{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:05:20Z","timestamp":1790197520676,"version":"4.1.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Cancer-related pain remains a critical clinical challenge, with existing opioid-based therapies often yielding inadequate relief and significant side effects. This study investigates the therapeutic potential of JK5G postbiotics\u2014a formulation of inactivated\n                      <jats:italic>Lactobacillus<\/jats:italic>\n                      strains and metabolites\u2014in modulating the gut-microbiome-immune axis to alleviate pain in cancer patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study employs a randomized, double-blind, placebo-controlled trial design involving 149 participants divided into two groups: a control group receiving patient-controlled subcutaneous analgesia (PCSA) plus placebo, and an experimental group receiving PCSA plus JK5G postbiotics. The primary outcomes were changes in gut microbiota composition assessed by 16S rRNA gene sequencing, and quality of life (QoL). The secondary outcomes included fecal metabolomics, adverse effects (AEs), blood inflammatory cytokines, and lymphocyte subsets. This study was registered at\n                      <jats:ext-link>www.chictr.org.cn<\/jats:ext-link>\n                      <jats:bold>(ChiCTR2500108811).<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      JK5G supplementation significantly improved pain scores, QoL, and cognitive and social functioning compared to controls. Microbiome analysis revealed enrichment of beneficial taxa such as\n                      <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                      and\n                      <jats:italic>Bifidobacterium<\/jats:italic>\n                      , alongside suppression of pathogenic\n                      <jats:italic>Escherichia-Shigella<\/jats:italic>\n                      . Machine learning identified five core microbial biomarkers (\n                      <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                      ,\n                      <jats:italic>Bifidobacterium<\/jats:italic>\n                      ,\n                      <jats:italic>Escherichia-Shigella<\/jats:italic>\n                      ,\n                      <jats:italic>Blautia<\/jats:italic>\n                      ,\n                      <jats:italic>Streptococcus<\/jats:italic>\n                      ), with SHAP analysis highlighting\n                      <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                      and\n                      <jats:italic>Bifidobacterium<\/jats:italic>\n                      as top contributors. Metabolomic profiling demonstrated upregulation of 236 metabolites, including kynurenic acid and butyric acid, with tryptophan and butyrate metabolism emerging as key altered pathways. Immune profiling showed elevated CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and reduced TNF-\u03b1 levels, while MIMOSA2 analysis linked microbial taxa to metabolic shifts, such as correlations between\n                      <jats:italic>Ruminococcus torques<\/jats:italic>\n                      and butyric acid.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that JK5G may contribute to the amelioration of cancer-related pain by reshaping gut microbiota, modulating host metabolism, and enhancing immune responses. This study highlights the potential of JK5G postbiotics as an adjunct therapy, supporting the need for further validation in larger cohorts and mechanistic investigations to advance its clinical translation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.chictr.org.cn\/showproj.html?proj=285304<\/jats:ext-link>\n                      , identifier ChiCTR2500108811.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1764491","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T05:42:43Z","timestamp":1772602963000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["JK5G postbiotics modulate gut microbiota and metabolome to alleviate cancer-related pain: a randomized controlled trial with multi-omics integration"],"prefix":"10.3389","volume":"17","author":[{"given":"Mengting","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Clinical Nutrition, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Oncology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]},{"name":"Department of Palliative Care, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Oncology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]},{"name":"Department of Palliative Care, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Geriatric Oncology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]},{"name":"Department of Palliative Care, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liejun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Oncology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]},{"name":"Department of Palliative Care, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sixiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Oncology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]},{"name":"Department of Palliative Care, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]},{"name":"Department of Geriatric