Gut Microbiota and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Emerging Pathogenic Mechanisms and Therapeutic Implications
Abstract
:1. Introduction
2. Gut Microbiota Dysbiosis and Microbial Signatures Associated with MASLD
3. Mechanisms of Microbiome Modulation
4. Microbiota-Based Biomarkers and Therapeutic Implications
5. Future Perspectives and Research Needs to Exploit/Target the Gut Microbiota in the Context of MASLD
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug [Ref.] | Selected Key Clinical Evidence to Date | Drug Target and Mechanism of Action | |
---|---|---|---|
Cohort | Key Results | ||
Nidufexor [98] | NASH patients | Improved NAFLD activity score and lower triglyceride levels | FXR agonists. FXR is a nuclear receptor primarily expressed in the liver. FXR activation regulates bile acid synthesis and improves lipid metabolism. This modulation of bile acids and cholesterol homeostasis has been shown to reduce hepatic inflammation and injury |
PX-104 [99] | Non-diabetic NAFLD patients | Improved insulin sensitivity and liver enzymes (ALT and GGT) levels | |
Cilofexor [100] | NASH patients | Reduction in elevated liver enzyme (GGT) levels, hepatic steatosis and serum bile acids | |
Tropifexor [101] | NASH patients | Reduction in elevated liver enzyme (ALT and AST) levels, and hepatic steatosis | |
Obeticholic acid [102,103] | NASH and NASH-related fibrosis patients | Improved NASH activity scores and fibrosis severity | |
Ursodeoxycholic acid [104] | NASH patients | Reduction in elevated liver enzyme (ALT and GGT) levels | FXR antagonist. FXR antagonists indirectly modulate bile acid synthesis, and thereby reduce bile acid-mediated hepatic stress. They also reduce ceramide levels, which have been implicated in lipid-induced hepatocyte injury |
Semaglutide [105] | NASH patients | Significant NASH resolution in patients on semaglutide compared to placebo | GLP-1 agonist. GLP-1 agonists act via GLP-1 receptors to enhance insulin secretion, delay gastric emptying, and reduce appetite. Reduces hepatic steatosis by improving hepatic insulin sensitivity and reducing systemic inflammation and lipotoxicity |
Aldafermin [106] | NASH and NASH-related fibrosis patients | Dose-dependent reductions in serum bile acids and improvements in fibrogenesis markers | FGF19 analogue. FGF analogues reduce bile acid synthesis and improve lipid metabolism. This reduces hepatic bile acid toxicity and reduces systemic inflammation and lipotoxicity |
Efruxifermin [107] | NASH-related fibrosis | Improvements in fibrosis stage and fibrogenesis markers | FGF21 analogue |
Saroglitazar [108] | NAFLD patients | Reduction in elevated liver enzyme (ALT) levels and improved hepatic stiffness and metabolic parameters | PPAR agonist. PPAR agonists enhance fatty acid oxidation and reduce lipogenesis. They also suppress pro-inflammatory cytokine production, improving insulin sensitivity and reducing oxidative stress in the liver |
Resmetirom [109] | NASH-related fibrosis | Significant NASH resolution and improvement in fibrosis stage compared to placebo | THR-β agonist. THR-β agonists activate the beta thyroid hormone receptors predominantly expressed in the liver. This enhances hepatic fatty acid oxidation, reduces lipogenesis, and lowers circulating triglycerides, resulting in reduced hepatic steatosis and improved glucose and lipid metabolic profiles |
Study [Ref.] | Design and Duration | Study Intervention | Study Groups | Key Study Outcomes | Key Study Limitations |
---|---|---|---|---|---|
