Bacterial Lipodipeptide, Lipid 654, Is a Microbiome-Associated Biomarker for Multiple Sclerosis
Open accessAbstract
Multiple sclerosis (MS) is an autoimmune disease of unknown etiology. Infectious agents have been suggested to have a role as environmental factors in MS, but this concept remains controversial. Recently, gastrointestinal commensal bacteria have been implicated in the pathogenesis of autoimmune diseases, but mechanisms underlying the relationship of human systemic autoimmunity with the commensal microbiome have yet to be identified. Consistent with the lack of understanding of pathogenic mechanisms and relevant environmental factors in MS, no blood biomarkers have been identified that distinguish MS patients from healthy individuals. We recently identified a unique gastrointestinal and oral bacteria-derived lipodipeptide, Lipid 654, which is produced by commensal bacteria and functions as a human and mouse Toll-like receptor 2 ligand. Using multiple-reaction-monitoring mass spectrometry, a critical approach in targeted lipidomics, we now report that Lipid 654 can be recovered in the serum of healthy individuals. Most interestingly, we find that Lipid 654 is expressed at significantly lower levels in the serum of patients with MS compared with both healthy individuals and patients with Alzheimer's disease. These results thus identify for the first time a potential mechanism relating the gastrointestinal and oral commensal microbiome to a human systemic autoimmune disease. In addition, these results also identify a potential etiologic environmental factor and novel clinically relevant serum biomarker for MS.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
GM-based biomarkers have recently been considered as promising early and prodromal diagnostic tools in various neurological diseases, such as multiple sclerosis, Alzheimer's disease and Parkinson's disease itself.
“GM-based biomarkers have recently been considered as promising early and prodromal diagnostic tools in various neurological diseases, such as multiple sclerosis, AD and PD itself [30,156,157]”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [156]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · see citing works
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/y59-099 · Cited by 23,189 · see citing works
Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly-Y, M., Glickman, J. N., & Garrett, W. S. (2013) · Science · doi:10.1126/science.1241165 · Cited by 5,413 · see citing works
A microbial symbiosis factor prevents intestinal inflammatory disease
Mazmanian, S. K., Round, J. L., & Kasper, D. L. (2008) · Nature · doi:10.1038/nature07008 · Cited by 2,340 · see citing works
Round, J. L., & Mazmanian, S. K. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909122107 · Cited by 2,233 · see citing works
Innate immunity and intestinal microbiota in the development of Type 1 diabetes
Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., Hu, C., Wong, F. S., Szot, G. L., Bluestone, J. A., et al. (2008) · Nature · doi:10.1038/nature07336 · Cited by 1,921 · see citing works
Ivanov, I. I., Frutos, R. D. L., Manel, N., Yoshinaga, K., Rifkin, D. B., Sartor, R. B., Finlay, B. B., & Littman, D. R. (2008) · Cell Host & Microbe · doi:10.1016/j.chom.2008.09.009 · Cited by 1,770 · see citing works
Gut-Residing Segmented Filamentous Bacteria Drive Autoimmune Arthritis via T Helper 17 Cells
Wu, H.-J., Ivanov, I. I., Darce, J., Hattori, K., Shima, T., Umesaki, Y., Littman, D. R., Benoist, C., & Mathis, D. (2010) · Immunity · doi:10.1016/j.immuni.2010.06.001 · Cited by 1,577 · see citing works
Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis
Lee, Y. K., Menezes, J. S., Umesaki, Y., & Mazmanian, S. K. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000082107 · Cited by 1,323 · see citing works
Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity
Clarke, T. B., Davis, K. M., Lysenko, E. S., Zhou, A. Y., Yu, Y., & Weiser, J. N. (2010) · Nature Medicine · doi:10.1038/nm.2087 · Cited by 1,154 · see citing works
Commensal bacteria calibrate the activation threshold of innate antiviral immunity
Abt, M. C., Osborne, L. C., Monticelli, L. A., Doering, T. A., Alenghat, T., Sonnenberg, G. F., Paley, M. A., Antenus, M., Williams, K. L., Erikson, J., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.04.011 · Cited by 993 · see citing works
Kriegel, M. A., Sefik, E., Hill, J. A., Wu, H.-J. J., Benoist, C. O., & Mathis, D. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1108924108 · Cited by 423 · see citing works
NKT Cell-Dependent Amelioration of a Mouse Model of Multiple Sclerosis by Altering Gut Flora
