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The Lachnospiraceae family ferments dietary fibers to produce short\u2010chain fatty acids (SCFAs), notably butyrate and propionate, with immunomodulatory potential. This critical review distinguishes established findings from hypotheses. Strain\u2010level functional heterogeneity is substantial; findings from one genus cannot be generalized. Specific substrates (inulin, pectin, resistant starch, and arabinoxylan) and food processing methods shape SCFA profiles. Mechanistically, SCFAs regulate immunity via histone deacetylase inhibition, G\u2010protein\u2010coupled receptor activation, and Treg\/Th17 modulation. However, most mechanistic data derive from rodent models; human evidence remains largely correlational and cross\u2010sectional. Three major knowledge gaps exist: the lack of strain\u2010level functional characterization, the absence of causal human intervention trials for the vast majority of Lachnospiraceae strains (with\n                    <jats:italic>A<\/jats:italic>\n                    naerobutyricum\n                    <jats:italic>soehngenii<\/jats:italic>\n                    being the sole exception, tested only in metabolic disease), and limited translation into food systems. Regulatory barriers (generally recognized as safe [GRAS] status exists only for\n                    <jats:italic>A. soehngenii<\/jats:italic>\n                    CH106 and strictly for food use; no other strain has GRAS or qualified presumption of safety [QPS]), safety concerns (rare opportunistic pathogenicity), and technological challenges (oxygen sensitivity and viability in food matrices) further hinder development. Postbiotics (preparations of inactivated microbial cells or their components) and metabolite\u2010based preparations (e.g., purified SCFAs or fermentation supernatants), alongside synbiotic formulations, offer practical near\u2010term alternatives. Importantly, under the International Scientific Association for Probiotics and Prebiotics (ISAPP) definition, purified metabolites without cellular biomass do not qualify as postbiotics. We conclude that although Lachnospiraceae hold promise for immunomodulatory functional foods, current evidence does not support clinical or commercial claims. Priority research directions include longitudinal human cohorts, strain\u2010level culturomics, and multi\u2010omics integration. This review provides a realistic, food science\u2013centered framework for future investigations.\n                  <\/jats:p>","DOI":"10.1111\/1541-4337.70655","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:40:53Z","timestamp":1790595653000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lachnospiraceae in the Food\u2013Gut Axis: A Critical Review of Dietary Modulation, Immune Regulation, and Translational Barriers"],"prefix":"10.1111","volume":"25","author":[{"given":"Ruijun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery The Affiliated Hospital of Inner Mongolia Medical University  Hohhot Inner Mongolia Autonomous Region China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqi","family":"Li","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8050-8047","authenticated-orcid":false,"given":"Yuanming","family":"Pan","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanbiao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The Affiliated Hospital of Inner Mongolia Medical University  Hohhot Inner Mongolia Autonomous Region 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