Biology subjects

Gregson, C. L.

Publications and source records attributed to Gregson, C. L..

4 recordsLinked to original sources

bioRxiv2025

The effect of vitamin D and calcium supplementation on gut microbiota composition in adolescents living with HIV in Southern Africa

Adolescents living with HIV are at risk of delayed growth and of increased susceptibility to infections, potentially linked to vitamin D insufficiency, which is common in people living with HIV. We analyzed rectal swab microbiota compositions before and after 48 weeks supplementation with high-dose vitamin D and calcium, or placebo, embedded in a randomized controlled trial conducted in Zambia and Zimbabwe (Pan African Clinical Trials Registry PACTR20200989766029). In a sub-cohort of 244 participants, we first assessed baseline associations of the rectal swab microbiota with vitamin D metabolites, parathyroid hormone (PTH), and bone mineral density (BMD). We then analyzed longitudinal changes in rectal swab microbiota and intestinal barrier integrity during supplementation and examined whether the baseline microbiota influenced the treatment response. At baseline, anaerobic taxa within the class Clostridia were positively associated with PTH, 1,25(OH)2D, and BMD, and negatively associated with 24,25(OH)2D. After supplementation, Shannon diversity was decreased ({beta}Std=-0.495, CI [-0.802, -0.188], p=0.0018), median Bray-Curtis dissimilarity from baseline samples was increased ({beta}Std=0.399, CI [0.086, 0.712], p=0.013), and abundance of Clostridia_vadinBB60_group was decreased (log2fc=-1.715, CI [-2.596, -0.835], q=0.043) in the intervention arm. The intervention did not affect the intestinal barrier integrity, measured by intestinal fatty acid binding protein (iFABP) concentration in blood plasma. On average, PTH concentrations decreased and BMD increased during supplementation. However, higher baseline abundance of Clostridia-member UCG-009 predicted a smaller reduction in PTH concentrations during supplementation (log2fcstd=1.200 CI [0.656, 1.744], q=0.012), while higher baseline abundances of Enterococcus (log2fcstd=-1.220 CI [-1.807, -0.632], q=0.022) and Fournierella (log2fcstd=-1.122 CI [-1.694, -0.551], q=0.025) predicted a smaller increase in BMD. In conclusion, there was a reduction of an anaerobic taxon of the class Clostridia following vitamin D supplementation. Further, the microbiota appeared to moderate the effect of the intervention on PTH and bone density.

microbiology↗

bioRxiv2020

LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity

WNT signalling is a developmental pathway which plays an important role in post-natal bone accrual. We have previously shown, that in addition to exhibiting extreme high bone mass, subjects with rare gain-of-function (GoF) mutations in the WNT co-receptor LRP5 also display increased lower-body fat mass. Here, we demonstrate using human physiological studies in GoF LRP5 mutation carriers and glucose uptake assays in LRP5 knockdown (KD) adipocytes that LRP5 promotes adipocyte insulin sensitivity. We also show that a low frequency missense variant in LRP5 shown to be associated with low heel bone mineral density in a genome wide association study meta-analysis, is associated with reduced leg fat mass. Finally, using genome wide transcriptomic analyses and in vitro functional studies in LRP5-KD adipose progenitors (APs) we demonstrate that LRP5 plays an essential role in maintaining AP fitness i.e. functional characteristics. Pharmacological activation of LRP5 signalling in adipose tissue provides a promising strategy to prevent the redistribution of adipose tissue and metabolic sequela associated with obesity and ageing.

cell biology↗

bioRxiv2019

Older age at Initiation of Antiretroviral Therapy Predicts Low Bone Mineral Density in Children with perinatally-infected HIV in Zimbabwe

BackgroundPerinatally-acquired HIV infection commonly causes stunting in children, but how this affects bone and muscle development is unclear. We investigated differences in bone and muscle mass and muscle function between children with HIV (CWH) and uninfected children.\n\nSettingCross-sectional study of CWH (6-16 years) receiving antiretroviral therapy (ART) for >6 months and children in the same age-group testing HIV-negative at primary health clinics in Zimbabwe.\n\nMethodsFrom Dual-energy X-ray Absorptiometry (DXA) we calculated total-body less-head (TBLH) Bone Mineral Content (BMC) for lean mass adjusted-for-height (TBLH-BMCLBM) Z-scores, and lumbar spine (LS) Bone Mineral Apparent Density (BMAD) Z-scores.\n\nResultsThe 97 CWH were older (mean age 12.7 vs. 10.0 years) and therefore taller (mean height 142cm vs. 134cm) than those 77 uninfected. However, stunting (height-for-age Z-score[≤]-2) was more prevalent in CWH (35% vs. 5%, p<0.001). Amongst CWH, 15% had low LS-BMAD (Z-score [≤]-2) and 13% had low TBLH-BMCLBM, vs. 1% and 3% respectively in those uninfected (both p[≤]0.02). After age, sex, height and puberty adjustment, LS-BMAD was 0.33 SDs (95%CI -0.01, 0.67; p=0.06) lower in CWH, with no differences in TBLH-BMCLBM, lean mass or grip strength by HIV status. However, there was a strong relationship between age at ART initiation and both LS-BMAD Z-score (r=-0.33, p=0.001) and TBLH-BMCLBM Z-score (r=-0.23, p=0.027); for each year ART initiation was delayed a 0.13 SD reduction in LS-BMAD was seen.\n\nConclusionSize-adjusted low bone density is common in CWH. Delay in initiating ART adversely affects bone density. Findings support immediate ART initiation at HIV diagnosis.

epidemiology↗

bioRxiv2019

A rare SMAD9 mutation identifies the BMP signalling pathway as a potential osteoanabolic target

To identify targets for novel anabolic medicines for osteoporosis, we recruited a large cohort with unexplained high bone mass (HBM). Exome sequencing identified a rare (minor allele frequency 0.0014) missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in an autosomal dominant family. The same mutation was identified in another two unrelated individuals with HBM. In-silico protein modelling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density [BMD] Z-Scores +3 to +5, with increased volumetric cortical and trabecular BMD, increased cortical thickness, and low/normal bone turnover. Fractures and nerve compressions are not seen. Both genome-wide, and gene-based association testing of heel estimated-BMD in >362,924 UK-Biobank British subjects showed strong associations with SMAD9 (PGWAS=6x10-16; PGENE =8x10-17). Smad9 is highly expressed in murine osteocytes and zebrafish bone tissue. Our findings support SMAD9 as a novel HBM gene, and a potential novel osteoanabolic target.

genetics↗