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

OBJECTIVE: The objective of this exploratory study was to determine if perturbations in gut microbial composition and the gut metabolome could be linked to individuals with obesity and osteoarthritis (OA). METHODS: Fecal samples were collected from obese individuals diagnosed with radiographic hand plus knee OA (n = 59), defined as involvement of at least 3 joints across both hands, and a Kellgren-Lawrence (KL) grade 2-4 (or total knee replacement) in at least one knee. Controls (n = 33) were without hand OA and with KL grade 0-1 knees. Fecal metabolomes were analyzed by a UHPLC/Q Exactive HFx mass spectrometer. Microbiome composition was determined in fecal samples by 16 S ribosomal RNA amplicon sequencing (rRNA-seq). Stepwise logistic regression models were built to determine microbiome and/or metabolic characteristics of OA. RESULTS: Untargeted metabolomics analysis indicated that OA cases had significantly higher levels of di- and tripeptides and significant perturbations in microbial metabolites including propionic acid, indoles, and other tryptophan metabolites. Pathway analysis revealed several significantly perturbed pathways associated with OA including leukotriene metabolism, amino acid metabolism and fatty acid utilization. Logistic regression models selected metabolites associated with the gut microbiota and leaky gut syndrome as significant predictors of OA status, particularly when combined with the rRNA-seq data. CONCLUSIONS: Adults with obesity and knee plus hand OA have distinct fecal metabolomes characterized by increased products of proteolysis, perturbations in leukotriene metabolism, and changes in microbial metabolites compared with controls. These metabolic perturbations indicate a possible role of dysregulated proteolysis in OA.

Untargeted analysis of first trimester serum to reveal biomarkers of pregnancy complications: a case-control discovery phase study.

Understanding of causal biology and predictive biomarkers are lacking for hypertensive disorders of pregnancy (HDP) and preterm birth (PTB). First-trimester serum specimens from 51 cases of HDP, including 18 cases of pre-eclampsia (PE) and 33 cases of gestational hypertension (GH); 53 cases of PTB; and 109 controls were obtained from the Global Alliance to Prevent Prematurity and Stillbirth repository. Metabotyping was conducted using liquid chromatography high resolution mass spectroscopy and nuclear magnetic resonance spectroscopy. Multivariable logistic regression was used to identify signals that differed between groups after controlling for confounders. Signals important to predicting HDP and PTB were matched to an in-house physical standards library and public databases. Pathway analysis was conducted using GeneGo MetaCore. Over 400 signals for endogenous and exogenous metabolites that differentiated cases and controls were identified or annotated, and models that included these signals produced substantial improvements in predictive power beyond models that only included known risk factors. Perturbations of the aminoacyl-tRNA biosynthesis, L-threonine, and renal secretion of organic electrolytes pathways were associated with both HDP and PTB, while pathways related to cholesterol transport and metabolism were associated with HDP. This untargeted metabolomics analysis identified signals and common pathways associated with pregnancy complications.

Metabolomics to reveal biomarkers and pathways of preterm birth: a systematic review and epidemiologic perspective.

INTRODUCTION: Most known risk factors for preterm birth, a leading cause of infant morbidity and mortality, are not modifiable. Advanced molecular techniques are increasingly being applied to identify biomarkers and pathways important in disease development and progression. OBJECTIVES: We review the state of the literature and assess it from an epidemiologic perspective. METHODS: PubMed, Embase, CINAHL, and Cochrane Central were searched on January 31, 2019 for original articles published after 1998 that utilized an untargeted metabolomic approach to identify markers of preterm birth. Eligible manuscripts were peer-reviewed and included original data from untargeted metabolomics analyses of maternal tissue derived from human studies designed to determine mechanisms and predictors of preterm birth. RESULTS: Of 2823 results, 14 articles met the inclusion requirements. There was little consistency in study design, outcome definition, type of biospecimen, or the inclusion of covariates and confounding factors, and few consistent associations with metabolites were identified in this review. CONCLUSION: Studies to date on metabolomic predictors of preterm birth are highly heterogeneous in both methodology and resulting metabolite identification. There is an urgent need for larger studies in well-defined populations, to determine biomarkers predictive of preterm birth, and to reveal mechanisms and targets for development of intervention strategies.