Derosa et al., 2022 [116] | Double-blind, placebo-controlled, RCT; 12 weeks | Probiotic group: 2 sachets daily in the morning of VSL#3 [a high-concentration multi-strain probiotic mix containing eight different strains: one strain of Streptococcus thermophilus BT01, three strains of Bifidobacteria (B. breve BB02; B. animalis subspecies [subsp.] lactis BL03, previously identified as B. longum BL03; and B. animalis subsp. lactis BI04, previously identified as B. infantis BI04), and four strains of Lactobacilli (L. acidophilus BA05, L. plantarum BP06, L. paracasei BP07, and L. helveticus BD08, previously identified as L. delbrueckii subsp. bulgaricus BD08)] Control group: placebo | Probiotic (VSL#3) group: 30 patients with NAFLD (mean age ± standard deviation: 55.7.0 ± 6.7 and 55.9 ± 7.5 years for males and females, respectively) Placebo control group: 30 patients with NAFLD (mean age: 55.8 ± 7.7 and 57.5 ± 7.9 years for males and females, respectively) | The VSL#3 group had significantly improved hepatic parameters, echography grading, inflammatory biomarkers and triglyceride levels, compared to the placebo | Small sample size. Short duration. |
Chong et al., 2021 [119] | Double-blind, placebo-controlled, proof-of-concept RCT; 10 weeks | Probiotic group: VSL#3 Control group: placebo | VSL#3 group: 19 patients with NAFLD (mean age: 57.0 ± 8.0 years) Placebo control group: 16 patients with NAFLD (mean age: 58.0 ± 7.0 years) | No significant differences in biomarkers of cardiovascular risk and liver injury between the VSL#3 and placebo groups. | Small sample size. Short duration. |
Duseja et al., 2019 [117] | Double-blind, placebo-controlled, RCT; 12 months | Probiotic group: 2 capsules three times daily (each capsule containing 112.5 billion live, lyophilised, lactic acid bacteria and bifidobacteria: Lactobacillus paracasei DSM 24733, L. plantarum DSM 24730, L. acidophilus DSM 24735, L. delbrueckii subsp. bulgaricus DSM 24734, Bifidobacterium longum DSM 24736, B. infantis DSM 24737, B. breve DSM 24732, Streptococcus thermophilus DSM 24731) Control group: placebo | Probiotic group: 19 patients with NASH (mean age: 38.0 ± 10.0 years) Placebo control group: 20 patients with NASH (mean age: 33.0 ± 6.0 years) | A significant improvement in liver histology, ALT, and cytokine profiles in the probiotic group compared to the placebo group. | Small initial sample size, with a further reduction in patients at follow-up for a repeat liver biopsy. At baseline, most patients had mild hepatic histology. Histopathology interpretation by a single pathologist at respective study centers. |
Mohamad Nor et al., 2021 [118] | Double-blind, placebo-controlled, RCT; 6 months | Probiotic group: One 3 g sachet twice daily of HEXBIO® microbial cell preparation (B-Crobes Laboratory Sdn. Bhd; each sachet consists of 30 billion CFU with six probiotic strains: Lactobacillus acidophilus BCMC® 12,130 (107 mg), L. casei subsp. BCMC® 12,313 (107 mg), L. lactis BCMC® 12,451 (107 mg), Bifidobacterium bifidum BCMC® 02290 (107 mg), B. infantis BCMC® 02129 (107 mg) and B. longum BCMC® 02120 (107 mg)] Control group: placebo | Probiotic group: 17 patients with NAFLD (mean age: 54.70 ± 10.19 years) Placebo control group: 22 patients with NAFLD (mean age: 52.47 ± 16.73 years) | Probiotics did not significantly improve clinical outcomes in NAFLD patients compared to placebo, but may help to stabilize the mucosal immune function and protect against increased intestinal permeability. | Small sample size. The unanticipated reduction in total fat intake in the probiotics group may have influenced the study outcomes. |
Ayob et al., 2023 [133] | Double-blind, placebo-controlled, RCT; 6 months | Probiotic group: one 3 g sachet twice daily of HEXBIO® microbial cell preparation (B-Crobes Laboratory Sdn. Bhd) Control group: placebo | Probiotic group: 18 patients with NAFLD (mean age: 55.00 ± 11.07 years) Placebo control group: 22 patients with NAFLD (mean age: 49.95 ± 14.05 years) | Compared to placebo, probiotic supplementation ameliorated dysbiosis in patients with NAFLD, leading to stabilization of pro-inflammatory cytokine expression and modulation of mucosal immune function. | Small sample size. Due to the COVID-19 pandemic, some study patients experienced interruptions in receiving probiotics. |
