Bifidobacterium bifidum alleviates adenine-induced acute kidney injury in mice by improving intestinal barrier function.

Acute kidney injury (AKI) is a kind of critical kidney disease characterized by tubular injury, rapid decline of renal function and renal inflammation, with high clinical incidence. AKI has been shown to be associated with dysregulation of the gut microbiota and impaired intestinal barrier. Bifidobacterium has a positive impact on the treatment of many diseases. However, little is known about the role and mechanism of Bifidobacterium in AKI. Based on previous experiments, Bifidobacterium bifidum FL228.1 and FL276.1, which can relieve intestinal inflammation, and Bifidobacterium bifidum ZL.1, which has anti-inflammatory potential, were screened. This study aimed to investigate the effects of Bifidobacterium bifidum FL228.1, FL276.1 and ZL.1 on AKI, focusing on their role in the gut microbiota composition and intestinal barrier function. Our results showed that Bifidobacterium bifidum FL228.1, FL276.1 and ZL.1 effectively improved kidney function in mice with AKI by regulating the gut microbiota dysregulation, inhibiting intestinal inflammation and rebuilding the intestinal mucosal barrier. In addition, intervention with probiotics turned the gut microbiota disturbance caused by AKI into a normalized trend, reversed the adverse outcome of microbiota imbalance, and increased the abundance of potentially beneficial bacteria Bifidobacterium and Faecalibaculum. In summary, Bifidobacterium bifidum FL228.1, FL276.1, and ZL.1 alleviate adenine-induced AKI based on the gut-kidney axis. Although their mechanisms of action are different, their effect on alleviating AKI is almost the same.

Regulation of Gut Microflora by Lactobacillus casei Zhang Attenuates Liver Injury in Mice Caused by Anti-Tuberculosis Drugs.

The gut-liver axis may provide a new perspective for treating anti-tuberculosis drug-induced liver injury (ATDILI). Herein, the protective effect of Lactobacillus casei (Lc) was investigated by modulating gut microflora (GM) and the toll like receptor 4 (TLR4)-nuclear factor (NF)-κB-myeloiddifferentiationfactor 88 (MyD88) pathway. C57BL/6J mice were given three levels of Lc intragastrically for 2 h before administering isoniazid and rifampicin for 8 weeks. Blood, liver, and colon tissues, as well as cecal contents, were collected for biochemical and histological examination, as well as Western blot, quantitative real time polymerase chain reaction (qRT-PCR), and 16S rRNA analyses. Lc intervention decreased alkaline phosphatase (ALP), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and tumor necrosis factor (TNF)-α levels (p < 0.05), recovered hepatic lobules, and reduced hepatocyte necrosis to alleviate liver injury induced by anti-tuberculosis drugs. Moreover, Lc also increased the abundance of Lactobacillus and Desulfovibrio and decreased Bilophila abundance, while enhancing zona occludens (ZO)-1 and claudin-1 protein expression compared with the model group (p < 0.05). Furthermore, Lc pretreatment reduced the lipopolysaccharide (LPS) level and downregulated NF-κB and MyD88 protein expression (p < 0.05), thus restraining pathway activation. Spearman correlation analysis indicated that Lactobacillus and Desulfovibrio were positively correlated with ZO-1 or occludin protein expression and negatively correlated with pathway protein expression. Desulfovibrio had significant negative relationships with alanine aminotransferase (ALT) and LPS levels. In contrast, Bilophila had negative associations with ZO-1, occludin, and claudin-1 protein expressions and positive correlations with LPS and pathway proteins. The results prove that Lactobacillus casei can enhance the intestinal barrier and change the composition of the gut microflora. Moreover, Lactobacillus casei may also inhibit TLR4-NF-κB-MyD88 pathway activation and alleviate ATDILI.

Lacticaseibacillus casei ATCC334 Ameliorates Radiation-Induced Intestinal Injury in Rats by Targeting Microbes and Metabolites.

SCOPE: Gastrointestinal side effects are frequently observed in patients receiving medical radiation therapy. As Lacticaseibacillus casei ATCC334 potentially affects microbial ecosystem, the study hypothesizes that it may improve radiation-induced intestinal injury in rats by modulating the "gut microbiota-metabolite-barrier axis." METHODS AND RESULTS: Rats are fed one of three or no doses of L. casei ATCC334 for 7 days and then expose to a single dose of 9 Gy X-ray total abdominal irradiation. Supplementation with L. casei ATCC334 promote the proliferation of intestinal stem cells (ISCs), increase the expression of tight junction proteins, reduce intestinal permeability, and protect intestinal barrier integrity. Moreover, 16S rRNA sequencing show that medium and high doses of L. casei ATCC334 inhibit the growth of Escherichia/Shigella and favor Akkermansia proliferation. L. casei ATCC334 intervention reprogram the metabolic profile and inhibit putrescine production but promote alpha-linolenic acid (ALA) production. Notably, a decrease in putrescine and an increase in ALA are significantly correlated with the proliferation of ISCs and enhanced intestinal barrier function following L. casei ATCC334 intervention. CONCLUSION: These results highlight that medium and high doses of L. casei ATCC334 alleviate radiation-induced intestinal damage by enhancing the mucosal barrier and remodeling the gut microbiota structure and metabolic activity.

