Table 2.
Studies reporting on the effects of therapies targeting the gut microbiota on systemic inflammation.
| Study | Agent studied | Experimental setting | Experimental results | Clinical results |
|---|---|---|---|---|
| Paula Izquierdo-Altarejos et al. 2024 [94] | MSC-EVs | Hyperammonemic rats | Ex vivo studies demonstrate that MSC-EVs reduce pro-inflammatory factors such as TNFα, suppress NF-κB activation, and inhibit key pathways responsible for motor incoordination. | MSC-EV administration suppressed the activation of cerebellar microglia and astrocytes, and ameliorated motor coordination deficits in a rat model of hyperammonemia. |
| Xueyan Lin et al. 2025 [95] | Rifaximin and lactulose | CCl4 induced rat model of MHE | ↑Portal and serum LPS levels and circulatory pro-inflammatory mediators, including IL-1β and TNF-α, ↑Clostridiales and Spirochaetia in MHE rats, ↑Lactobacillus, Erysipelotrichia, Allobaculum, and Bifidobacterium in rifaximin group, ↑Proteobacteria and Bacteroides in lactulose group, ↓portal LPS levels,IL-1β and TNF-α in rifaximin and lactulose group | Rifaximin and lactulose↑cognitive performance in MHE rats |
| Keyvan Amirshahrokhi et al. 2025 [96] | Edaravone | HE mice induced by the injection of thioacetamide | ↓the expression of p-NF-κB and iNOS. ↓the levels of NO, MPO and MMP-9 in the brain of mice. ↓the brain levels and expressions of inflammatory cytokines IL-1β, IL-6, TNF-α and IFN-γ. | ↑the locomotor function and ↓brain histopathological changes in mice with HE |
| Hao Wu et al. 2016 [97] | STAT3 | HCC patients | ↑Serum levels of IL-1β, IL-6, IL-17a, IFNγ and IFNλ3 in patients with MHE. ↑STAT3 in circulating PBMCs of MHE. | STAT3 inhibitor treatment prevented cytokine-induced neuronal apoptosis in vitro. |
| Alba Mangas-Losada et al. 2019 [98] | Rifaximin | 30 controls without liver disease, 30 cirrhotic patients without MHE and 22 patients with MHE. Patients with MHE were treated with rifaximin. | ↓IL-17, CXCL13, CX3CL1 (fractalkine) and IL-22 to normal values in responders but not in non-responders. | Rifaximin improved MHE in 59% of patients with MHE. |
| Vishal C Patel et al. 2022 [76] | Rifaximin-α | 38 cirrhosis patients with HE were randomised 1:1 to receive either rifaximin-α or placebo for 90 days. | Rifaximin-α↓circulating neutrophil TLR-4 expression and plasma TNF-α,↓oralisation of the gut, ↓the abundance of mucin-degrading and sialidase-rich species such as Streptococcus spp., Veillonella atypica, V. parvula, Akkermansia, and Hungatella. Rifaximin-α↑a TNF-α- and interleukin-17E-enriched intestinal microenvironment,↑antibacterial responses to invading pathobionts,↑gut barrier repair | Resolution of overt and covert HE, ↓the likelihood of infection, ↓oralisation of the gut and ↓systemic inflammation. |
| Arpan Jain et al. 2022 [99] | A combination of LOLA, lactulose, and rifaximin (n = 70) or placebo, lactulose, and rifaximin (n = 70). | Patients of cirrhosis with OHE grade III-IV | ↓Levels of inflammatory markers. ↓levels of blood ammonia, IL-6, and TNF-α in the LOLA group. | LOLA combined with lactulose and rifaximin demonstrated superior efficacy compared to lactulose and rifaximin alone, resulting in greater improvement in HE grading, shorter recovery time from encephalopathy, and reduced 28-day mortality. |
| Bajaj et al. 2019 [59] | FMT | 20 cirrhotic patients with recurrent HE and MELD < 17 receiving standard of care therapy. | ↑ Gut microbiota diversity with ↑ abundance of Ruminococcaceae and Bifidobacteriacceae, ↓ Streptococcaceae and Veillonellaceae. ↑ E-cadherin and defensin alpha 5. ↓ pro-inflammatory cytokines. |
↑ Cognition. |
| Andrew Fagan et al. 2023 [100] | Albumin infusions | Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE. | ↓IL-1β and endothelial dysfunction markers was also observed in the albumin group. | ↑Cognitive function and psychosocial QoL |
STAT3: signal transducer and activator of transcription; HCC: hepatocellular carcinoma; IL: interleukin; IFN: interferon; PBMC: peripheral blood mononuclear cell; MHE: minimal hepatic encephalopathy; MSC-EVs: extracellular vesicles from mesenchymal stem cells; CCl4: carbon tetrachloride; LPS: lipopolysaccharide; TNF: tumor necrosis factor; HE: hepatic encephalopathy; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS: inducible nitric oxide synthase; NO: nitric oxide; MPO: myeloperoxidase; MMP-9: matrix metalloproteinase-9; CXCL13: C-X-C motif chemokine ligand 13; CX3CL1: C-X3-C motif chemokine ligand 1; TLR-4: Toll-Like receptor 4; LOLA: L-Ornithine L-Aspartate; OHE: overt hepatic encephalopathy; FMT: fecal microbiota Transplantation; MELD: model for end-stage liver disease; QoL: quality of life.