Interplay between gut microbiota, bone health and vascular calcification in chronic kidney disease

Deregulations in gut microbiota may play a role in vascular and bone disease in chronic kidney disease (CKD). As glomerular filtration rate declines, the colon becomes more important as a site of excretion of urea and uric acid, and an increased bacterial proteolytic fermentation alters the gut microbial balance. A diet with limited amounts of fibre, as well as certain medications (eg phosphate binders, iron supplementation, antibiotics) further contribute to changes in gut microbiota composition among CKD patients. At the same time, both vascular calcification and bone disease are common in patients with advanced kidney disease. This narrative review describes emerging evidence on gut dysbiosis, vascular calcification, bone demineralization and their interrelationship termed the ‘gut‐bone‐vascular axis’ in progressive CKD. The role of diet, gut microbial metabolites (ie indoxyl sulphate, p‐cresyl sulphate, trimethylamine N‐oxide (TMAO) and short‐chain fatty acids (SCFA)), vitamin K deficiency, inflammatory cytokines and their impact on both bone health and vascular calcification are discussed. This framework may open up novel preventive and therapeutic approaches targeting the microbiome in an attempt to improve cardiovascular and bone health in CKD

Fish Oil Supplementation Reduces Inflammation but Does Not Restore Renal Function and Klotho Expression in an Adenine-Induced CKD Model

BACKGROUND: Chronic kidney disease and inflammation promote loss of Klotho expression. Given the well-established anti-inflammatory effects of omega-3 fatty acids, we aimed to investigate the effect of fish oil supplementation in a model of CKD. METHODS: Male C57BL/6 mice received supplementation with an adenine-enriched diet (AD, n = 5) or standard diet (CTL, n = 5) for 10 days. Two other experimental groups were kept under the adenine diet for 10 days. Following adenine withdrawal on the 11th day, the animals returned to a standard diet supplemented with fish oil (Post AD-Fish oil, n = 9) or not (Post AD-CTL, n = 9) for an additional period of 7 days. RESULTS: Adenine mice exhibited significantly higher mean serum urea, creatinine, and renal expression of the pro-inflammatory markers Interleukin-6 (IL-6), C-X-C motif chemokine 10 (CXCL10), and Interleukin-1β (IL-1β), in addition to prominent renal fibrosis and reduced renal Klotho gene expression compared to the control. Post AD-Fish oil animals demonstrated a significant reduction of IL-6, C-X-C motif chemokine 9 (CXCL9), and IL-1β compared to Post AD-CTL animals. However, serum creatinine, renal fibrosis, and Klotho were not significantly different in the fish oil-treated group. Furthermore, renal histomorphological changes such as tubular dilatation and interstitial infiltration persisted despite treatment. CONCLUSIONS: Fish oil supplementation reduced renal pro-inflammatory markers but was not able to restore renal function nor Klotho expression in an adenine-induced CKD model

Dietary Recommendations for Bariatric Patients to Prevent Kidney Stone Formation

Bariatric surgery (BS) is one of the most common and efficient surgical procedures for sustained weight loss but is associated with long-term complications such as nutritional deficiencies, biliary lithiasis, disturbances in bone and mineral metabolism and an increased risk of nephrolithiasis, attributed to urinary metabolic changes resultant from low urinary volume, hypocitraturia and hyperoxaluria. The underlying mechanisms responsible for hyperoxaluria, the most common among all metabolic disturbances, may comprise increased intestinal oxalate absorption consequent to decreased calcium intake or increased dietary oxalate, changes in the gut microbiota, fat malabsorption and altered intestinal oxalate transport. In the current review, the authors present a mechanistic overview of changes found after BS and propose dietary recommendations to prevent the risk of urinary stone formation, focusing on the role of dietary oxalate, calcium, citrate, potassium, protein, fat, sodium, probiotics, vitamins D, C, B6 and the consumption of fluids

Deletion of Kinin B2 receptor alters muscle metabolism and exercise performance

Metabolic syndrome is a cluster of metabolic risk factors such as obesity, diabetes and cardiovascular diseases. Mitochondria is the main site of ATP production and its dysfunction leads to decreased oxidative phosphorylation, resulting in lipid accumulation and insulin resistance. Our group has demonstrated that kinins can modulate glucose and lipid metabolism as well as skeletal muscle mass. By using B2 receptor knockout mice (B2R-/-) we investigated whether kinin action affects weight gain and physical performance of the animals. Our results show that B2R-/- mice are resistant to high fat diet-induced obesity, have higher glucose tolerance as well as increased mitochondrial mass. These features are accompanied by higher energy expenditure and a lower feed efficiency associated with an increase in the proportion of type I fibers and intermediary fibers characterized by higher mitochondrial content and increased expression of genes related to oxidative metabolism. Additionally, the increased percentage of oxidative skeletal muscle fibers and mitochondrial apparatus in B2R-/- mice is coupled with a higher aerobic exercise performance. Taken together, our data give support to the involvement of kinins in skeletal muscle fiber type distribution and muscle metabolism, which ultimately protects against fat-induced obesity and improves aerobic exercise performance

Deletion of Kinin B2 Receptor Alters Muscle Metabolism and Exercise Performance.

