{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:06:41Z","timestamp":1788962801426,"version":"build-2803163510"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"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. Microbiol."],"abstract":"<jats:p>Metabolic reprogramming is a central determinant of host defense and pathogen persistence during infection. Although the bacterial type VI secretion system (T6SS) is primarily recognized as a contact-dependent apparatus for interbacterial competition and effector delivery, emerging evidence indicates that T6SS activity can also influence host metabolism at cellular, nutritional, and microbial-community levels. Here, we organize current evidence into three mechanistic tiers: direct biochemical interference with lipids, metabolites, or metal ions; organelle- and signaling-mediated immunometabolic reprogramming; and indirect metabolic effects arising from T6SS-dependent remodeling of microbial communities. T6SS effectors can disrupt endoplasmic-reticulum lipid homeostasis, activate the unfolded protein response and autophagy, alter mitochondrial Ca2+ handling and dynamics, promote redox imbalance, and modulate metabolically sensitive immune pathways including phosphoinositide 3-kinase (PI3K)-Akt, inflammasome, and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. T6SS-associated proteins also mediate manganese and zinc acquisition or sequestration, linking microbial nutrient acquisition to host nutritional immunity. At the community level, T6SS-mediated competition may reshape resource allocation, horizontal gene transfer, and microbiome-derived metabolite production. However, while T6SS-induced organelle stress is well established, direct causal links to systemic metabolic diseases, including type 2 diabetes and dyslipidemia, remain unproven. We therefore distinguish direct metabolic measurements from inferences based on organelle damage or signaling changes and discuss strategies to define T6SS-driven metabolic fluxes and evaluate host-directed, anti-virulence, and microbiome-engineering approaches. Viewing the T6SS through an immunometabolic framework may reveal therapeutic vulnerabilities overlooked by conventional models of bacterial toxicity and competition.<\/jats:p>","DOI":"10.3389\/fmicb.2026.1951748","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:07:30Z","timestamp":1788959250000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Type VI secretion system effectors as modulators of host immunometabolism: organelle stress, nutritional immunity, and therapeutic opportunities"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhenzhen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, The People\u2019s Hospital of Weifang","place":["Weifang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Anorectal Surgery, Weifang Hospital of Traditional Chinese Medicine","place":["Weifang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"eaat8657","DOI":"10.1126\/science.aat8657","article-title":"cGAS in action: Expanding roles in immunity and inflammation.","volume":"363","author":"Ablasser","year":"2019","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"001367","DOI":"10.1099\/mic.0.001367","article-title":"Killing in the name of: T6SS structure and effector diversity.","volume":"169","author":"Allsopp","year":"2023","journal-title":"Microbiology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.chom.2016.04.004","article-title":"A burkholderia type VI effector deamidates Rho GTPases to activate the pyrin inflammasome and trigger inflammation.","volume":"19","author":"Aubert","year":"2016","journal-title":"Cell Host Microbe"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1177\/00220345251337745","article-title":"Aggregatibacteraphrophilus T6SS effectors in host-bacterial interactions.","volume":"104","author":"Bao","year":"2025","journal-title":"J. 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