The immunomodulatory effect of Withania somnifera (WS) extract was tested in healthy adults. In this randomized placebo-controlled double-blinded study, subjects were allocated either 60 mg WS extract or placebo. It consists of a blinded 30-day period and an open-label extension study of another 30 days with crossover of only placebo to test. After the 30-day blinded study period, the WS test group reported significant increase (p < 0.05) in Ig’s (IgA, IgM, IgG, IgG2, IgG3 and IgG4), Cytokines (IFN-γ, IL4), TBNK (CD45+, CD3+, CD4+, CD8+, CD19+, NK cells) whereas in the placebo group TBNK cells showed significant decrease (p < 0.05) and Ig’s and cytokines showed no change (p > 0.05). In the extension period on day 60, the subjects on placebo who were crossed over to the WS test group showed significant increase (p < 0.05) in Ig’s, cytokines and TBNK cells and the subjects who continued on the WS group showed a further significant improvement (p < 0.05) in Ig’s, cytokines and TBNK cells. There were no adverse events reported in the study. WS extract significantly improved the immune profile of healthy subjects by modulating the innate and adaptive immune systems. Boosting the immune system of people at risk of infection and during widespread infections can be targeted with WS extract.

Severe alcohol-associated hepatitis (SAH) patients with infections have a high short-term mortality rate. Gut microbiota dysbiosis plays an important role in the pathogenesis of SAH. Preliminary studies have demonstrated long-term benefits with healthy donor fecal microbiota transplantation (FMT). Data on FMT compared with pentoxifylline for SAH and relevant gut microbial changes are lacking in literature. From January 2019 to February 2021, retrospective analysis of a single hospital’s records revealed 47 SAH patients undergoing FMT (100 mL/day via nasoduodenal tube for 7 days) and 25 matched patients receiving pentoxifylline (400 mg/8 h for 28 days). The primary end point was a 6-month survival rate. Secondary end points included incidence of ascites, hepatic encephalopathy, infections, acute kidney injury, and gut microbiota changes between post-therapy groups. Biomarker discovery and network analysis were also performed to identify significant taxa of gut microbiota in post-treatment groups in retrospectively stored stool samples. All were males. The 6-month survival rate was higher in the patients undergoing FMT than in patients receiving pentoxifylline (83.0% vs 56.0%, P = 0.012). At the end of 6-month follow-up, the incidences of clinically significant ascites (56.0% vs 25.5%, P = 0.011), hepatic encephalopathy (40.0% vs 10.6%, P = 0.003), and critical infections (52.0% vs 14.9%, P < 0.001) in patients administered pentoxifylline were significantly higher than those in patients treated with FMT. At 3 months, biomarker analysis revealed a significant abundance of Bifidobacterium and Eggerthella in the FMT group and the pentoxifylline group, respectively. At 6 months, Bifidobacterium in the FMT group and pathogenic Aerococcaceae in the pentoxifylline group were notable. Network analysis showed beneficial taxa (Bifidobacterium) as a central influencer in those undergoing FMT at 6 months. Healthy donor FMT improved survival rate and reduced liver-related complications compared with pentoxifylline. These clinical benefits were associated with favorable modulation of intestinal bacterial communities. Difficult-to-treat SAH patients may be safely bridged to transplantation using FMT. Controlled trials evaluating long-term outcomes are an unmet need.

Alcohol-associated hepatitis (AH) is a critical condition with high mortality rates and is worsened by infections. Organ failure is strongly associated with intestinal dysbiosis. Emerging research suggests that gut microbiota modulation with probiotics can improve AH outcomes. This study investigated the clinical and microbiome effects of high-dose probiotic infusion (HDPI) compared with corticosteroid therapy (CST) and fecal microbiota transplantation (FMT) in severe AH. Patients with biopsy-proven severe-AH were enrolled from March 2019 to June 2020 and matched for age and disease severity. The patients received HDPI (n = 20), FMT (n = 16), or CST (n = 14). HDPI consists of a potent probiotic mix delivered via a nasoduodenal tube for 6 days. The primary outcome was survival at 90-days. Stool samples were subjected to 16S and 18S rRNA sequencing to assess significant bacterial and fungal taxa and their interactions at baseline and post treatment. At 90-days, survival rates were 55%, 64.3%, and 87.5% (HDPI, CST, respectively). HDPI did not beneficially impact bacterial alpha-diversity but significantly altered beta-diversity. Notably, the number of pathogenic bacteria, such as Bilophila and Roseburia increased. Fungal analysis revealed no significant changes in alpha diversity, but significant dissimilarities in beta diversity post-HDPI. New fungal genera such as Basidiomycota and Phragmoplastophyta have emerged, with significant deleterious expansion in fungal communities and damaging modifications between fungal–bacterial interactions. HDPI failed to outperform CST in improving the clinical outcomes of patients with severe AH. While HDPI influenced both bacterial and fungal microbiomes, it also led to the persistence of pathogenic communities. FMT showed superior survival outcomes, highlighting the urgent need for further controlled trials.