Oncology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]},{"name":"Department of Palliative Care, Chongqing University Cancer Hospital, School of Medicine, Chongqing University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdm056","article-title":"Prevalence of pain in patients with cancer: a systematic review of the past 40 years","volume":"18","author":"van den Beuken-van Everdingen","year":"2007","journal-title":"Ann Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(09)70200-1","article-title":"Baseline quality of life as a prognostic indicator of survival: a meta-analysis of individual patient data from EORTC clinical trials","volume":"10","author":"Quinten","year":"2009","journal-title":"Lancet Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1184961","article-title":"Combined early palliative care for non-small-cell lung cancer patients: a randomized controlled trial in Chongqing, China","volume":"13","author":"Chen","year":"2023","journal-title":"Front Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1382496","article-title":"Knowledge, attitudes, and current practices toward lung cancer palliative care management in China: a national survey","volume":"14","author":"Chen","year":"2024","journal-title":"Front Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00393-7","article-title":"Chronic pain: an update on burden, best practices, and new advances","volume":"397","author":"Cohen","year":"2021","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"977","DOI":"10.6004\/jnccn.2019.0038","article-title":"Adult cancer pain, version 3.2019, NCCN clinical practice guidelines in oncology","volume":"17","author":"Swarm","year":"2019","journal-title":"J Natl Compr Cancer Network: JNCCN"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2010.06.025","article-title":"Predicting the analgesic effect to oxycodone by \u2018static\u2019 and \u2018dynamic\u2019 quantitative sensory testing in healthy subjects","volume":"151","author":"Eisenberg","year":"2010","journal-title":"Pain"},{"key":"B8","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s11912-020-00906-x","article-title":"Percutaneous management of cancer pain","volume":"22","author":"Filippiadis","year":"2020","journal-title":"Curr Oncol Rep"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s40122-022-00386-w","article-title":"Clinical observation of the effects of oral opioid on inflammatory cytokines and gut microbiota in patients with moderate to severe cancer pain: A retrospective cohort study","volume":"11","author":"Wang","year":"2022","journal-title":"Pain Ther"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-024-01017-9","article-title":"The gut-brain axis and pain signalling mechanisms in the gastrointestinal tract","volume":"22","author":"Meerschaert","year":"2025","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1612567","article-title":"Nutritional status, immunonutrition, and gut microbiome: a coming of age for immunotherapy","volume":"16","author":"Mattavelli","year":"2025","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1155592","article-title":"JK5G postbiotics attenuate immune-related adverse events in NSCLC patients by regulating gut microbiota: a randomized controlled trial in China","volume":"13","author":"Chen","year":"2023","journal-title":"Front Oncol"},{"key":"B13","volume-title":"Guidelines of Chinese Society of Clinical Oncology nutrition in cancer patients","year":"2021"},{"key":"B14","volume-title":"Chinese Dietary Guidelines (2022)","year":"2022"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1177\/10499091211072502","article-title":"Early palliative care in patients with non-small-cell lung cancer: A randomized controlled trial in southwest China","volume":"39","author":"Chen","year":"2022","journal-title":"Am J hospice palliative Care"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-016-3246-7","article-title":"How does pain experience relate to the need for pain relief? A secondary exploratory analysis in a large sample of cancer patients","volume":"24","author":"Johnsen","year":"2016","journal-title":"Supportive Care Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2019.05.020","article-title":"Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system","volume":"39","author":"Chen","year":"2020","journal-title":"Clin Nutr (Edinburgh Scotland)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e1800612","DOI":"10.1002\/mnfr.201800612","article-title":"SIRT3 deficiency promotes high-fat diet-induced nonalcoholic fatty liver disease in correlation with impaired intestinal permeability through gut microbial dysbiosis","volume":"63","author":"Chen","year":"2019","journal-title":"Mol Nutr Food Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2024.136691","article-title":"Chronic exposure of adult zebrafish to polyethylene and polyester-based microplastics: metabolomic and gut microbiome alterations reflecting dysbiosis and resilience","volume":"484","author":"Medriano","year":"2025","journal-title":"J hazardous materials"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btac003","article-title":"MIMOSA2: a metabolic network-based tool for inferring mechanism-supported relationships in microbiome-metabolome data","volume":"38","author":"Noecker","year":"2022","journal-title":"Bioinf (Oxford