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In our prior work, we engineered probiotic\n                  <jats:italic>Bacillus subtilis PY79<\/jats:italic>\n                  to produce lactate oxidase (LOX) intracellularly, allowing it to rapidly convert intestinal lactate to pyruvate. Following oral administration, LOX reduced systemic lactate concentrations at rest and under challenge conditions, providing a platform for investigating lactate\u2019s influence on host metabolism and microbiota. In the present work, we demonstrate that acute LOX administration effectively rewired microbiota function and host energy balance, as revealed by 16S sequencing and indirect calorimetry.\n                  <jats:italic>In silico<\/jats:italic>\n                  microbial community modeling via MICOM and metagenomic inference via PICRUSt2 suggested that acute shunting of lactate to pyruvate induced microbiota remodeling towards anabolic processes, reflected by increased flux of pyruvate, acetate, and formate, alongside moderate to large increases (Cohen\u2019s d = 0.60-1.00) in pathways for fructan degradation, B-vitamin biosynthesis, and lipid synthesis. These anabolic shifts temporally aligned with transient increases in host energy expenditure (\u03b2 = 1.08, p&lt;0.05) via glucose oxidation (\u03b2 = 0.01, p&lt;0.05), hinting at functional coupling between microbial biosynthesis and host energy balance via lactate exchange. Of note, acute LOX administration also improved thermoregulation and survival following LPS-induced sepsis, demonstrating functional relevance of these metabolic effects during acute inflammatory challenge. To assess chronic effects, we administered LOX for 6 weeks during diet-induced obesity. LOX treatment persistently reduced blood lactate. However, this chronic lactate reduction did not curtail the progression of diet-induced obesity or induce sustained modulation of host energy expenditure. This disconnect between acute and chronic findings suggests that gut-centric lactate conversion affects energy balance through microbiome and\/or host-dependent mechanisms, but cannot override homeostatic forces in the long term to produce clinical benefit during chronic disease. Our results validate LOX probiotics as a tool for acute metabolic augmentation, and highlight a clear homeostatic limit to gut-centric therapies. This platform may enable targeted design of probiotic interventions matched to therapeutic timescale and inform synbiotic formulations that overcome homeostatic compensation.\n                <\/jats:p>","DOI":"10.64898\/2026.04.07.716956","type":"posted-content","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T06:20:18Z","timestamp":1775715618000},"source":"Crossref","is-referenced-by-count":0,"title":["Engineered Lactate Catabolizing Probiotics Reveal Timescale Dependent Microbiome-Host Metabolic Coupling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9035-9241","authenticated-orcid":false,"given":"Noah T.","family":"Hutchinson","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningyuan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Jennings","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengyuan","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States."},{"name":"Department of Esophageal and Mediastinum, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9889-8546","authenticated-orcid":false,"given":"Jiahe","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041004201227000_2026.04.07.716956v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38778-x"},{"key":"2026041004201227000_2026.04.07.716956v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2015.07.002"},{"key":"2026041004201227000_2026.04.07.716956v1.3","doi-asserted-by":"crossref","first-page":"4709","DOI":"10.2147\/IJGM.S539237","article-title":"Gut Microbiota Metabolites Targeting the Immune Response in Sepsis: Mechanisms and Therapies","volume":"18","year":"2025","journal-title":"Int J Gen Med"},{"key":"2026041004201227000_2026.04.07.716956v1.4","doi-asserted-by":"crossref","first-page":"1266579","DOI":"10.3389\/fimmu.2024.1266579","article-title":"The causality of gut microbiota on onset and progression of sepsis: a bi-directional Mendelian randomization analysis","volume":"15","year":"2024","journal-title":"Front Immunol"},{"key":"2026041004201227000_2026.04.07.716956v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1241214"},{"key":"2026041004201227000_2026.04.07.716956v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature07540"},{"key":"2026041004201227000_2026.04.07.716956v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.03.005"},{"key":"2026041004201227000_2026.04.07.716956v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02546-x"},{"key":"2026041004201227000_2026.04.07.716956v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.advnut.2023.03.015"},{"key":"2026041004201227000_2026.04.07.716956v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3145"},{"key":"2026041004201227000_2026.04.07.716956v1.11","unstructured":"Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease | Nature[date unknown]; [cited 2025 Sept 24] Available from: https:\/\/www.nature.com\/articles\/nature09922."},{"key":"2026041004201227000_2026.04.07.716956v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.041"},{"key":"2026041004201227000_2026.04.07.716956v1.13","doi-asserted-by":"crossref","unstructured":"Wu L , Feng J , Li J , et al. 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