Association of urinary metabolites with radiographic progression of knee osteoarthritis in overweight and obese adults: an exploratory study.

INTRODUCTION: Metabolic factors may contribute to osteoarthritis (OA). This study employed metabolomics analyses to determine if differences in metabolite profiles could distinguish people with knee OA who exhibited radiographic progression. METHODS: Urine samples obtained at baseline and 18 months from overweight and obese adults in the Intensive Diet and Exercise for Arthritis (IDEA) trial were selected from two subgroups (n = 22 each) for metabolomics analysis: a group that exhibited radiographic progression (≥0.7 mm decrease in joint space width, JSW) and an age, gender, and body mass index (BMI) matched group who did not progress (≤0.35 mm decrease in JSW). Multivariate analysis methods, including orthogonal partial least square discriminate analysis, were used to identify metabolite profiles that separated progressors and non-progressors. Plasma levels of IL-6 and C-reactive protein (CRP) were evaluated as inflammatory markers. RESULTS: Multivariate analysis of the binned metabolomics data distinguished progressors from non-progressors. Library matching revealed that glycolate, hippurate, and trigonelline were among the important metabolites for distinguishing progressors from non-progressors at baseline whereas alanine, N,N-dimethylglycine, glycolate, hippurate, histidine, and trigonelline, were among the metabolites that were important for the discrimination at 18 months. In non-progressors, IL-6 decreased from baseline to 18 months while IL-6 was unchanged in progressors; the change over time in IL-6 was significantly different between groups. CONCLUSION: These findings support a role for metabolic factors in the progression of knee OA and suggest that measurement of metabolites could be useful to predict progression. Further investigation in a larger sample that would include targeted investigation of specific metabolites is warranted.

Parenting and the decline of physical activity from age 9 to 15.

BACKGROUND: There is a rapid decline in moderate-to-vigorous physical activity (MVPA) during middle childhood and adolescence. Information on the environmental factors implicated in this decline is limited. This study focuses on family factors associated with the rate of decline in objectively measured physical activity during middle childhood and adolescence. METHODS: Longitudinal analysis of 801 participants from 10 US sites in the NICHD Study of Early Child Care and Youth Development whose data included accelerometer-determined levels of moderate-to-vigorous physical activity (MVPA) between ages 9 and 15 years, as well as family process, BMI and demographic information. The sample included an even split of boys (49%) and girls (51%), was predominantly white (77%), and contained about 26% low income and 19% single parent families. The outcome measure was mean MVPA. It was based on 4 to 7 days of monitored physical activity. RESULTS: Boys with lower parental monitoring scores and more days of parental encouragement had significantly more minutes of MVPA at age 9 years. The effect of parental monitoring, however, was moderated by early puberty. High parental monitoring was associated with decreased activity levels for boys experiencing later puberty and increased activity for boy experiencing early puberty. Minutes of MVPA for boys living in the Midwest decreased at significantly faster rates than boys living in any other region; and boys in the South declined faster than boys in the West. Girls in the Midwest and South declined faster than girls in the West and Northeast. Among girls, more days of parental exercise and transportation to activities were associated with more MVPA per day at age 9. However, more parental transportation to activities and less monitoring was associated with faster linear declines in daughters' MVPA between the ages of 9 and 15 years. For girls who experienced puberty early, parental encouragement was associated with more MVPA. CONCLUSIONS: Parenting processes, such as monitoring and encouragement, as well as the parents' own level of physical activity, showed significant, but small, gender-specific associations with MVPA levels at age nine and the linear rate of decline in MVPA between ages 9 and 15.