Wong et al., 2013 [134] | Open-label RCT; 6 months | Probiotic group: one 10 g sachet of Lepicol probiotic (200 million probiotic cultures) formula (Healthy Bowels Company Ltd., UK) twice daily. The Lepicol probiotic formula contains: Lactobacillus plantarum, L. deslbrueckii, L. acidophilus, L. rhamnosus, and Bifidobacterium bifidum, as well as 3 g of fructo-oligo-saccharides (prebiotics). Control group: usual care | Probiotic group: 10 patients with biopsy-proven NASH (mean age: 42.0 ± 9.0 years) Control group: 10 patients with biopsy-proven NASH (mean age: 55.0 ± 9.0 years) | Probiotic treatment may be more effective than usual care in reducing liver fat and AST levels in patients with NASH. | Small sample size. Open-label RCT. Results cannot be extrapolated directly to other probiotic formulae [the Lepicol probiotic formula contains also 3 g of fructo-oligo-saccharides (prebiotics)]. |
Sepideh et al., 2016 [135] | Double-blind, placebo-controlled, RCT; 8 weeks | Probiotic group: 1 g daily of Lactocare (Zist-takhmir Co., Tehran, Iran) which contains 7 strains of naturally occurring bacteria (Lactobacillus casei, L. acidophilus, L. rhamnosus, L. bulgaricus, Bifidobacterium breve, Bifidobacterium longum, Streptococcus thermophiles) Control group: placebo | Probiotic group: 11 patients with NAFLD (mean age: 42.10 ± 1.99 years) Placebo control group: 11 patients with NAFLD (mean age: 47.33 ± 2.53 years) | The probiotic group exhibited a reduction in insulin resistance, glycemic and inflammatory markers compared to the placebo group. | Small sample size. Short duration. Significant dropout rate. |
Aller et al., 2011 [136] | Double-blind, placebo-controlled, RCT; 12 weeks | Probiotic group: one tablet daily (500 million of Lactobacillus bulgaricus and Streptococcus thermophiles; Nutricion Medica, SL, Spain) Control group: placebo (one placebo tablet daily with 120 mg of starch) | Probiotic group: 14 patients with biopsy-diagnosed NAFLD (mean age: 49.4 ± 10.9 years) Placebo control group: 14 patients with biopsy-diagnosed NAFLD (mean age: 44.3 ± 15.1 years) | Significantly reduced liver enzymes in the probiotic group compared to the placebo group. | Small sample size. Short duration. |
Ahn et al., 2019 [137] | Double-blind, placebo-controlled, RCT; 12 weeks | Probiotic group: mixture (109 CFU/1.4 g) of six probiotics [L. acidophilus CBT LA1, L. rhamnosus CBT LR5 isolated from Korean human feces, L. paracasei CBT LPC5 isolated from Korean fermented food (jeotgal), P. pentosaceus CBT SL4 isolated from a Korean fermented vegetable product (kimchi), B. lactis CBT BL3, and B. breve CBT BR3 isolated from Korean infant feces] Control group: placebo | Probiotic group: 30 patients with NAFLD (mean age: 41.7 ± 12.49 years) Placebo control group: 35 patients with NAFLD (mean age: 44.71 ± 13.31 years) | Significantly reduced levels of triglycerides and intrahepatic fat in the probiotic group compared to the placebo group. | Small sample size. Short duration. The controlled attenuation parameter was measured with the M FibroScan probe, while patients with BMI ≥ 28 kg/m2 should be assessed with an XL probe to increase the reliability of steatosis measurements and to reduce scan failures. Eight study patients were excluded due to unreliable measurement results. |
Escouto et al., 2023 [138] | Double-blind, placebo-controlled, RCT; 24 weeks | Probiotic group: one capsule daily (1 × 109 CFU Lactobacillus acidophilus ATCC SD5221 and 1 × 109 CFU Bifidobacterium lactis HN019; Beneflora Caps; Biolab Sanus Farmaceutica Ltd.a.) Control group: placebo | Probiotic group: 23 patients with NASH (median age: 58.0 years) Placebo control group: 25 patients with NASH (median age: 57.0 years) | No statistically significant differences for liver fibrosis, steatosis, and inflammatory activity between the RCT groups. Significantly improved APRI score with probiotic supplementation compared to placebo. | Small sample size. Short duration. Inclusion of patients with liver cirrhosis. Most study participants were on statins and/or metformin treatment, which may have influenced relevant metabolic markers. |