England)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41522-022-00367-z","article-title":"Inflammatory microbes and genes as potential biomarkers of Parkinson\u2019s disease","volume":"8","author":"Nie","year":"2022","journal-title":"NPJ biofilms microbiomes"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2025.08.017","article-title":"Microbiome-metabolome generated bile acids gatekeep infliximab efficacy in Crohn\u2019s disease by licensing M1 suppression and Treg dominance","volume":"12","author":"Liu","year":"2025","journal-title":"J advanced Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.fshw.2022.10.003","article-title":"The protective effect of carnosic acid on dextran sulfate sodium-induced colitis based on metabolomics and gut microbiota analysis","volume":"12","author":"Du","year":"2023","journal-title":"Food Sci Hum Wellness"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.62347\/lujf9626","article-title":"Altered gut microbiome drives heightened pain sensitivity in a murine model of metastatic triple-negative breast cancer","volume":"14","author":"Dutta","year":"2024","journal-title":"Am J Cancer Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1186\/s12967-024-05066-1","article-title":"Multi-omics analysis of the gut microbiome and metabolites associated with the psychoneurological symptom cluster in children with cancer receiving chemotherapy","volume":"22","author":"Bai","year":"2024","journal-title":"J Trans Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.6004\/jnccn.2022.7034","article-title":"Intravenous patient-controlled analgesia versus oral opioid to maintain analgesia for severe cancer pain: A randomized phase II trial","volume":"20","author":"Lin","year":"2022","journal-title":"J Natl Compr Cancer Network: JNCCN"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1901182116","article-title":"Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome","volume":"116","author":"Zhang","year":"2019","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e70154","DOI":"10.1111\/jnc.70154","article-title":"Exploring the role of microglial cells in the gut-brain axis communication: A systematic review","volume":"169","author":"Ortiz-Samur","year":"2025","journal-title":"J neurochemistry"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2023.2246184","article-title":"Multi-omics analysis revealing the interplay between gut microbiome and the host following opioid use","volume":"15","author":"Kolli","year":"2023","journal-title":"Gut Microbes"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1186\/s12885-025-14473-6","article-title":"Cancer pain and quality of life structural equation model based on the biopsychosocial model","volume":"25","author":"Hu","year":"2025","journal-title":"BMC Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.apjon.2024.100535","article-title":"Review of the microbiome and metabolic pathways associated with psychoneurological symptoms in children with cancer","volume":"11","author":"Webster","year":"2024","journal-title":"Asia-Pacific J Oncol Nurs"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2020.08.017","article-title":"Gut microbiome improves postoperative cognitive function by decreasing permeability of the blood-brain barrier in aged mice","volume":"164","author":"Wen","year":"2020","journal-title":"Brain Res Bull"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.680038","article-title":"Changes in the vaginal microbiome and associated toxicities following radiation therapy for gynecologic cancers","volume":"11","author":"Tsementzi","year":"2021","journal-title":"Front Cell infection Microbiol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"152","DOI":"10.3390\/antibiotics10020152","article-title":"Antimicrobial prophylaxis and modifications of the gut microbiota in children with cancer","volume":"10","author":"Boss\u00f9","year":"2021","journal-title":"Antibiotics (Basel Switzerland)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharep.2018.10.002","article-title":"Kynurenic acid and zaprinast diminished CXCL17-evoked pain-related behaviour and enhanced morphine analgesia in a mouse neuropathic pain model","volume":"71","author":"Rojewska","year":"2019","journal-title":"Pharmacol reports: PR"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.14336\/ad.2022.0916","article-title":"Tryptophan metabolism in central nervous system diseases: pathophysiology and potential therapeutic strategies","volume":"14","author":"Huang","year":"2023","journal-title":"Aging Dis"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.3390\/ph17091205","article-title":"Association of the serotonin and kynurenine pathways as possible therapeutic targets to modulate pain in patients with fibromyalgia","volume":"17","author":"Alfaro-Rodr\u00edguez","year":"2024","journal-title":"Pharm (Basel Switzerland)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1764491\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T05:42:44Z","timestamp":1772602964000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1764491\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,4]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2026.1764491"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1764491","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,4]]},"article-number":"1764491"}}