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Safety and Efficacy of Treatment for Nonalcoholic Liver Disease

In this clinical trial designed to look at the safety and efficacy of CMAs, Metabolon helped reveal the underlying molecular mechanism in nonalcoholic fatty liver disease (NAFLD) patients.

Metabolon helped reveal the underlying molecular mechanisms associated with reduced hepatic fat and inflammation in NAFLD patients and identified the key players. These findings suggest that targeting multiple pathways by CMAs is a potentially effective pharmacological therapeutic strategy for NAFLD patients.

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Metabolon helped reveal the underlying molecular mechanisms associated with reduced hepatic fat and inflammation in NAFLD patients and identified the key players. These findings suggest that targeting multiple pathways by CMAs is a potentially effective pharmacological therapeutic strategy for NAFLD patients.

Talk With An Expert About Your Project
nafld clinical trial

The Challenge: Testing the Safety and Efficacy of Drugs for Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of people who drink little or no alcohol. NAFLD comprises pathologies that include hepatic steatosis, steatohepatitis, hepatic fibrosis, and cirrhosis. Current management strategies include increased physical activity and dietary intervention but have limited adherence and marginal long-term success. No drugs have been approved to treat NAFLD; therefore, effective treatment options are urgently required. Although a few drugs have made it to clinical trials, the results of drugs targeting single pathways have been mostly unsuccessful. This research group recently found that the administration of combined metabolic activators (CMAs) promotes fat oxidation, attenuates the resulting oxidative stress, and eventually removes excess fat from the liver. In this phase 2 clinical trial, Metabolon helped reveal the mechanism of CMAs in NAFLD patients.1

Metabolon Insight: Characterizing Combined Metabolic Activators (CMA)

In this study, the Metabolon Global Discovery Panel was used to profile the plasma of NAFLD patients on CMAs (n = 19) or placebo (n = 11) to test the efficacy and safety of CMAs in NAFLD patients. Plasma samples were collected on Days 0, 14, and 70 of treatment. The Global Discovery Panel’s unrivaled coverage of up to 5,400 semi-quantifiable metabolites offered this group the most comprehensive solution for characterizing the metabolic signature of the plasma samples, revealing the underlying molecular mechanisms associated with the decrease in liver fat in the CMA group.

The Solution: Metabolomics Helps Reveal the Mechanism of CMAs

Here, metabolomics was used to help test the safety and efficacy of CMA in NAFLD patients. Untargeted metabolomics of plasma samples identified 1,032 metabolites. Metabolomics showed that 110 metabolites differed significantly on Day 70 versus Day 0 in the CMA group; 44 metabolites were involved in lipid metabolism. Fatty acid oxidation and carnitine metabolism were significantly upregulated on Day 70 versus Day 0 in the CMA group, as judged by the high plasma levels of deoxycarnitine, acetylcarnitine, and butyrylcarnitine. Plasma levels of kynurenate, kynurenine, and 3-amino-2-piperidone were significantly lower on Day 70 versus Day 0 in the CMA group. On the other hand, the kynurenate and 3-amino-2-piperidone plasma levels were significantly increased on Day 70 versus Day 0 in the placebo group.

Metabolomics analysis also revealed decreased metabolism of purine and xanthine in the CMA group on Day 70. Specifically, plasma levels of urate, xanthine, hypoxanthine 5-acetylamino-6-amino-3-methyluracil, 1,7- dimethylurate, and theophylline were significantly downregulated in the CMA group on Day 70. N-trimethyl-5-aminovalerate (TMAVA) was the most significantly reduced metabolite in the CMA group on Day 70 and was substantially lower than in the placebo group. Metabolomics data also demonstrated that the plasma level of N,N,N-trimethyl-alanylproline betaine (TMAP) was significantly downregulated in the CMA group on Day 70.

The Outcome: CMAs are Potentially an Effective Therapy for NAFLD Patients

This study showed that CMAs are safe and well-tolerated in NAFLD patients. The research group integrated plasma metabolomics data with inflammatory proteomics and oral and gut metagenomic data to reveal the underlying molecular mechanisms associated with reduced hepatic fat and inflammation in NAFLD patients, and identified the key players involved. These findings suggest that targeting multiple pathways by CMAs is a potentially effective pharmacological therapeutic strategy for NAFLD patients.

References

1. Zeybel M, Altay O, Arif M, et al. Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients. Mol Syst Biol. Oct 2021;17(10):e10459. doi:10.15252/msb.202110459

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References

1. Zgoda-Pols, J.R., et al., Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: investigation of nicotinic acid receptor agonists. Toxicol Appl Pharmacol, 2011. 255(1): p. 48-56.

