Chemo-Omics Integration of the Gut-Brain-Liver Triad in Hepatic Encephalopathy: A Multi-Omics Trans-Integrated Bio-Intelligence Network Framework for Molecular Biomarkers and AI-Driven Precision Therapeutics
DOI:
https://doi.org/10.64229/91238e13Keywords:
Hepatic encephalopathy, Gut-brain-liver axis, Multi-omics, Artificial intelligence, Precision hepatoneurologyAbstract
Hepatic encephalopathy (HE) is a multifactorial neuropsychiatric comorbidity that develops as a result of hepatic dysfunction, and its pathogenesis is determined by a complex of interactions of gut dysbiosis, hepatic metabolic failure, and neuroinflammation. This study presents the multi-omics framework called Trans-Integrated Bio-Intelligence Network (TIBIN), which explains the gut-brain-liver triad of molecular and microbial interactions based on the combination of metagenomic, metabolomic, proteomic, and epigenomic data with artificial-intelligence-based analytics. This review will fill the gap between systems biology and computational modelling to outline mechanistic pathways between ammonia dysmetabolism, bile-acid signalling and neuroimmune cross-talk in HE pathogenesis by synthesising evidence systematically between 2020 and 2025. The TIBIN model also suggests an AI-written diagnostic algorithm to be used in accurate stratification, which involves microbial signatures, serum-CSF biomarkers, and predictive metabolite panel. This transdisciplinary philosophy highlights a paradigm change in symptom-based management to predictive and personalized hepatoneurology, and provides a guide to clinical translation in the future. Through the combination of omics convergence and machine learning (ML), the paper results in a scalable platform of biomarker discovery, real-time integration of biosensors, and adaptive optimisation of therapeutics.
References
[1]Anand S, Mande SS. Host-microbiome interactions: Gut-Liver axis and its connection with other organs. NPJ Biofilms and Microbiomes, 2022, 8(1), 89. DOI: 10.1038/s41522-022-00352-6
[2]Dubbelman MA, Vromen EM, Tijms BM, Berkhof J, Ottenhoff L, Vijverberg EG, et al. Pooling alzheimer's disease clinical trial data to develop personalized medicine approaches is easier said than done: A proof‐of‐principle study and call to action. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2024, 10(3), e12485. DOI: 10.1002/trc2.12485
[3]Chidambaram SB, Essa MM, Rathipriya AG, Bishir M, Ray B, Mahalakshmi AM, Tousif AH, et al. Gut dysbiosis, defective autophagy and altered immune responses in neurodegenerative diseases: Tales of a vicious cycle. Pharmacology & Therapeutics, 2022, 231, 107988. DOI: 10.1016/j.pharmthera.2021.107988
[4]Dong TS, Mayer E. Advances in brain-gut-microbiome interactions: A comprehensive update on signaling mechanisms, disorders, and therapeutic implications. Cellular and Molecular Gastroenterology and Hepatology, 2024, 18(1), 1-13. DOI: 10.1016/j.jcmgh.2024.01.024
[5]Hudson M, Schuchmann M. Long-term management of hepatic encephalopathy with lactulose and/or rifaximin: A review of the evidence. European Journal of Gastroenterology & Hepatology, 2019, 31(4), 434-450. DOI: 10.1097/MEG.0000000000001311
[6]Faccioli J, Nardelli S, Gioia S, Riggio O, Ridola L. Primary prophylaxis of overt hepatic encephalopathy: Is it time to consider it? Journal of Clinical Medicine, 2023, 12(12), 3903. DOI: 10.3390/jcm12123903