Export Introduction: Homeopathic remedies are highly diluted formulations without proven clinical benefits, traditionally believed not to cause adverse events. Nonetheless, published literature reveals severe local and non–liver-related systemic side effects. We present the first series on homeopathy-related severe drug-induced liver injury (DILI) from a single center. Methods: A retrospective review of records from January 2019 to February 2022 identified 9 patients with liver injury attributed to homeopathic formulations. Competing causes were comprehensively excluded. Chemical analysis was performed on retrieved formulations using triple quadrupole gas chromatography-mass spectrometry and inductively coupled plasma atomic emission spectroscopy. Results: Males predominated with a median age of 54 years. The most typical clinical presentation was acute hepatitis, followed by acute on chronic liver failure. All patients developed jaundice, and ascites were notable in one-third of the patients. Five patients had underlying chronic liver disease. COVID-19 prevention was the most common indication for homeopathic use. Probable DILI was seen in 77.8%, and hepatocellular injury predominated (66.7%). Four (44.4%) patients died (3 with chronic liver disease) at a median follow-up of 194 days. Liver histopathology showed necrosis, portal and lobular neutrophilic inflammation, and eosinophilic infiltration with cholestasis. A total of 29 remedies were consumed between 9 patients, and 15 formulations were analyzed. Toxicology revealed industrial solvents, corticosteroids, antibiotics, sedatives, synthetic opioids, heavy metals, and toxic phyto-compounds, even in ‘supposed’ ultra-dilute formulations. Conclusion: Homeopathic remedies potentially result in severe liver injury, leading to death in those with underlying liver disease. The use of mother tinctures, insufficient dilution, poor manufacturing practices, adulteration and contamination, and the presence of direct hepatotoxic herbals were the reasons for toxicity. Physicians, the public, and patients must realize that Homeopathic drugs are not ‘gentle placebos.’

Background and Aims: Severe alcohol-associated hepatitis (SAH) can trigger unstable decompensations in cirrhosis patients. They experience high rates of emergency department visits and hospitalization. We evaluated real-world clinical outcomes following palliative-faecal microbiota transplantation (pFMT) compared to best supportive care (BSC) in this critically ill population. Patients and Methods: From July 2021 to April 2024, 28 patients on pFMT were compared with 37 on BSC. Patients on pFMT received nasoduodenal healthy donor stool infusion daily for 5-days. Patients were followed up for portal hypertension-related events, infections, hospitalizations, extrahepatic organ failure and 6- and 12-months survival. 16S rRNA sequencing on stool samples collected at baseline and on follow up were analysed for changes in relative abundance (RA) of bacterial communities. Results: Patients were matched for age, type of decompensation and liver disease severity at enrolment. Twelve-month survival was 64.3% in pFMT versus 51.4% in BSC groups. pFMT dramatically reduced hospital readmissions (mean 0.76 ± 0.76 vs. 2.29 ± 1.27, p < 0.001). Unstable decompensations beyond 3 months occurred in 14.3% of pFMT versus 64.9% of BSC (p < 0.001). Organ failures were lesser with pFMT: acute kidney injury 7.7% versus 93.8% (p < 0.001), hepatic encephalopathy 7.1% versus 68.2% (p < 0.001). Infection burden was significantly lower (53.6% vs. 83.8%, p = 0.008), particularly infections requiring admission (17.4% vs. 66.7%, p < 0.001) with pFMT. Microbiome analysis revealed progressive expansion of Gram-negative genera in BSC, and beneficial Actinobacteria in pFMT-treated patients at 3, 6, and 12 months. Conclusions: Palliative FMT represents a unique disease-modifying intervention in end-stage alcohol-related cirrhosis, preventing organ failure progression, reducing healthcare utilization, and improving survival trajectories.

Background: Fatigue affects 60%–80% of patients with cirrhosis, yet no universally effective pharmacologic therapy exists. Taurine, an amino sulfonic acid with antioxidant and membrane-stabilizing properties, may address metabolic mechanisms underlying fatigue. We hypothesized that L -taurine supplementation would significantly reduce fatigue severity compared to standard care in patients with decompensated cirrhosis. Methods: This single-center, parallel-arm, open-label randomized controlled trial enrolled adults with decompensated cirrhosis (Child-Turcotte-Pugh score 7–13) and clinically significant fatigue (Fatigue Assessment Scale score >22) at a tertiary care center in South India. Participants were randomized via block randomization to L -taurine (1000 mg/d) plus standard care or standard care alone for 12 weeks. The primary outcome was the change in the Fatigue Assessment Scale score. Analysis of covariance examined treatment-by-anaemia interactions. Effect sizes were calculated using Cohen’s d . Results: Of 220 randomized patients, 202 completed the study (standard care: n=100; taurine: n=102). The mean FAS change was −6.83±8.70 (standard care) versus −8.08±7.95 (taurine), with no significant difference (mean difference −1.25; 95% CI: −3.55 to 1.05; p =0.288; Cohen’s d =−0.15). However, a significant treatment-by-anemia interaction was observed ( p =0.009). In patients without anemia (n=41), taurine produced a large treatment effect (−11.90±4.04 vs. −4.57±9.23; p =0.002; Cohen’s d =−1.02), whereas patients with anemia (n=161) showed no benefit ( p =0.832). Adverse events occurred in 11.8% of patients treated with taurine, all of which were mild. Conclusions: L -taurine did not improve fatigue in unselected patients with decompensated cirrhosis. A post hoc subgroup analysis suggested potential benefit in patients without anemia; however, given the open-label design, small subgroup size, post hoc nature of the analysis, and the inherent limitations of unblinded patient-reported outcomes, this finding should be considered hypothesis-generating. A confirmatory, placebo-controlled trial enrolling patients without anemia is warranted (Clinical Trials Registry India number CTRI/2023/06/054455).