Limits...
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

Lipid 654 expression is lower in the serum of MS patients versus Alzheimer's patients. Frozen banked serum samples from MS and Alzheimer's patients were obtained from the UCLA Human Brain and Spinal Fluid Resource Center. Total serum lipids were derived and analyzed using MRM-mass spectrometry to identify and quantify the absolute ion abundance of Lipid 654 using three transitions of Lipid 654 (Transitions 1, 2 and 3, as in Figure 2). As in Figure 3, a defined quantity of 13C-labeled total lipids derived from P. gingivalis was added to each sample and used to adjust each value based on the efficiency of the analysis of that sample. Ion abundance is expressed as 105. MS patients, N=13; Alzheimer's patients, N=15. Means: Transition 1, MS patients 112 139; Alzheimer's patients 1 297 909; Transition 2, MS patients 26 333; Alzheimer's patients 295 680; Transition 3: MS patients 13 786; Alzheimer's patients 142 076. Wilcoxon's rank-sum test was used to determine statistical significance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4232052&req=5

fig4: Lipid 654 expression is lower in the serum of MS patients versus Alzheimer's patients. Frozen banked serum samples from MS and Alzheimer's patients were obtained from the UCLA Human Brain and Spinal Fluid Resource Center. Total serum lipids were derived and analyzed using MRM-mass spectrometry to identify and quantify the absolute ion abundance of Lipid 654 using three transitions of Lipid 654 (Transitions 1, 2 and 3, as in Figure 2). As in Figure 3, a defined quantity of 13C-labeled total lipids derived from P. gingivalis was added to each sample and used to adjust each value based on the efficiency of the analysis of that sample. Ion abundance is expressed as 105. MS patients, N=13; Alzheimer's patients, N=15. Means: Transition 1, MS patients 112 139; Alzheimer's patients 1 297 909; Transition 2, MS patients 26 333; Alzheimer's patients 295 680; Transition 3: MS patients 13 786; Alzheimer's patients 142 076. Wilcoxon's rank-sum test was used to determine statistical significance.

Mentions: Total lipids were derived from these serum samples and analyzed for levels of Lipid 654 using MRM-mass spectrometry as described above. As with the samples that were derived in our laboratory, we quantified levels of expression of Lipid 654 using Transitions 1, 2 and 3 (see Figures 2 and 3). Strikingly, although these were banked frozen samples obtained from another institution, we nevertheless found that the levels of Lipid 654 in these MS serum samples were significantly lower than those of the Alzheimer's patients (Figure 4). Two of the three transitions demonstrated statistically significant differences between the MS and Alzheimer's samples, whereas the other transition yielded a P-value of 0.052. As seen in Figure 4, two Alzheimer's samples demonstrated extremely high serum expression of Lipid 654. These values are consistent with our overall findings that MS serum samples demonstrate low Lipid 654 expression. However, dropping these two high expressors from the data resulted in the P-values becoming slightly nonsignificant (not shown), but the interpretation of the data remains unchanged.


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)

Lipid 654 expression is lower in the serum of MS patients versus Alzheimer's patients. Frozen banked serum samples from MS and Alzheimer's patients were obtained from the UCLA Human Brain and Spinal Fluid Resource Center. Total serum lipids were derived and analyzed using MRM-mass spectrometry to identify and quantify the absolute ion abundance of Lipid 654 using three transitions of Lipid 654 (Transitions 1, 2 and 3, as in Figure 2). As in Figure 3, a defined quantity of 13C-labeled total lipids derived from P. gingivalis was added to each sample and used to adjust each value based on the efficiency of the analysis of that sample. Ion abundance is expressed as 105. MS patients, N=13; Alzheimer's patients, N=15. Means: Transition 1, MS patients 112 139; Alzheimer's patients 1 297 909; Transition 2, MS patients 26 333; Alzheimer's patients 295 680; Transition 3: MS patients 13 786; Alzheimer's patients 142 076. 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

fig4: Lipid 654 expression is lower in the serum of MS patients versus Alzheimer's patients. Frozen banked serum samples from MS and Alzheimer's patients were obtained from the UCLA Human Brain and Spinal Fluid Resource Center. Total serum lipids were derived and analyzed using MRM-mass spectrometry to identify and quantify the absolute ion abundance of Lipid 654 using three transitions of Lipid 654 (Transitions 1, 2 and 3, as in Figure 2). As in Figure 3, a defined quantity of 13C-labeled total lipids derived from P. gingivalis was added to each sample and used to adjust each value based on the efficiency of the analysis of that sample. Ion abundance is expressed as 105. MS patients, N=13; Alzheimer's patients, N=15. Means: Transition 1, MS patients 112 139; Alzheimer's patients 1 297 909; Transition 2, MS patients 26 333; Alzheimer's patients 295 680; Transition 3: MS patients 13 786; Alzheimer's patients 142 076. Wilcoxon's rank-sum test was used to determine statistical significance.
Mentions: Total lipids were derived from these serum samples and analyzed for levels of Lipid 654 using MRM-mass spectrometry as described above. As with the samples that were derived in our laboratory, we quantified levels of expression of Lipid 654 using Transitions 1, 2 and 3 (see Figures 2 and 3). Strikingly, although these were banked frozen samples obtained from another institution, we nevertheless found that the levels of Lipid 654 in these MS serum samples were significantly lower than those of the Alzheimer's patients (Figure 4). Two of the three transitions demonstrated statistically significant differences between the MS and Alzheimer's samples, whereas the other transition yielded a P-value of 0.052. As seen in Figure 4, two Alzheimer's samples demonstrated extremely high serum expression of Lipid 654. These values are consistent with our overall findings that MS serum samples demonstrate low Lipid 654 expression. However, dropping these two high expressors from the data resulted in the P-values becoming slightly nonsignificant (not shown), but the interpretation of the data remains unchanged.

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