[7]Giuli L, Maestri M, Santopaolo F, Pompili M, Ponziani FR. Gut microbiota and neuroinflammation in acute liver failure and chronic liver disease. Metabolites, 2023, 13(6), 772. DOI: 10.3390/metabo13060772
[8]Gorlé N, Bauwens E, Haesebrouck F, Smet A, Vandenbroucke RE. Helicobacter and the potential role in neurological disorders: There is more than Helicobacter pylori. Frontiers in Immunology, 2021, 11, 584165. DOI: 10.3389/fimmu.2020.584165
[9]Gupta H, Suk KT, Kim DJ. Gut microbiota at the intersection of alcohol, brain, and the liver. Journal of Clinical Medicine, 2021, 10(3), 541. DOI: 10.3390/jcm10030541
[10]Hurley MJ, Bates R, Macnaughtan J, Schapira AHV. Bile acids and neurological disease. Pharmacology & Therapeutics, 2022, 240, 108311. DOI: 10.1016/j.pharmthera.2022.108311
[11]Jain A, Madkan S, Patil P. The role of gut microbiota in neurodegenerative diseases: Current insights and therapeutic implications. Cureus, 2023, 15(10), e47861. DOI: 10.7759/cureus.47861
[12]Lim L. Modifying alzheimer’s disease pathophysiology with photobiomodulation: Model, evidence, and future with EEG-guided intervention. Frontiers in Neurology, 2024, 15, 1407785. DOI: 10.3389/fneur.2024.1407785
[13]Llansola M, Arenas YM, Sancho-Alonso M, Mincheva G, Palomares-Rodriguez A, Doverskog M, et al. Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination: Mechanisms and therapeutic implications. Frontiers in Pharmacology, 2024, 15, 1358323. DOI: 10.3389/fphar.2024.1358323
[14]Won SM, Oh KK, Gupta H, Ganesan R, Sharma SP, Jeong JJ, et al. The link between gut microbiota and hepatic encephalopathy. International Journal of Molecular Sciences, 2022, 23(16), 8999. DOI: 10.3390/ijms23168999
[15]Shahreen N, Osinuga A, Malla S, Razmpour T, Tabibian M, Saha R. Multi-omics integration in genome-scale metabolic models: A review of constraint-based approaches. Molecular Omics, 2026, 22(2), aaiag005. DOI: 10.1093/molecular-omics/aaiag005
[16]Mukherjee U, Reddy PH. Gut-brain relationship in dementia and Alzheimer’s disease: Impact on stress and immunity. Ageing Research Reviews, 2025, 93, 102843. DOI: 10.1016/j.arr.2025.102843
[17]Park JC, Chang L, Kwon H, Im S. Beyond the gut: Decoding the gut-immune-brain axis in health and disease. Cellular & Molecular Immunology, 2025, 22, 1287-1312. DOI: 10.1038/s41423-025-01333-3
[18]Cascarano A, Mur-Petit J, Hernández-González J, Camacho M, Eadie NT, Gkontra P, et al. Machine and deep learning for longitudinal biomedical data: A review of methods and applications. Artificial Intelligence Review, 2023, 56, 1711-1771. DOI: 10.1007/s10462-023-10561-w
[19]Wu PS, Lee PC, Chang TE, Hsieh YC, Chiou JJ, Lin CH, et al. Fecal carriage of multidrug-resistant organisms increases the risk of hepatic encephalopathy in patients with cirrhosis: Insights from gut microbiota and metabolite features. Gut Pathogens, 2025, 17(1), 30. DOI: 10.1186/s13099-025-00706-3
[20]Sepehrinezhad A, Shahbazi A. The pathophysiology of hepatic encephalopathy at the level of gut-liver-brain axis: The role of resident innate immune cells. Liver Cirrhosis and Its Complications - Advances in Diagnosis and Management, 2024, DOI: 10.5772/intechopen.1004125
[21]Shah YR, Ali H, Tiwari A, Guevara-Lazo D, Nombera-Aznaran N, Pinnam BSM, et al. Role of fecal microbiota transplant in management of hepatic encephalopathy: Current trends and future directions. World Journal of Hepatology, 2024, 16(1), 17-34. DOI: 10.4254/wjh.v16.i1.17
[22]Singh VV, Prasad SK, Acharjee A, Srivastava S, Acharjee P. Investigating hippocampal proteome dynamics in aging rats with minimal hepatic encephalopathy via high-resolution mass spectrometry. Research Square, 2024. DOI: 10.21203/rs.3.rs-5107499/v1
[23]Solanki R, Karande AA, Ranganathan P. Emerging role of gut microbiota dysbiosis in neuroinflammation and neurodegeneration. Frontiers in Neurology, 2023, 14, 1149618. DOI: 10.3389/fneur.2023.1149618
[24]Sun X, Shukla M, Wang W, Li S. Unlocking gut-liver-brain axis communication metabolites: Energy metabolism, immunity and barriers. NPJ Biofilms Microbiomes, 2024, 10(1), 136. DOI: 10.1038/s41522-024-00610-9
[25]Yan M, Man S, Sun B, Ma L, Guo L, Huang L, et al. Gut-liver-brain axis in diseases: The implications for therapeutic interventions. Signal Transduction and Targeted Therapy, 2023, 8(1), 443. DOI: 10.1038/s41392-023-01673-4
[26]Zheng Y, Bonfili L, Wei T, Eleuteri AM. Understanding the gut-brain axis and its therapeutic implications for neurodegenerative disorders. Nutrients, 2023, 15(21), 4631. DOI: 10.3390/nu15214631
[27]Acharya C, Bajaj JS. Altered microbiome in patients with cirrhosis and complications. Clinical Gastroenterology and Hepatology, 2019, 17(2), 307-321. DOI: 10.1016/j.cgh.2018.08.008
[28]Montagnese S, Rautou PE, Romero-Gómez M, Larsen FS, Shawcross DL, Thabut D, et al. EASL clinical practice guidelines on the management of hepatic encephalopathy. Journal of Hepatology, 2022, 77(3), 807-824. DOI: 10.1016/j.jhep.2022.06.001
[29]Ntuli Y, Shawcross DL. Infection, inflammation and hepatic encephalopathy from a clinical perspective. Metabolic Brain Disease, 2024, 39(8), 1689-1703. DOI: 10.1007/s11011-024-01402-y
[30]Nguyen HH, Swain MG. Avenues within the gut-liver-brain axis linking chronic liver disease and symptoms. Frontiers in Neuroscience, 2023, 17, 1171253. DOI: 10.3389/fnins.2023.1171253
[31]Louissaint J, Vargas HE. Picture perfect: Artificial intelligence in the management of hepatic encephalopathy. The American Journal of Gastroenterology, 2024, 119(5), 801-802. DOI: 10.14309/ajg.0000000000002659
[32]He XL, Hu MY, Xu Y, Xia FB, Tan Y, Wang YQ, et al. The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis. Nature Medicine, 2025, 31(2), 627-638. DOI: 10.1038/s41591-024-03405-9
[33]Rocco A, Sgamato C, Compare D, Coccoli P, Nardone OM, Nardone G. Gut microbes and hepatic encephalopathy: From the old concepts to new perspectives. Frontiers in Cell and Developmental Biology, 2021, 9, 748253. DOI: 10.3389/fcell.2021.748253
[34]Giner-Pérez L, Gallego J, Giménez‐Garzó C, Batallas D, Jarquín‐Díaz VH, Casanova-Ferrer F, et al. The analysis of the gut microbiome during liver disease progression led to the identification of biomarkers for related mild cognitive impairment. Frontiers in Microbiology, 2025, 16, 1670512. DOI: 10.3389/fmicb.2025.1670512
[35]Wang Q, Chen CX, Zuo S, Cao K, Li HY. Integrative analysis of the gut microbiota and faecal and serum short-chain fatty acids and tryptophan metabolites in patients with cirrhosis and hepatic encephalopathy. Journal of Translation Medicine, 2023, 21(1), 395. DOI: 10.1186/s12967-023-04262-9
[36]Xu XT, Jiang MJ, Fu YL, Xie F, Li JJ, Meng QH. Gut microbiome composition in patients with liver cirrhosis with and without hepatic encephalopathy: A systematic review and meta-analysis. World Journal of Hepatology, 2025, 17(1), 100377. DOI: 10.4254/wjh.v17.i1.100377
[37]Kang EJ, Cha M, Kwon GH, Han SH, Yoon SJ, Lee S, et al. Akkermansia muciniphila improve cognitive dysfunction by regulating BDNF and serotonin pathway in gut-liver-brain axis. Microbiome, 2024, 12(1), 181. DOI: 10.1186/s40168-024-01924-8