Yokote, H., Miyake, S., Croxford, J. L., Oki, S., Mizusawa, H., & Yamamura, T. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.080622 · Cited by 264 · see citing works
Kawashima, T., Kosaka, A., Yan, H., Guo, Z., Uchiyama, R., Fukui, R., Kaneko, D., Kumagai, Y., You, D., Carreras, J., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.024 · Cited by 206 · see citing works
Touil, T., Fitzgerald, D. C., Zhang, G., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.7505 · Cited by 141 · see citing works
Serine Lipids of Porphyromonas gingivalis Are Human and Mouse Toll-Like Receptor 2 Ligands
Clark, R. B., Cervantes, J., Maciejewski, M. W., Farrokhi, V., Nemati, R., Yao, X., Anstadt, E. J., Fujiwara, M., Wright, K., Riddle, C., et al. (2013) · Infection and Immunity · doi:10.1128/iai.00803-13 · Cited by 86 · see citing works
Self-citationStructures and biological activity of phosphorylated dihydroceramides of Porphyromonas gingivalis
Nichols, F. C., Riep, B., Mun, J.-Y., et al. (2004) · Journal of Lipid Research · doi:10.1194/jlr.m400278-jlr200 · Cited by 76 · see citing works
Self-citationPerkins, D. J., Polumuri, S. K., Pennini, M. E., Lai, W., Xie, P., & Vogel, S. N. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003479 · Cited by 47 · see citing works
Specific Gut Commensal Flora Locally Alters T Cell Tuning to Endogenous Ligands
Chappert, P., Bouladoux, N. J., Naik, S., & Schwartz, R. H. (2013) · Immunity · doi:10.1016/j.immuni.2013.06.005 · Cited by 44 · see citing works
Regulation of Th17 cell differentiation by intestinal commensal bacteria
Atarashi, K., Tanoue, T., Umesaki, Y., & Honda, K. (2010) · Beneficial Microbes · doi:10.3920/bm2010.0026 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Miyake, S., Kim, S., Suda, W., Oshima, K., Nakamura, M., Matsuoka, T., Chihara, N., Tomita, A., Sato, W., Kim, S.-W., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0137429 · Cited by 809 · see citing works
The gut microbiome in human neurological disease: A review
Tremlett, H., Bauer, K. C., Appel‐Cresswell, S., Finlay, B. B., & Waubant, E. (2017) · Annals of Neurology · doi:10.1002/ana.24901 · Cited by 535 · see citing works
The Potential Role of Gut Microbiota in Alzheimer’s Disease: From Diagnosis to Treatment
Varesi, A., Pierella, E., Romeo, M., Piccini, G. B., Alfano, C., Bjørklund, G., Oppong, A., Ricevuti, G., Esposito, C., Chirumbolo, S., et al. (2022) · Nutrients · doi:10.3390/nu14030668 · Cited by 225 · see citing works
Intestinal Microbiota Influences Non-intestinal Related Autoimmune Diseases
Opazo, M. C., Ortega-Rocha, E. M., Coronado-Arrázola, I., Bonifaz, L. C., Boudin, H., Neunlist, M., Bueno, S. M., Kalergis, A. M., & Riedel, C. A. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00432 · Cited by 179 · see citing works
Environmental Basis of Autoimmunity
Floreani, A., Leung, P. S. C., & Gershwin, M. E. (2016) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-015-8493-8 · Cited by 122 · see citing works
Varesi, A., Campagnoli, L. I. M., Fahmideh, F., Pierella, E., Romeo, M., Ricevuti, G., Nicoletta, M., Chirumbolo, S., & Pascale, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012289 · Cited by 88 · see citing works
Breaking down the gut microbiome composition in multiple sclerosis
Budhram, A., Parvathy, S., Kremenchutzky, M., & Silverman, M. (2017) · Multiple Sclerosis Journal · doi:10.1177/1352458516682105 · Cited by 51 · see citing works
- Authors
- Farrokhi, V., Nemati, R., Nichols, F. C., Yao, X., Anstadt, E., Fujiwara, M., Grady, J., Wakefield, D., Castro, W., Donaldson, J., & Clark, R. B.
- Affiliations
- University of Connecticut (US)
- Corresponding author
- Clark, Robert B
- ORCID
- Venue
- Clinical & Translational Immunology
- Publisher
- Wiley
- Published
- 2013-11
- Volume
- 2
- Issue
- 11
- Pages
- e8-e8
- ISSN
- 2050-0068 (ISSN-L)
- PMC
- PMC4232052
- OpenAlex
- W1982813749
- Cited by
- 109
- References
- 20
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 7 · 2023: 12 · 2022: 11 · 2021: 12 · 2020: 9 · 2019: 9 · 2018: 17 · 2017: 6 · 2016: 7 · 2015: 7 · 2014: 1
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Clinical & Translational Immunology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Multiple Sclerosis Society
- University of Connecticut
- Multiple Sclerosis Society
- National Institutes of Health
- National Cancer Institute
- National Institute of Dental and Craniofacial Research (R01DE021055)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- multiple sclerosis, commensal bacteria, gut microbiota, oral microbiota, serum biomarkers, autoimmune disease, environmental risk factors, Alzheimer's disease, lipidomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
