{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:01:04Z","timestamp":1790204464658,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University","award":["IMSIU-DDRSP2601"],"award-info":[{"award-number":["IMSIU-DDRSP2601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The axis linking the gut to the brain to the immune system connects all tissues involved\u2014bacteria, immune cells, metabolism and the CNS\u2014through a multidirectional communication network. Several studies have confirmed that when this axis is disrupted, it can be responsible for Alzheimer\u2019s disease, Parkinson\u2019s disease, obesity, type 2 diabetes, and NAFLD, and the main consequences come from increased systemic inflammation, altered regulation of immune cells, the production of microbial metabolites that alter signals to the immune cells and nervous system, increase in oxidative stress, breakdown of the gut barrier, and more. In recent years, advanced multi-omics technologies, such as metagenomics, transcriptomics, metabolomics, proteomics, and single-cell sequencing, have provided significant advancement in our understanding of all of the interacting nodes involved in the gut\u2013brain\u2013immune axis. These advanced sequencing technologies can characterize the microbial communities, host immune cells, metabolic profiles, and the degree of cell heterogeneity during a specific disease. Combining multi-omics information can reveal a few shared pathways between neurodegenerative and metabolic disorders, such as NF-\u03baB, NLRP3 inflammasome activation, mitochondrial dysfunction, changes in SCFA metabolism, and the alteration of microbial populations in Alzheimer\u2019s and Parkinson\u2019s disease; metabolic dysbiosis and increased risk for Parkinson\u2019s disease; or changes in gut-to-brain-to-immune signaling contributing to diabetes complications and NAFLD. Artificial intelligence (AI) and machine learning are becoming promising tools for detecting biomarkers from these datasets, extracting knowledge, interpreting systems biology, and helping with developing precision medicine. In this review, we summarize current evidence that supports the role of the gut\u2013brain\u2013immune axis in neurodegenerative and metabolic diseases, highlighting results gained with the utilization of multi-omics approaches. We will describe the key microbial, immune, and metabolic pathways involved in pathogenesis and therapeutic approaches including psychobiotics, tailored nutrition, modulation of the microbiome, and metabolite interventions, discussing future perspectives of the translation of the gut\u2013brain\u2013immune axis knowledge into clinical practice.<\/jats:p>","DOI":"10.3390\/cells15121089","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:46:28Z","timestamp":1781588788000},"page":"1089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Gut\u2013Brain\u2013Immune Axis: Multi-Omics Insights into Neurodegenerative and Metabolic Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7466-5633","authenticated-orcid":false,"given":"Salah-Ud-Din","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Biochemistry, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Multidisciplinary Research Unit, Government Institute of Medical Sciences, Greater Noida 201310, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1506-7836","authenticated-orcid":false,"given":"Anis Ahmad","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsin","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Education, Government of Jharkhand, Ranchi 834006, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1152\/physrev.00018.2018","article-title":"The microbiota\u2013gut\u2013brain axis","volume":"99","author":"Cryan","year":"2019","journal-title":"Physiol. 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