Gut microbiota-derived butyrate restores impaired regulatory T cells in patients with AChR myasthenia gravis via mTOR-mediated autophagy.

More than 80% of patients with myasthenia gravis (MG) are positive for anti-acetylcholine receptor (AChR) antibodies. Regulatory T cells (Tregs) suppress overproduction of these antibodies, and patients with AChR antibody-positive MG (AChR MG) exhibit impaired Treg function and reduced Treg numbers. The gut microbiota and their metabolites play a crucial role in maintaining Treg differentiation and function. However, whether impaired Tregs correlate with gut microbiota activity in patients with AChR MG remains unknown. Here, we demonstrate that butyric acid-producing gut bacteria and serum butyric acid level are reduced in patients with AChR MG. Butyrate supplementation effectively enhanced Treg differentiation and their suppressive function of AChR MG. Mechanistically, butyrate activates autophagy of Treg cells by inhibiting the mammalian target of rapamycin. Activation of autophagy increased oxidative phosphorylation and surface expression of cytotoxic T-lymphocyte-associated protein 4 on Treg cells, thereby promoting Treg differentiation and their suppressive function in AChR MG. This observed effect of butyrate was blocked using chloroquine, an autophagy inhibitor, suggesting the vital role of butyrate-activated autophagy in Tregs of patients with AChR MG. We propose that gut bacteria derived butyrate has potential therapeutic efficacy against AChR MG by restoring impaired Tregs.

Gut microbiome and metabolome in aneurysm rat with hypertension after ginsenoside Rb1 treatment.

Introduction: Hypertension is a well-known risk factor for aneurysms, as high blood pressure can worsen the development and rupture of aneurysms. Ginsenoside, derived from ginseng and widely used in traditional herbal medicine, is believed to have antihypertensive properties. Recent research has also shown a connection between gut microbiota and various diseases, including hypertension. However, the relationship between ginsenosides, gut microbiota, blood pressure, and intracranial aneurysms needs further exploration. Methods: In this study, a rat model was used to investigate the effects of ginsenosides on both blood pressure and intracranial arteries. Comparative analysis was conducted, and 16S rRNA sequencing was employed to identify marker genera within the gut microbiota. Metabolites were also analyzed to uncover potential mediators of blood pressure regulation. Results and Discussion: The results of this study revealed that ginsenosides, particularly ginsenoside Rb1, demonstrated positive effects in reducing both blood pressure and the development of intracranial aneurysms in rats. Furthermore, the analysis of gut microbiota showed that certain genera, including Clostridium, Roseburia, Ruminococcus, and Treponema, were significantly influenced by ginsenoside treatment. Several metabolites, such as behenic acid, N-Acetylserotonin, Prostaglandin F2a, and Vitamin D2, were also detected, all of which play a role in regulating blood pressure. These findings provide valuable insights into the potential benefits of ginsenosides in hypertension and atheroma development. Furthermore, they suggest a possible link between ginsenosides, gut microbiota, and blood pressure regulation. Further research is needed to fully understand the mechanisms underlying these effects and to determine the clinical implications for treating hypertension and reducing the risk of aneurysm development.

Paris polyphylla extract attenuates colitis in mice by regulating PPAR-γ mediated Treg/Th17 balance.

ETHNOPHARMACOLOGICAL RELEVANCE: Paris polyphylla Sm. (P.P), is a widely-used traditional Chinese medicine (TCM) in the treatment of wound, throat sores and snakebites. Furthermore, P.P was recorded as an anti-inflammatory drug by the Chinese Pharmacopoeia. AIM OF THE STUDY: We sought to decipher the anti-inflammatory effect of P.P on ulcerative colitis (UC); specifically, to explore whether P.P attenuates colitis by restoring the regulatory T cells (Tregs) and T helper 17 (Th17) cells balance and its mechanism. MATERIAL AND METHODS: We treated experimental colitis mice with extracts of Paris polyphylla (EPP). The percentage of Tregs and Th17 cells were measured using flow cytometry, and their secreted cytokines levels were evaluated employing ELISA. The expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) in colon tissues was detected using immunofluorescence. Furthermore, GW9662, a PPAR-γ antagonist, was used to validate the mechanism of EPP in restoring the Treg/Th17 balance. RESULTS: The EPP effectively alleviated the clinical symptoms and inflammatory cytokine levels in mice with colitis. EPP treatment also restored the impaired Treg/Th17 balance in mice. Furthermore, EPP treatment promoted PPAR-γ expression and reduced HIF-1α and p-STAT3 expression in colon tissues, whereas PPAR-γ inhibition blocked the effects of EPP in mice models. CONCLUSION: Our study indicates that EPP exhibit excellent anti-inflammatory properties via restoring PPAR-γ/STAT3/HIF-1α axis-mediated Treg/Th17 balance in colitis mice. Hence, P. polyphylla is a promising medicinal plant-based alternative for managing colitis that requires further clinical validation.