Metabolic syndrome is a cluster of metabolic risk factors such as obesity, diabetes and cardiovascular diseases. Mitochondria is the main site of ATP production and its dysfunction leads to decreased oxidative phosphorylation, resulting in lipid accumulation and insulin resistance. Our group has demonstrated that kinins can modulate glucose and lipid metabolism as well as skeletal muscle mass. By using B2 receptor knockout mice (B2R-/-) we investigated whether kinin action affects weight gain and physical performance of the animals. Our results show that B2R-/- mice are resistant to high fat diet-induced obesity, have higher glucose tolerance as well as increased mitochondrial mass. These features are accompanied by higher energy expenditure and a lower feed efficiency associated with an increase in the proportion of type I fibers and intermediary fibers characterized by higher mitochondrial content and increased expression of genes related to oxidative metabolism. Additionally, the increased percentage of oxidative skeletal muscle fibers and mitochondrial apparatus in B2R-/- mice is coupled with a higher aerobic exercise performance. Taken together, our data give support to the involvement of kinins in skeletal muscle fiber type distribution and muscle metabolism, which ultimately protects against fat-induced obesity and improves aerobic exercise performance

Indirect calorimetry and mitochondrial activity.

<p><b>(A)</b> Oxygen consumption and <b>(B)</b> CO₂ production in WT or B2R^-/- mice fed an HFD for 8 weeks (n = 5 each). <b>(C)</b> Respiratory quotient ratio in WT or B2R^-/- mice fed an HFD for 8 weeks. (n = 5 each). <b>(D)</b> Histochemical analysis of SDH and COX staining in skeletal muscle of 3-month-old WT or B2R^-/- mice (n = 5) Scale bar = 50μm. <b>(E)</b> Dihydroethidium (DHE) and 4’,6-diamidino-2-phenylindole dihydrochloride (DAPI) colocalization. Representative images of gastrocnemius muscle in 3-month-old mouse showing fluorescent labeling of DAPI (blue) in and DHE (red) at the corresponding location and focal plane, with merged pictures, showing colocalization (pink). Scale bar = 20μm. <i>(*P < 0.05;</i><i>**P<0.005)</i><i>Data are presented as mean ± S</i>.<i>E</i>.<i>M</i>.</p

Mitochondrial biogenesis.

<p><b>(A)</b> Mitochondrial DNA quantification in skeletal muscle of 3-month-old WT or B2R^-/- mice (n = 5 each). <b>(B)</b> Expression of genes related to mitochondrial biogenesis (PGC1b; PGC1a; LCAD; SCD1; UCP3; PPARg) and OxPhos (CPT) in skeletal muscle of 3-month-old WT or B2R^-/- mice (<i>n</i> = 7 each). <i>(*P < 0</i>.<i>05; **P<0</i>.<i>005) Data are presented as mean ± S</i>.<i>E</i>.<i>M</i>.</p

B2R^-/- is protected from obesity.

<p><b>(A)</b> Total body weight of wild type (WT) or B2 knockout mice (B2R^-/-) under control diet (Control) or high-fat diet (HFD) (<i>n</i> = 5 each). Obesity was induced after 8 weeks of HFD treatment. <b>(B)</b> Feed efficiency of WT and B2R^-/- mice during 8 weeks of HFD treatment. Body composition analysis showing <b>(C)</b> fat mass, <b>(D)</b> lean mass and percent body fat <b>(E)</b> of WT and mice after 8 weeks of HFD treatment. <b>(F)</b> Epididmal and <b>(G)</b> perirenal fat pad depots and <b>(H)</b> total mass after 8 weeks of HFD treatment. (<i>n</i> = 5 for each group) <i>(*P<0.05;</i>^<i>#</i><i>P<0.05</i>, ^<i>##</i><i>P<0.01) Data are presented as mean ± S</i>.<i>E</i>.<i>M</i>.</p