Bomhof et al., 2019 [121] | Single-blinded (participants blinded to treatment), placebo-controlled, RCT; 36 weeks | Prebiotic group: oligofructose (Orafti P95, Beneo-Orafti Inc., Tienen, Belgium) 8 g once daily for 12 weeks followed by 16 g daily for 24 weeks Control group: placebo | Prebiotic group: 8 patients with biopsy-confirmed NASH (mean age: 45.3 ± 5.6 years) Placebo control group: 6 patients with biopsy-confirmed NASH (mean age: 53.3 ± 4.8 years) | Significantly improved NAS score and steatosis in the probiotic group compared to the placebo group. | Small sample size. Single-blind RCT. The placebo group had poorer glycemic control compared to the prebiotic group. Following the NASH diagnosis, several study participants made lifestyle changes resulting in significant weight loss prior to randomization. |
Reshef et al., 2024 [139] | Double-blind, placebo-controlled, RCT; 12 weeks | Prebiotic group: 8 g twice daily of inulin-type fructans (ITF) supplementation with inulin/oligofructose (75/25) Control group: placebo | Prebiotic group: 8 patients with NASH (median age: 47.8 years) Placebo control group: 11 patients with NASH (median age: 50.0 years) | The prebiotic group had a significant increase in the relative abundance of fecal Bifidobacterium; however, no significant improvement was observed in liver fat content or inflammatory biomarkers. | Small sample size. Short duration. Potential confounders, such as the use of metformin. |
Scorletti et al., 2020 [140] | Double-blind, placebo-controlled, RCT; ≈12 months (10 months minimum to 14 months maximum) | Synbiotic group: synbiotic consisting of fructo-oligosaccharides with a polymerization degree < 10 (4 g twice daily; two sachets daily) plus Bifidobacterium animalis subsp. lactis BB-12 (10 billion CFU daily minimum; one capsule daily). Actilight®950P was the prebiotic component of the synbiotic Control group: placebo (4 g twice daily of maltodextrin; one capsule daily, plus two sachets daily) | Synbiotic group: 45 patients with NAFLD (mean age: 50.2 ± 12.4 years) Placebo control group: 44 patients with NAFLD (mean age: 51.6 ± 13.1 years) | Compared to placebo, the synbiotic supplementation induced changes in the fecal microbiome (growth of Faecalibacterium and Bifidobacterium at the expense of Oscillibacter and Alistipes). The gut microbiota composition changes were not associated with any primary outcome. No significant difference in hepatic fat reduction between the two RCT groups. | Small sample size. Selection of one strain of bacteria for the synbiotic. |
Mofidi et al., 2017 [141] | Double-blind, placebo-controlled, RCT; 28 weeks | Synbiotic group: synbiotic supplementation capsule twice daily [Protexin; Probiotics International Ltd.; each capsule contained: 200 million bacteria (seven strains: Lactobacillus casei, L. rhamnosus, L. acidophilus, L. bulgaricus, Streptococcus thermophilus, Bifidobacterium breve, and B. longum); prebiotic (125 mg fructo-oligosaccharide; probiotic cultures (magnesium stearate); and hydroxyl-propylmethyl cellulose] Control group: placebo | Synbiotic group: 21 patients with NAFLD (mean age: 40.09 ± 11.44 years) Placebo control group: 21 patients with NAFLD (mean age: 44.61 ± 10.12 years) | Both RCT groups exhibited reductions in hepatic steatosis and fibrosis with the mean reduction being significantly greater in the synbiotic group compared to the placebo. | Small sample size. Only participants with BMI ≤ 25 kg/m2 were included in this RCT, thus these findings cannot be directly extrapolated for patients with NAFLD and overweightness or obesity. |
