared. Thus maintaining exercise seems to be required if one wants to reap the benefits of exercise in the long-term.