Punicalagin Attenuates Neuronal Apoptosis by Upregulating 5-Hydroxymethylcytosine in the Diabetic Mouse Brain.

Punicalagin exerts neuroprotective activity by improving AMP-activated kinase (AMPK) and mitochondrial Krebs cycle. AMPK and Krebs cycle metabolites regulate 5-hydroxymethylcytosine (5hmC) via acting on ten-eleven translocation (TET) enzymes. Therefore, we hypothesized that punicalagin inhibits diabetes-related neuronal apoptosis by upregulating 5hmC in the diabetic mouse brain. C57BL/6J mice aged 8 weeks were randomly separated into five groups (n = 10), normal control (NC), diabetes mellitus (DM), resveratrol (RES), low-dose punicalagin (LPU), and high-dose punicalagin (HPU). Compared with other groups, the neuronal apoptosis rate was significantly higher and the 5hmC level of the cerebral cortex was significantly lower in the DM group. The levels of TET2 and P-AMPKα/AMPKα were significantly lower in the DM group than in both LPU and HPU groups. The ratio of (succinic acid + fumaric acid)/α-ketoglutarate was significantly higher in the DM group than in other groups. The present results suggest that punicalagin upregulates 5hmC via activating AMPK and maintaining Krebs cycle homeostasis, thus inhibiting neuronal apoptosis in the diabetic mouse brain.

Preventive Effect of Apple Polyphenol Extract on High-Fat Diet-Induced Hepatic Steatosis in Mice through Alleviating Endoplasmic Reticulum Stress.

In this work, the protective effect of apple polyphenol extract (APE) on hepatic steatosis was investigated. Thirty-two C57BL/6J mice were assigned randomly to control group, hepatic steatosis group, lovastatin group, and APE group. After 8 weeks of intervention, APE supplementation markedly decreased the body weight gain, liver weight, liver index, epididymal adipose weight, epididymal adipose index, serum, and hepatic lipid levels. Hematoxylin and eosin staining revealed that APE supplementation alleviated histopathological changes of hepatic steatosis. Western blot revealed that APE downregulated the protein levels of GRP78, IRE1α, p-IRE1α, XBP1, PERK, p-PERK, p-eIF2α, ATF6, PPAR-γ, SREBP-1c, FAS, and ACC1. In conclusion, this study found that APE inhibited IRE1α-XBP1, PERK-eIF2α, and ATF6 signaling pathways to alleviate endoplasmic reticulum stress, thereby improving HFD-induced hepatic steatosis.

Preventive Effect of Ellagic Acid on Cardiac Dysfunction in Diabetic Mice through Regulating DNA Hydroxymethylation.

Ellagic acid (EA) improves mitochondrial dysfunction and protects diabetic hearts. The mitochondrial tricarboxylic acid (TCA) cycle regulates DNA 5-hydroxymethylcytosine (5hmC) levels by affecting activity of 10-11 translocation enzymes (TETs). Therefore, we hypothesized that EA prevents diabetic cardiac dysfunction by modulating DNA 5hmC levels. C57BL/6J mice were fed a high-fat diet to induce diabetes and treated with EA (100 mg kg-1 day-1) for 8 weeks. Serum concentrations of glucose, insulin, and triglyceride and aspartate transaminase and creatine kinase activities were significantly lower in the EA group than the diabetes mellitus (DM) group. DNA 5hmC levels of mice hearts were significantly higher in the EA group than the DM group. The protein levels of TET, complexes I/III/V were significantly higher in the EA group than the DM group. The results shows that EA has a preventive effect on diabetic cardiac dysfunction, which may be achieved by upregulating TET activity through improving the TCA cycle, to reshape DNA 5hmC levels of mice hearts.

Punicalagin alleviates renal injury via the gut-kidney axis in high-fat diet-induced diabetic mice.

Diabetic renal injury was associated with dysbiosis of the gut microbiota and intestinal barrier. Punicalagin (PU) from pomegranates potentially impacts the microbial ecosystem, intestinal barrier, and renal function. Therefore, we hypothesized that PU may improve diabetic renal injury by modulating the gut-kidney axis. The present study evaluated the effect of PU on the gut-kidney axis and kidney function in a diabetic renal injury mouse model induced by a high-fat diet (HFD). Mice were fed a HFD without PU or with at doses of 50 and 100 mg kg-1 d-1 for 8 weeks. Targeted metabolomics by GC-MS and 16S rRNA sequencing were implemented to determine short-chain fatty acids (SCFAs) and microbes. Further RNA sequencing analyses were performed to determine which differentially expressed genes were changed by PU. Compared with the DM model group, PU supplementation improved diabetic renal injury, ameliorated kidney architecture and function, and reshaped gut microbial ecology. Additionally, PU reversed HFD-induced gut barrier dysfunction, promoted cecal SCFA concentrations and inhibited serum lipopolysaccharide (LPS) and diamine oxidase (DAO) levels. Moreover, correlation analysis found that cecal SCFAs were significantly negatively correlated with inflammation-related genes in the kidney. The present results indicated that PU, a promising bioactive polyphenol, successfully improved diabetic renal injury, most likely through the gut-kidney axis.