Malaguarnera et al., 2012 [142] | Double-blind, placebo-controlled, RCT; 24 weeks | Synbiotic group: sachet of Bifidobacterium longum and fructo-oligosaccharides (Fos) (Zirfos, Alfa Wassermann, Bologna, Italy) 2.5 g, vitamin B1 (1.4 mg), vitamin B2 (1.6 mg), vitamin B6 (2.0 mg), and vitamin B12 (1.0 mg) plus lifestyle modification (diet and exercise) Control group: placebo plus lifestyle modification (diet and exercise) | Synbiotic group: 34 patients with NASH (mean age: 46.9 ± 5.4 years) Placebo control group: 32 patients with NASH (mean age: 46.7 ± 5.7 years) | Significantly reduced NASH activity index and steatosis, as well as serum endotoxin, AST, CRP, TNF-α levels and HOMA-IR, in the synbiotic group compared to the placebo group. | Small sample size. Short duration. Potential diet-related confounding. |
Asgharian et al., 2016 [143] | Double-blind, placebo-controlled, RCT; 8 weeks | Synbiotic group: 500 mg capsule (Familact by Zisttakhmir) once daily containing seven probiotic bacteria species (Lactobacillus casei, L. acidophilus, L. rhamnosus, L. bulgaricus, Bifidobacterium breve, B. longum, and Streptococcus thermophilus) and fructo-oligosaccharides Control group: placebo | Synbiotic group: 38 patients with NAFLD (mean age: 46.57 ± 1.7 years) Placebo control group: 36 patients with NAFLD (mean age: 47.78 ± 1.7 years) | The synbiotic group demonstrated significantly reduced steatosis grade on ultrasound compared to baseline. No association of synbiotic supplementation with changes in ALT, AST and CRP levels. | Small sample size. Short duration. |
Abhari et al., 2020 [144] | Double-blind, placebo-controlled, RCT; 12 weeks | Synbiotic group: one synbiotic capsule daily containing 109 spore of Bacillus coagulans (GBI-30) plus 0.4 g inulin Control group: placebo | Synbiotic group: 23 patients with NAFLD (mean age: 47.7 ± 11.4 years) Placebo control group: 22 patients with NAFLD (mean age: 46.7 ± 12.4 years) | Hepatic steatosis measured by the controlled attenuation parameter score in Fibroscan, serum ALT and GGT levels decreased significantly more in the synbiotic group compared to the placebo. Synbiotic supplementation significantly reduced serum TNF-α levels and nuclear factor-kB activity. | Small sample size. Short duration. |
Sayari et al., 2018 [145] | Double-blind, placebo-controlled, RCT; 16 weeks | Sitagliptin plus Synbiotic group: Sitagliptin (50 mg once daily) plus synbiotic [500 mg once daily; each capsule (Familakt) contained 109 CFU of Lactobacillus casei, L. rhamnosus, L. acidophilus, L. bulgaricus, Bifidobacterium breve, B. longum, Streptococcus thermophiles; prebiotic (fructo-oligosaccharide); probiotic cultures (magnesium stearate); and hydroxyl-propyl methylcellulose] Sitagliptin plus placebo group: Sitagliptin (50 mg once daily) plus placebo (maltodexterin; once daily) | Sitagliptin plus Synbiotic group: 70 patients with NAFLD and BMI from 25 to 29.9 kg/m2 who had impaired fasting blood glucose and/or impaired glucose tolerance (mean age: 42.48 ± 11.41 years) Sitagliptin plus Placebo group: 70 patients with NAFLD and BMI from 25 to 29.9 kg/m2 and who had impaired fasting blood glucose and/or impaired oral glucose tolerance test (mean age: 43.42 ± 11.65 years) | The Sitagliptin [a dipeptidyl peptidase-4 (DPP-4) inhibitor] plus Synbiotic group had significantly greater improvements in AST, fasting glucose, cholesterol and LDL levels compared to the Sitagliptin plus Placebo group. | Small sample size. Short duration. |
Xue et al., 2022 [129] | RCT; 4 weeks (RCT participants returned for re-examination 1 month post-treatment) | FMT group: allogenic FMT (heterologous from healthy donors via colonoscopy followed by three enemas over 3 days) Non-FMT control group: oral probiotics (a Bifidobacterium viable preparation and Lactobacillus acidophilus capsules) | FMT group: 47 patients with NAFLD (mean age: 57.3 ± 13.4 years) Non-FMT group: 28 patients with NAFLD (mean age: 60.2 ± 8.5 years) Healthy control group: 10 healthy undergraduate students (control group that received no intervention) | The mean hepatic fat attenuation values decreased from 278.3 to 263.9 dB/m in the FMT group (p = 0.049), while these increased from 265.5 to 282.5 dB/m in the Non-FMT group (p < 0.01). Compared to healthy controls, patients with NAFLD before the FMT had lower Chaol indices (p < 0.05), suggesting lower abundances of gut microbiota. Post-FMT, there was no statistical difference in the Chaol indices between the FMT NALFD patients and healthy controls. In the FMT group, better effects on the gut microbiota reconstruction were noted in lean patients with NAFLD, compared to those with obesity. | Small sample size. Short duration. Patients with NAFLD were randomly divided into the FMT and non-FMT RCT group based on the wishes of the participants. Age difference between the FMT/non-FMT groups and the healthy control group. Potential confounders relating to exercise/diet. |
Witjes et al., 2020 [146] | Double-blind (all study participants, i.e., vegan donors and patients with NAFLD and all trial physicians/authors were blinded for the treatment until trial completion), proof-of-principle RCT; 24 weeks (FMT performed three times at 8-week intervals) | Allogenic FMT group: FMT with feces from healthy, lean, vegan donors three times at 8-week intervals (same donor for the three FMTs in each participant) Autologous FMT group: 8-week intervals Allogenic/Autologous FMT via gastroduodenoscopy at baseline, and via a duodenal tube via a CORTRAK enteral access (Medline Industries, Northfield, IL), at 8 weeks and 16 weeks | Allogenic FMT group: 10 omnivorous adults with treatment-naïve biopsy-proven NAFLD (hepatic steatosis on ultrasound) and obesity (mean age: 51.2 ± 6.6 years) Autologous FMT group: 11 omnivorous adults with treatment-naïve biopsy-proven NAFLD (hepatic steatosis on ultrasound) and obesity (mean age: 48.5 ± 10.2 years) | No statistically significant changes in the overall NAFLD activity score, steatosis grade and fibrosis scores. In the allogenic FMT group a trend for an improved necro-inflammation score was noted. Significant changes in the expression of hepatic genes involved in inflammation and lipid metabolism were also noted in the allogenic FMT group, compared with the autologous FMT. Intestinal microbial community structure changed following allogenic FMT, and was associated with changes in plasma metabolites and markers of steatohepatitis. | Underpowered study due to slow recruitment. Differences in baseline AST and ALT levels between the allogenic and autologous FMT groups. Study participants were relatively healthy, and, thus, the study sample was not representative of the entire spectrum of patients with NAFLD. |
Craven et al., 2020 [147] | Double-blind, RCT (3:1 ratio to allogenic or autologous FMT); 24 weeks (follow-up appointments for 6 months post-FMT) | Allogenic FMT group: FMT with feces from healthy lean donors Autologous FMT group Allogenic/autologous FMT was delivered to the duodenum via endoscopy | Allogenic FMT group: 15 patients with NAFLD (mean age: 47.6 ± 14.9 years) Autologous FMT group: 6 patients with NAFLD (mean age: 57.5 ± 13.0 years) | No significant changes in hepatic proton density fat fraction or HOMA-IR in the allogenic or autologous FMT group. NAFLD patients (n = 7) with elevated small intestinal permeability at baseline had a significant reduction 6 weeks post allogenic FMT. | Small sample size. The two FMT groups differed regarding biochemical data, intestinal permeability. and fibrosis staging. |
Abdel-Razik et al., 2018 [148] | Double-blind, placebo-controlled, RCT; 6 months | Rifaximin group: rifaximin 1100 mg daily (550 mg tablets 1 × 2 before meals) Control group: placebo | Rifaximin group: 25 patients with biopsy-proven NASH (mean age: 40.2 ± 9.88 years) Placebo control group: 25 patients with biopsy-proven NASH (mean age: 38.4 ± 9.21 years) | Significantly reduced NAFLD-liver fat score, HOMA-IR and toll-like receptor-4 expression, as well as ALT, AST, GGT, TNF-α, IL-6, CK-18 and endotoxin levels, were noted in the Rifaximin group, but not in the placebo group. | Small sample size. A second liver biopsy at 6 months post-treatment was not performed for any participants. The effect of rifaximin treatment on the gut flora was not assessed. |