2. Bryant, J.A., et al., The impact of an oral purified microbiome therapeutic on the gastrointestinal microbiome. Nat Med, 2026. 32(1): p. 186-196

3. McGovern, B .H., et al., SER-109, an Investigational Microbiome Drugto Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial. Clin Infect Dis, 2021. 72(12): p. 2132-2140.

4. Feuerstadt, P., et al., SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med, 2022. 386(3): p. 220-229.

5. Hu, Z., et al., Targeted metabolomics reveals novel diagnostic biomarkers for colorectal cancer. Mol Oncol, 2025. 19(6): p. 1737-1750.

6. Butler, F.M., et al., Vegetarian Dietary Patterns and Diet-Related Metabolites Are Associated With Kidney Function in the Adventist Health Study-2 Cohort. J Ren Nutr, 2025.

7. Stanford, J., et al., Metabolomic Profiling and Diet Quality Scoring in a Randomized Crossover Trial of Healthy and Typical Dietary Patterns. Mol Nutr Food Res, 2025 . 69(23): p. e70271.

8. O’Connor, L.E., et al., Metabolomic Profiling of an Ultraprocessed Dietary Pattern in a Domiciled Randomized Controlled Crossover Feeding Trial. J Nutr, 2023. 153(8): p. 2181-2192.

9. Fritsch, D.A., et al., Microbiome function underpins the efficacy of a fiber-supplemented dietary intervention in dogs with chronic large bowel diarrhea. BMC Vet Res, 2022. 18(1): p. 245.

10. Leal, L.N., et al., Preweaning nutrient supply improves lactation productivity and reduces the risk of culling in Holstein cows. J Dairy Sci, 2025. 108(6): p. 5875-5888.

11. Ahsin, M., et al., Soil and pasture health underlie improved beef nutrient density determined by untargeted metabolomics in Southern US grass finished beef systems. NPJ Sci Food, 2025. 9(1): p. 151.

12. Yin, W., et al., Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia. J Lipid Res, 2012. 53(1): p. 51-65.

13. Porter, F .D., et al., Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med, 2010. 2(56): p. 56ra81.

14. Needham, B .D., et al., Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder. Biol Psychiatry, 2021. 89(5): p. 451-462

15. Li, C., et al., Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med, 2014. 211(1): p. 15-28.

16. Green, P.G., et al., Metabolic flexibility and reverse remodelling of the failing human heart. Eur Heart J, 2025. 46(25): p. 2422-2433.

17. Maekawa, H., et al., SGLT2 inhibition protects kidney function by SAM-dependent epigenetic repression of inflammatory genes under metabolic stress. J Clin Invest, 2025. 135(19).

18. Wu, D., et al., Integrated screens reveal that guanine nucleotide depletion, which is irreversible via targeting IMPDH2, inhibits pancreatic cancer and potentiates KRAS inhibition. Gut, 2026.

19. Schwerdtfeger, L.A., et al., Gut microbiota and metabolites are linked to disease progression in multiple sclerosis. Cell Rep Med, 2025. 6(4): p. 102055.

20. Wu, H., et al., Microbiome-metabolome dynamics associated with impaired glucose control and responses to lifestyle changes. Nat Med, 2025. 31(7): p. 2222-2231.

21. Jacobs, J.P., et al., Cognitive behavioral therapy for irritable bowel syndrome induces bidirectional alterations in the brain-gut-microbiome axis associated with gastrointestinal symptom improvement. Microbiome, 2021. 9(1): p. 236.

22. Pietzner, M., et al., Plasma metabolites to profile pathways in noncommunicable disease multimorbidity. Nat Med, 2021. 27(3): p. 471-479.

23. Faquih, T.O., et al., Robust Metabolomic Age Prediction Based on a Wide Selection of Metabolites. J Gerontol A Biol Sci Med Sci, 2025. 80(3).

24. Scherer, N., et al., Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits. Nat Genet, 2025. 57(1): p. 193-205.

25. Holmes, Z.C., et al., Untargeted metabolomic analysis of human milk from healthy mothers reveals drivers of metabolite variability. Sci Rep, 2024. 14(1): p. 20827.

26. Titz, B., et al., Implications of Ocular Confounding Factors for Aqueous Humor Proteomic and Metabolomic Analyses in Retinal Diseases. Transl Vis Sci Technol, 2024. 13(6): p. 17.

27. Bloom, S.M., et al., Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation. Nat Microbiol, 2022. 7(3): p. 434-450.

28. Leimer, E.M., et al., Lipid profile of human synovial fluid following intra-articular ankle fracture. J Orthop Res, 2017. 35(3): p. 657-666.