[38]Siddle M, Gallego Durán R, Goel D, Renquist BJ, Holt MK, Hadjihambi A. Mechanistic insights into the liver-brain axis during chronic liver disease. Nature Reviews Gastroenterology & Hepatology, 2026, 23(2), 166-188. DOI: 10.1038/s41575-025-01142-z
[39]Ramírez-Mejía MM, Ponciano-Rodríguez G, Méndez-Sánchez N. Implications of the liver-gut axis in liver disease: From mechanisms to therapeutic targets. Archives of Medical Research, 2025, 56(8), 103335. DOI: 10.1016/j.arcmed.2025.103335
[40]Clift AK, Hagness M, Lehmann K, Rosen CB, Adam R, Mazzaferro V, et al. Transplantation for metastatic liver disease. Journal of Hepatology, 2023, 78(6), 1137-1146. DOI: 10.1016/j.jhep.2023.03.029
[41]Li SP, Xu ZG, Diao H, Zhou A, Tu DJ, Wang SM, et al. Gut microbiome alterations and hepatic encephalopathy post-TIPS in liver cirrhosis patients. Journal of Translational Medicine, 2025, 23(1), 745. DOI: 10.1186/s12967-025-06774-y
[42]He XL, Hu MY, Xu Y, Xia FB, Tan Y, Wang YQ, et al. The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis. Nature Medicine, 2025, 31(2), 627-638. DOI: 10.1038/s41591-024-03405-9
[43]Bessone F, García-Cortés M, Medina-Caliz I, Hernandez N, Parana R, Mendizabal M, et al. Herbal and dietary supplements-induced liver injury in Latin America: Experience from the LATINDILI network. Clinical Gastroenterology and Hepatology, 2022, 20(3), e548-e563. DOI: 10.1016/j.cgh.2021.01.011
[44]Higuera-de-la-Tijera F, Alvares-da-Silva MR, Castro-Narro GE, Barahona-Garrido J, Carrera-Estupiñán E, Garavito-Rentería J, et al. First Latin American consensus on the treatment and prophylaxis of hepatic encephalopathy. Annals of Hepatology, 2026, 31(1), 102142. DOI: 10.1016/j.aohep.2025.102142
[45]Xu XY, Ding HG, Li WG, Han Y, Guan YJ, Xu JH, et al. Chinese guidelines on the management of hepatic encephalopathy in cirrhosis (2024). Journal of Clinical and Translational Hepatology, 2025, 13(3), 253-267. DOI: 10.14218/JCTH.2024.00484
[46]Sibilio P, De Smaele E, Paci P, Conte F. Integrating multi-omics data: Methods and applications in human complex diseases. Biotechnology Reports, 2025, 48, e00938. DOI: 10.1016/j.btre.2025.e00938
[47]Sepehrinezhad A, Shahbazi A. Linking brain and immune transcriptomes to gut-derived metabolites in hepatic encephalopathy: An explorative integrative multi-omics approach. Hepatic Medicine: Evidence and Research, 2025, 17, 105-124. DOI: 10.2147/HMER.S546200
[48]Listopad S, Magnan C, Day L, Asghar A, Stolz A, Tayek JA, et al. Identification of integrated proteomics and transcriptomics signature of alcohol-associated liver disease using machine learning. PLOS Digit Health, 2024, 3(2), e0000447. DOI: 10.1371/journal.pdig.0000447
[49]Rubio T, Felipo V, Tarazona S, Pastorelli R, Escudero-García D, Toscá J, et al. Multi-omic analysis unveils biological pathways in peripheral immune system associated to minimal hepatic encephalopathy appearance in cirrhotic patients. Scientific Reports, 2021, 11(1), 1907. DOI: 10.1038/s41598-020-80941-7
[50]Chen JH, Jin HW, Zhou H, Hei XF, Liu K. Research into the characteristic molecules significantly affecting liver cancer immunotherapy. Frontiers in Immunology, 2023, 14, 1029427. DOI: 10.3389/fimmu.2023.1029427
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Ansar Bilyaminu Adam, Mariya Nasir Danbatta (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
