Fecal metabolomics reveals products of dysregulated proteolysis and altered microbial metabolism in obesity-related osteoarthritis

Rushing, Blake R.; McRitchie, Susan; Arbeeva, Liubov; Nelson, Amanda; Azcarate‐Peril, M. Andrea; Li, Y.-Y.; Qian, Yuqing; Pathmasiri, Wimal; Sumner, Susan; Loeser, Richard F.

doi:10.1016/j.joca.2021.10.006

Cited by 28 publications

(23 citation statements)

References 59 publications

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“…In humans, Clostridiales and the genus Streptococcus were associated with OA pain [ 4 ], and nutrient metabolism influenced functional changes in the gut microbiome in OA [ 5 ]. Our pre-clinical data showing that LA restores gut microbial balance and improves OA pain and joint pathology can be applied to human subjects.…”

Section: Discussionmentioning

confidence: 99%

“…In human subjects, the order Clostridiales correlates negatively with OA and genus Streptococcus associates with OA pain [ 4 ]. Metabolomic studies on fecal samples from human OA subjects have revealed associations of leukotriene and amino acid metabolism, glycosylphosphatidylinositol anchor biosynthesis, and pyruvate metabolism with OA reflecting functional changes in the gut microbiome in OA [ 5 ]. Similar but more robust observations have been made in mice.…”

Section: Introductionmentioning

confidence: 99%

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Lactobacillus acidophilus Mitigates Osteoarthritis-Associated Pain, Cartilage Disintegration and Gut Microbiota Dysbiosis in an Experimental Murine OA Model

et al. 2022

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To test probiotic therapy for osteoarthritis (OA), we administered Lactobacillus acidophilus (LA) by oral gavage (2×/week) after induction of OA by partial medial meniscectomy (PMM). Pain was assessed by von Frey filament and hot plate testing. Joint pathology and pain markers were comprehensively analyzed in knee joints, spinal cords, dorsal root ganglia and distal colon by Safranin O/fast green staining, immunofluorescence microscopy and RT-qPCR. LA acutely reduced inflammatory knee joint pain and prevented further OA progression. The therapeutic efficacy of LA was supported by a significant reduction of cartilage-degrading enzymes, pain markers and inflammatory factors in the tissues we examined. This finding suggests a likely clinical effect of LA on OA. The effect of LA treatment on the fecal microbiome was assessed by 16S rRNA gene amplicon sequencing analysis. LA significantly altered the fecal microbiota compared to vehicle-treated mice (PERMANOVA p < 0.009). Our pre-clinical OA animal model revealed significant OA disease modifying effects of LA as reflected by rapid joint pain reduction, cartilage protection, and reversal of dysbiosis. Our findings suggest that LA treatment has beneficial systemic effects that can potentially be developed as a safe OA disease-modifying drug (OADMD).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lactobacillus acidophilus Mitigates Osteoarthritis-Associated Pain, Cartilage Disintegration and Gut Microbiota Dysbiosis in an Experimental Murine OA Model

et al. 2022

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“…Because this is an exploratory study with a modest sample size, p -values were calculated between pairwise comparisons and were not adjusted for multiple comparisons. This exploratory hypothesis-generating approach has been used by our group in several recent publications [ 30 , 33 , 34 , 35 , 36 ]. This information will set the foundation for future targeted studies with larger sample sizes to validate the untargeted results.…”

Section: Methodsmentioning

confidence: 99%

Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice

et al. 2022

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ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism, is highly expressed in the liver. It regulates the overall flux of folate-bound one-carbon groups by converting 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in a NADP+-dependent reaction. Our previous study revealed that Aldh1l1 knockout (KO) mice have an altered liver metabotype with metabolic symptoms of folate deficiency when fed a standard chow diet containing 2 ppm folic acid. Here we performed untargeted metabolomic analysis of liver and plasma of KO and wild-type (WT) male and female mice fed for 16 weeks either standard or folate-deficient diet. OPLS-DA, a supervised multivariate technique that was applied to 6595 and 10,678 features for the liver and plasma datasets, respectively, indicated that genotype and diet, alone or in combination, gave distinct metabolic profiles in both types of biospecimens. A more detailed analysis of affected metabolic pathways based on most confidently identified metabolites in the liver and plasma (OL1 and OL2a ontology level) indicated that the dietary folate restriction itself does not fully recapitulate the metabolic effect of the KO. Of note, dietary folate withdrawal enhanced the metabolic perturbations linked to the ALDH1L1 loss only for a subset of metabolites. Importantly, both the ALDH1L1 loss and dietary folate deficiency produced sex-specific metabolic effects.

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“…The individual study samples were randomized, and blanks and QCSP injections were interspersed amongst the study sample in the run sequence. Data were acquired using a Vanquish UHPLC system coupled to a Q Exactive™ HF-X Hybrid Quadrupole-Orbitrap Mass Spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) using previously published methods [24][25][26][27]. Metabolites were separated via an HSS T3 C18 column (2.1 × 100 mm, 1.7 µm, Waters Corporation) at 50 • C with a binary mobile phase of water (A) and methanol (B), each containing 0.1% formic acid (v/v).…”

Section: Uhplc-hrms Data Acquisition and Multivariate Statistical Ana...mentioning

confidence: 99%

Comparison of Lysis and Detachment Sample Preparation Methods for Cultured Triple-Negative Breast Cancer Cells Using UHPLC–HRMS-Based Metabolomics

2022

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Dysregulation of cellular metabolism is now a well-recognized hallmark of cancer. Studies investigating the metabolic features of cancer cells have shed new light onto processes in cancer cell biology and have identified many potential novel treatment options. The advancement of mass spectrometry-based metabolomics has improved the ability to monitor multiple metabolic pathways simultaneously in various experimental settings. However, questions still remain as to how certain steps in the metabolite extraction process affect the metabolic profiles of cancer cells. Here, we use ultra-high-performance liquid chromatography–high-resolution mass spectrometry (UHPLC–HRMS) untargeted metabolomics to investigate the effects of different detachment and lysis methods on the types and abundances of metabolites extracted from MDA-MB-231 cells through the use of in-house standards libraries and pathway analysis software. Results indicate that detachment methods (trypsinization vs. scraping) had the greatest effect on metabolic profiles whereas lysis methods (homogenizer beads vs. freeze–thaw cycling) had a lesser, though still significant, effect. No singular method was clearly superior over others, with certain metabolite classes giving higher abundances or lower variation for each detachment–lysis combination. These results indicate the importance of carefully selecting sample preparation methods for cell-based metabolomics to optimize the extraction performance for certain compound classes.

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Fecal metabolomics reveals products of dysregulated proteolysis and altered microbial metabolism in obesity-related osteoarthritis

Cited by 28 publications

References 59 publications

Lactobacillus acidophilus Mitigates Osteoarthritis-Associated Pain, Cartilage Disintegration and Gut Microbiota Dysbiosis in an Experimental Murine OA Model

Lactobacillus acidophilus Mitigates Osteoarthritis-Associated Pain, Cartilage Disintegration and Gut Microbiota Dysbiosis in an Experimental Murine OA Model

Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice

Comparison of Lysis and Detachment Sample Preparation Methods for Cultured Triple-Negative Breast Cancer Cells Using UHPLC–HRMS-Based Metabolomics

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