Abstract

Background: Severe alcoholic hepatitis (SAH) is associated with malnutrition, dysbiosis and inflammatory cytokines augmenting liver injury resulting in high mortality. Experimental studies have reported that in comparison to unsaturated fat (UF), saturated fat (SF) improves dysbiosis, inflammation, liver enzymes and protects against alcoholic liver injury, but effect on clinical outcome and gut microbiota (GM) in SAH patients is lacking.

Aim: Primary aim was to compare the effects of diet rich in SF versus UF on 60-day mortality. Secondary aims included effects on clinical outcomes, inflammatory markers and GM profile.

Methods: Of 169 SAH patients screened, 67 with mDF between 32-100, without sepsis, acute kidney injury (AKI), or malignancy were randomized into SF (Ghee i.e., clarified butter; n=34) or UF (Soyabean Oil; n=33) arm. Patients in both arms received 35 kcal and 1.2-1.5g protein/ kg /day (55-60% carbohydrate, 20% protein, 30-35% fat) for 60 days. GM was assessed using 16S V3-V4 region analysis by Novaseq. Changes in the clinical [MELD, CTP, mDF, FIB-4], biochemical, pro-inflammatory [TNF-ɑ, NF-κB] and anti-inflammatory [IL-10, adiponectin] parameters, at 60-days were assessed.

Results: Baseline parameters [age 40±7.37 yrs; ascites 47 (84%); BMI 21.3±3.8 kg/m²; mDF 62.4±21.4; MELD 28±9.3; CTP 10.6±1.4], GM phyla and species were comparable between groups. SF and UF were well tolerated. 60 day mortality was significantly lower in SF (12.2%) vs. UF (33%) arm; p=0.014 (Fig.1 C) as per ITT analysis. Five patients from each arm were lost to follow-up. A significant improvement in AST, ALT, IL-10 levels and a trend towards reduction in TNF-ɑ levels was seen in SF compared to UF (Fig.1-B). In the GM, commensal taxa like Bacteriodes plebius, B. coprocoia, Denoccota, Fusobacteria and Bacterium NLAE-z1-H40 increased significantly only in SF group (p<0.05). But, pathogenic taxa, Protobacteria, Deferribacterota, Aquificota, Bdellovibrionota, Camplylobacteria, Acidobacteria, Verrucomicrobiota, Desulfobacteriota, Klebisella pneumonia, Escherichia coli, Haeomophilus pittmaniae, increased in the UF group. (p<0.05) (Fig. 1-A).

Conclusion: Two months of saturated fat as a therapeutic intervention, improved survival in SAH patients compared with unsaturated fat. This could be related to promotion of the growth of commensal bacteria which attenuated inflammation, disease severity and improved liver disease indices.