Neuschwander-Tetri et al., 2015 [149] | Double-blind, placebo-controlled, RCT; 72 weeks | Obeticholic acid group: 25 mg of 6-ethylchenodeoxycholic acid (obeticholic acid) once daily, per os (orally) Control group: placebo | Obeticholic acid group: 141 patients with biopsy-proven non-cirrhotic NASH (mean age: 52.0 ± 11.0 years) Placebo control group: 142 patients with biopsy-proven non-cirrhotic NASH (mean age: 51.0 ± 12.0 years) | More patients in the obeticholic acid group compared with placebo had improvement in the NAFLD activity score, fibrosis, hepatocellular ballooning, steatosis, and lobular inflammation. The mean change in the NAFLD activity score was also greater in the obeticholic acid group compared with placebo. The proportion of patients with resolution of NASH (change from baseline NASH diagnosis to non-NASH) did not differ between the two RCT groups. Compared with placebo, obeticholic acid treatment was associated more with pruritus and a temporary increase in total and LDL cholesterol with a modest decrease in HDL cholesterol. | Missing detailed tracking of interventions for the treatment of hyperlipidemia during the RCT, including dosing information. Smoking history was not captured until midway of the RCT. |
Harrison et al., 2018 [150] | Double-blind, placebo-controlled, RCT; 12 weeks | NGM282 groups: (a) 3 mg NGM282 (an engineered FGF19 analogue) subcutaneously once daily (b) 6 mg NGM282 subcutaneously once daily Control group: Placebo | 3 mg NGM282 group: 27 patients with biopsy-proven NASH (mean age: 52.0 ± 7.1 years) 6 mg NGM282 group: 28 patients with biopsy-proven NASH (mean age: 56.4 ± 7.8 years) Placebo control group: 27 patients with biopsy-proven NASH (mean age: 52.8 ± 11.3 years) | Between baseline and 12 weeks, at least a 5% reduction in absolute hepatic fat content was noted for 74% and 79% of the participants in the 3 mg and 6 mg dose group, respectively (only for 7% in the placebo group). Adverse events were more frequent in the NGM282 groups compared to placebo, with injection site reactions, diarrhea, abdominal pain and nausea being the most commonly (≥10%) reported adverse events. | Small sample size. Short duration. Inclusion of few non-white participants and numerically more men (non-significantly) in the NGM282 groups, although, in post hoc analysis, sex and race had no effect on reductions in hepatic fat content. |
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Abdelhameed, F.; Mustafa, A.; Kite, C.; Lagojda, L.; Dallaway, A.; Than, N.N.; Kassi, E.; Kyrou, I.; Randeva, H.S. Gut Microbiota and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Emerging Pathogenic Mechanisms and Therapeutic Implications. Livers 2025, 5, 11. https://doi.org/10.3390/livers5010011
Abdelhameed F, Mustafa A, Kite C, Lagojda L, Dallaway A, Than NN, Kassi E, Kyrou I, Randeva HS. Gut Microbiota and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Emerging Pathogenic Mechanisms and Therapeutic Implications. Livers. 2025; 5(1):11. https://doi.org/10.3390/livers5010011
Chicago/Turabian StyleAbdelhameed, Farah, Attia Mustafa, Chris Kite, Lukasz Lagojda, Alexander Dallaway, Nwe Ni Than, Eva Kassi, Ioannis Kyrou, and Harpal S. Randeva. 2025. "Gut Microbiota and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Emerging Pathogenic Mechanisms and Therapeutic Implications" Livers 5, no. 1: 11. https://doi.org/10.3390/livers5010011
APA StyleAbdelhameed, F., Mustafa, A., Kite, C., Lagojda, L., Dallaway, A., Than, N. N., Kassi, E., Kyrou, I., & Randeva, H. S. (2025). Gut Microbiota and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Emerging Pathogenic Mechanisms and Therapeutic Implications. Livers, 5(1), 11. https://doi.org/10.3390/livers5010011