Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: A randomized clinical trial.

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• In obese individuals following dietary interventions, specifically CR, IF and KD, may help to improve mitochondrial efficiency due to their positive impact on the microbiome and inflammation improving metabolic resilience in these individuals.

Introduction -

• Mitochondrial dysfunction in monocytes is linked to inflammation in obesity.
• This study assessed the impact of calorie restriction (CR), intermittent fasting (IF), and a ketogenic diet (KD) and ad libitum habitual diet (AL) on mitochondrial function in monocytes.
• In addition, it evaluated how changes in the gut microbiota, resulting from these dietary interventions and treatment with rifaximin, a broad-spectrum, non-absorbed rifamycin antibiotic, impacted monocyte function.

Methods -

• The study was an open randomised controlled clinical trial conducted in Mexico City (July 2022-March 2023).
• Participants were aged between 18-60 with a BMI between 30- 50kg/m2.
• 44 of 58 participants completed the 8 week long study, and were randomly assigned to each group, CR, IF, KD or AL; 11 per group.
• Participants followed the diet for 1 month, then 7 days of rifixamin was administered.
• Mitochondrial function parameters included several markers oxygen consumption rate (OCR), ATP linked respiration, proton leakage, bioenergetic health index (BHI), nonmitochondrial respiration, spare capacity and glycolysis, amongst others.
• Lipopolysaccharide (LPS) was used as a marker of inflammation.
• Gut microbiota diversity was measured using the Shannon diversity index.

Results –

• Maximal respiration significantly improved comparing all three groups to AL (p = 0.025, n2p = 0.159, CI 95% = 0.05,0.27)
• BHI increased in all three dietary interventions by week 8 (p = 0.0003, n2p = 0.203, 95% CI = 0.09,0.32).
• Serum LPS decreased in CR (p = 0.001), IF (p = 0.0001), KD (p = 0.004) and was inversely correlated with mitochondrial health (MR: r2 = -0.4, p = 0.02; BHI: r2 = -0.3, p = 0.057).
• Gut microbiota diversity increased in IF and KD at 8 weeks (p=0.0001).
• Beneficial bacteria increased: Phascolarctobacterium faecium (CR; p = 0.019) and Ruminococcus bromii (CR and KD; p = 0.02).

Conclusion -

• In individuals with obesity, the following dietary interventions CR, IF and KD improved mitochondrial bioenergetic marker levels.
• Decreased serum LPS and gut modulation may play a role in the changes observed in the monocyte energetic profile.

• Measuring mitochondrial function might help to provide evidence of the effectiveness of dietary interventions including CR, IF and KD where it can be used as an indicator of metabolic and inflammatory status.

• As there are few studies to report the use of this analysis in dietary intervention studies more research is needed to support these findings.
• A larger sample size with balanced gender representation would reduce result variability and provide more robust data to support new interventions and guide future research.
• Including metabolomic analysis in future research could help to identify if there are any mediators which contribute to mitochondrial dysfunction.
• To understand if the observations found stem from dietary intervention, rifaximin administration or both, further studies would benefit from including a placebo alongside the rifaximin administration.