Network pharmacology dissection of multiscale mechanisms for jiaoqi powder in treating ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence of ulcerative colitis (UC) is increasing worldwide, making it a serious public health challenge. Currently, there are no accepted curative treatments for UC. As such, the exploration of new therapeutic strategies for UC treatment is of considerable clinical importance. Jiaoqi powder (JQP) is a classic Chinese medicinal formula commonly used as a complementary and alternative medicine for treating gastrointestinal bleeding. JQP is thus a potential alternative medicine for UC treatment. However, the protective mechanism underlying the action of JQP has not been elucidated, thereby, necessitating further studies to decipher the mechanisms involved in the complex interplay among its components. AIM OF THE STUDY: To explore the protective effect of JQP against UC and to further investigate its mechanism in silico and in vivo using a systems pharmacology approach. MATERIALS AND METHODS: A systems pharmacology approach was used to predict the active components of JQP. Putative targets and the potential mechanism of JQP on UC were obtained through target fishing, network construction, and enrichment analyses. An animal-based model of dextran sodium sulfate (DSS)-induced colitis in C57BL/6 mice was further used to validate the treatment mechanisms of JQP. The underlying pharmacological mechanisms of JQP in UC were determined using polymerase chain reaction tests, histological staining, immunohistochemistry, enzyme-linked immunoassays, and flow cytometry analysis. RESULTS: In this study, 17 effective components and 941 potential targets of JQP were identified. Similarly, 2104 UC-related targets were also identified. Construction of PPI networks led to the identification of 184 putative therapeutic targets of JQP. Sixty-nine core targets among these 184 were further screened based on their DC values. Gene ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the core targets were primarily enriched in immune response and inflammatory signalling pathways. Subsequent animal-based in vivo experiments revealed that JQP ameliorated symptoms and histological changes in DSS colitis by significantly impairing DSS's ability to induce high expression levels of NF-κB/p65, IL-1ß, IL-6, and TNF-α. JQP also reduced the levels of COX-2, CCL2, CXCL2, HIF-1α, MMP3 and MMP9 and regulated the Th17/Treg cell balance in DSS-induced mice. CONCLUSIONS: This study demonstrated that JQP could treat UC by improving the mucosal inflammatory response, repairing the intestinal barrier, and modulating the Th17/Treg immune balance. The results of this study provide new insights into UC treatment and further elucidate the theoretical and practical implications of the pharmaceutical development of TCMs.

Regulation of MFN2 by berberine alleviates obesity exacerbated colitis.

Obesity has become a global health issue, which can cause metabolic abnormalities systemically leading to increased morbidity of series diseases. At present, researches have presented obesity is a high-risk factor for colitis, and berberine shows positive therapeutic effect on colitis. Thus, we explored the beneficial effects and potential mechanisms of berberine on obesity-exacerbated colitis in this article. High-fat diet (HFD) exacerbated dextran sulfate sodium (DSS) induced colitis mice model was applied, the results showed that HFD promoted DSS-induced weight loss and inflammatory manifestations in intestine. The results of cytokines in serum and mRNA expression of inflammatory indicators in colon showed that HFD increased all their levels evidently, and the outcomes of Western blot analyses presented that HFD downregulated the MFN2 expression, inhibited the phosphorylation of AMPK as well as upregulated the BIP/Grp78 expression, while berberine could significantly reverse all these situations. In vitro, we stimulated Caco-2 cells with palmitic acid (PA) to replicate the lipotoxicity damage in the intestine, and the results presented that intervention therapy of berberine effectively enhanced the MFN2 expression, inhibited the mRNA levels of inflammatory factors, and reversed the PA induced protein level changes of AMPK and BIP/Grp78. In general, we proposed that berberine could regulate MFN2 to alleviate obesity exacerbated colitis.