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Lipoteichoic acid from the cell wall of a heat killed Lactobacillus paracasei D3-5 ameliorates aging-related leaky gut, inflammation and improves physical and cognitive functions: from C. elegans to mice

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Increased inflammation associated with leaky gut is a major risk factor for morbidity and mortality in older adults; however, successful preventive and therapeutic strategies against these conditions are not available. In this study, we demonstrate that a human-origin Lactobacillus paracasei D3-5 strain (D3-5), even in the non-viable form, extends life span of Caenorhabditis elegans. In addition, feeding of heat-killed D3-5 to old mice (> 79 weeks) prevents high- fat diet-induced metabolic dysfunctions, decreases leaky gut and inflammation, and improves physical and cognitive functions. D3-5 feeding significantly increases mucin production, and proportionately, the abundance of mucin-degrading bacteria Akkermansia muciniphila also increases. Mechanistically, we show that the lipoteichoic acid (LTA), a cell wall component of D3-5, enhances mucin (Muc2) expression by modulating TLR-2/p38-MAPK/NF-kB pathway, which in turn reduces age-related leaky gut and inflammation. The findings indicate that the D3-5 and its LTA can prevent/treat age-related leaky gut and inflammation.

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We would like to thank Sandy Sink for help in metabolic phenotyping studies, and Cynthia Zimmerman from Wake Forest Regenerative Medicine Histology Core for tissue processing and slide preparations. We are also thankful to Dr. John Parks and Dr. Martha Alexander Miller for providing valuable advices, suggestions, and departmental resources. C. elegans strains were generously provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We are also thankful to all the participating researchers, technicians, and the staff members of the animal facilities and laboratory members for their consistent help during the study.


This work was supported by National Institutes of Health grant R01DK081842 (DAM), R01HL142930 (KK), R01HL132035 (XZ), R01AG059416, U13AG040938, R01AG052419, U24AG058556, KL2TR001421 (SBK), R01AG018915, R01AG045551, and U24AG059624 (DWK); the Pepper Older Americans for Independence Center (P30AG21332); and the Department of Defense funding W81XWH-18-1-0118, GRANT12726940/AZ180098, R01AG018915 (HY), as well as funds and services provided from the Center for Diabetes, Obesity and Metabolism, Wake Forest Baptist Medical Center, and the National Center for Advancing Translational Sciences (NCATS), the National Institutes of Health-funded Wake Forest Clinical, and Translational Science Institute (WF CTSI) through Grant Award Number UL1TR001420.

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SW, SA, RN, SJ, SPM, KK, XZ, and ZW performed and/or helped in various experiments conducted in this study as well as data compilations and interpretations, and writing first draft of manuscript. DAM, SBK, and DWK significantly contributed as intellects for experimental designs and data interpretations. HY conceived the project idea, supervised the study, compiled and interpreted data, and wrote the manuscript.

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Correspondence to Hariom Yadav.

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Wang, S., Ahmadi, S., Nagpal, R. et al. Lipoteichoic acid from the cell wall of a heat killed Lactobacillus paracasei D3-5 ameliorates aging-related leaky gut, inflammation and improves physical and cognitive functions: from C. elegans to mice. GeroScience 42, 333–352 (2020).

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