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Bacterial lipodipeptide, Lipid 654, is a microbiome-associated biomarker for multiple sclerosis.

Farrokhi V, Nemati R, Nichols FC, Yao X, Anstadt E, Fujiwara M, Grady J, Wakefield D, Castro W, Donaldson J, Clark RB - Clin Transl Immunology (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Connecticut , Storrs, CT, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Addition of an internal standard to the MRM-mass spectrometry analysis confirms that Lipid 654 is significantly lower in the serum of MS patients. Serum was obtained from MS patients and healthy individuals (Tables 1A and B) and total serum lipids were analyzed by MRM-mass spectrometry for expression of Lipid 654 using Transitions 1, 2 and 3 as in Figure 2. As an additional control for MRM-mass spectrometry efficiency, a defined quantity of 13C-labeled total lipids derived from P. gingivalis was added to each sample. The level of recovery of 13C-labeled Lipid 654 was then used to adjust each value based on the efficiency of the analysis of that sample. Ion abundance is expressed as 105. MS patients, N=17; healthy individuals, N=12. Means: Transition1, MS patients 414  891; control patients 3 003 525; Transition 2: MS patients 66 482; control patients 497 055; Transition 3: MS patients 26 762; control patients 211 245. Wilcoxon's rank-sum test was used to determine statistical significance.
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fig3: Addition of an internal standard to the MRM-mass spectrometry analysis confirms that Lipid 654 is significantly lower in the serum of MS patients. Serum was obtained from MS patients and healthy individuals (Tables 1A and B) and total serum lipids were analyzed by MRM-mass spectrometry for expression of Lipid 654 using Transitions 1, 2 and 3 as in Figure 2. As an additional control for MRM-mass spectrometry efficiency, a defined quantity of 13C-labeled total lipids derived from P. gingivalis was added to each sample. The level of recovery of 13C-labeled Lipid 654 was then used to adjust each value based on the efficiency of the analysis of that sample. Ion abundance is expressed as 105. MS patients, N=17; healthy individuals, N=12. Means: Transition1, MS patients 414  891; control patients 3 003 525; Transition 2: MS patients 66 482; control patients 497 055; Transition 3: MS patients 26 762; control patients 211 245. Wilcoxon's rank-sum test was used to determine statistical significance.

Mentions: To correct for potential variations arising from slight chromatographic and mass spectrometric alterations occurring during the analysis, an internal standard was added to each sample for Run no. 3. This internal standard permitted quantification of Lipid 654 by correcting, for example, for diminished instrument sensitivity with increasing sample number or variations in lipid infusion by the automatic sampler. As seen in Figure 3, adjusting for the efficiency of Lipid 654 detection using the internal standard yielded essentially identical results as those depicted in Figure 2, that is, a very significant difference in serum levels of Lipid 654 between MS patients and healthy controls was found again. Note again in Figure 3 that the values for all of the 17 MS patients are clustered together at the lower levels of ion abundance.


Bacterial lipodipeptide, Lipid 654, is a microbiome-associated biomarker for multiple sclerosis.

Farrokhi V, Nemati R, Nichols FC, Yao X, Anstadt E, Fujiwara M, Grady J, Wakefield D, Castro W, Donaldson J, Clark RB - Clin Transl Immunology (2013)

Addition of an internal standard to the MRM-mass spectrometry analysis confirms that Lipid 654 is significantly lower in the serum of MS patients. Serum was obtained from MS patients and healthy individuals (Tables 1A and B) and total serum lipids were analyzed by MRM-mass spectrometry for expression of Lipid 654 using Transitions 1, 2 and 3 as in Figure 2. As an additional control for MRM-mass spectrometry efficiency, a defined quantity of 13C-labeled total lipids derived from P. gingivalis was added to each sample. The level of recovery of 13C-labeled Lipid 654 was then used to adjust each value based on the efficiency of the analysis of that sample. Ion abundance is expressed as 105. MS patients, N=17; healthy individuals, N=12. Means: Transition1, MS patients 414  891; control patients 3 003 525; Transition 2: MS patients 66 482; control patients 497 055; Transition 3: MS patients 26 762; control patients 211 245. Wilcoxon's rank-sum test was used to determine statistical significance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232052&req=5

fig3: Addition of an internal standard to the MRM-mass spectrometry analysis confirms that Lipid 654 is significantly lower in the serum of MS patients. Serum was obtained from MS patients and healthy individuals (Tables 1A and B) and total serum lipids were analyzed by MRM-mass spectrometry for expression of Lipid 654 using Transitions 1, 2 and 3 as in Figure 2. As an additional control for MRM-mass spectrometry efficiency, a defined quantity of 13C-labeled total lipids derived from P. gingivalis was added to each sample. The level of recovery of 13C-labeled Lipid 654 was then used to adjust each value based on the efficiency of the analysis of that sample. Ion abundance is expressed as 105. MS patients, N=17; healthy individuals, N=12. Means: Transition1, MS patients 414  891; control patients 3 003 525; Transition 2: MS patients 66 482; control patients 497 055; Transition 3: MS patients 26 762; control patients 211 245. Wilcoxon's rank-sum test was used to determine statistical significance.
Mentions: To correct for potential variations arising from slight chromatographic and mass spectrometric alterations occurring during the analysis, an internal standard was added to each sample for Run no. 3. This internal standard permitted quantification of Lipid 654 by correcting, for example, for diminished instrument sensitivity with increasing sample number or variations in lipid infusion by the automatic sampler. As seen in Figure 3, adjusting for the efficiency of Lipid 654 detection using the internal standard yielded essentially identical results as those depicted in Figure 2, that is, a very significant difference in serum levels of Lipid 654 between MS patients and healthy controls was found again. Note again in Figure 3 that the values for all of the 17 MS patients are clustered together at the lower levels of ion abundance.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Connecticut , Storrs, CT, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus