Zi Shen Wan Fang Attenuates Neuroinflammation and Cognitive Function Via Remodeling the Gut Microbiota in Diabetes-Induced Cognitive Impairment Mice

Abstract

Background: Cognitive dysfunction is a critical complication of diabetes mellitus, and there are still no clinically approved drugs. Zi Shen Wan Fang (ZSWF) is an optimized prescription composed of Anemarrhenae Rhizoma, Phellodendri Chinensis Cortex, and Cistanches Herba. The purpose of this study is to investigate the effect of ZSWF on DCI and explore its mechanism from the perspective of maintaining intestinal microbial homeostasis in order to find an effective prescription for treating DCI.Methods: The diabetes model was established by a high-fat diet combined with intraperitoneal injections of streptozotocin (STZ, 120 mg/kg) and the DCI model was screened by Morris water maze (MWM) after 8 weeks of continuous hyperglycemic stimulation. The DCI mice were randomly divided into the model group (DCI), the low- and high-ZSWF–dose groups (9.63 g/kg, 18.72 g/kg), the mixed antibiotic group (ABs), and the ZSWF combined with mixed antibiotic group (ZSWF + ABs). ZSWF was administered orally once a day for 8 weeks. Then, cognitive function was assessed using MWM, neuroinflammation and systemic inflammation were analyzed by enzyme-linked immunosorbent assay kits, intestinal barrier integrity was assessed by hematoxylin-eosin (HE) staining and Western blot and high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Furthermore, the alteration to intestinal flora was monitored by 16S rDNA sequencing.Results: ZSWF restored cognitive function in DCI mice and reduced levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α. Moreover, ZSWF protected the integrity of the intestinal barrier by increasing intestinal ZO-1 and occludin protein expression and decreasing urinary lactulose to mannitol ratio. In addition, ZSWF reshaped the imbalanced gut microbiota in DCI mice by reversing the abundance changes of a wide range of intestinal bacteria at the phyla and genus levels. In contrast, removing gut microbiota with antibiotics partially eliminated the effects of ZSWF on improving cognitive function and reducing inflammation, confirming the essential role of gut microbiota in the improvement of DCI by ZSWF.Conclusion: ZSWF can reverse cognitive impairment in DCI mice by remolding the structure of destructed gut microbiota community, which is a potential Chinese medicine prescription for DCI treatment.

AR/PCC herb pair inhibits osteoblast pyroptosis to alleviate diabetes‐related osteoporosis by activating Nrf2/Keap1 pathway

“…Anemarrhenae Rhizoma/Phellodendri Chinensis Cortex herb pair, diabetes, Nrf2/Keap1 signalling, osteoporosis, pyroptosis as diabetic nephropathy and diabetes-induced cognitive impairment, through the reduction in Nlrp3 and Caspase1 levels. 26,27 Based on the above findings, it is reasonable to speculate that AR/PPC herb pair may yield a similar role in attenuating osteoblast pyroptosis and mitigating the development of DOP.…”

“…5 The AR/PCC is a traditional Chinese herbal pair that has been widely utilized for the management of DM. 9,27,45 Importantly, both our latest discoveries and other studies using zebrafish or rodent DM models have demonstrated the effective attenuation of osteoporotic phenotypes by AR/PCC or certain AR/PCC-derived compounds. [8][9][10][11] Based on these findings, we hypothesized that AR/PCC exhibits beneficial properties against DOP progression.…”

“…Emerging evidence shows that the chronic inflammatory microenvironment induced by hyperglycaemia activates the NLRP3 inflammasome and promotes the production of inflammatory factors, leading to the inhibition of proliferation and differentiation of osteoblasts; however, the silencing of Nlrp3 or inhibition of Caspase1 in osteoblasts could restore their ability to proliferate, differentiate and protect against bone mineralization deficiency in DM mice 23–25 . Of note, AR and PCC have been documented to ameliorate inflammatory responses in a variety of diabetic complications, such as diabetic nephropathy and diabetes‐induced cognitive impairment, through the reduction in Nlrp3 and Caspase1 levels 26,27 . Based on the above findings, it is reasonable to speculate that AR/PPC herb pair may yield a similar role in attenuating osteoblast pyroptosis and mitigating the development of DOP.…”

Cholinergic drugs reduce metabolic inflammation and diabetic myocardial injury by regulating the gut bacterial component lipopolysaccharide‐induced ERK/Egr‐1 pathway

“…49 Hyperglycemia has been shown to result in intestinal barrier dysfunction, 21 and a study in mice fed a high-fat diet combined with intraperitoneal injections of streptozotocin confirmed that diabetes could affect intestinal permeability. 50 Our study demonstrated that db/db mice exhibited impaired intestinal barrier function. After the administration of PYR, intestinal ultrastructural morphology and TJ protein expression improved.…”

“…This low‐grade chronic inflammation, which is triggered by the influx of bacterial component LPS and inflammatory bacterial fragments into the circulation through a defective gut barrier, has significant knock‐on effects on obesity, insulin resistance, and multiple organ failure 49 . Hyperglycemia has been shown to result in intestinal barrier dysfunction, 21 and a study in mice fed a high‐fat diet combined with intraperitoneal injections of streptozotocin confirmed that diabetes could affect intestinal permeability 50 . Our study demonstrated that db/db mice exhibited impaired intestinal barrier function.…”