https://www.nature.com/articles/s41574-023-00833-4.pdf

Metformin: update on mechanisms of action and repurposing potential

Gut microbes and their metabolites are actively involved in the development and regulation of host immunity, which can influence disease susceptibility. Herein, we review the most recent research advancements in the gut microbiota–immune axis. We discuss in detail how the gut microbiota is a tipping point for neonatal immune development as indicated by newly uncovered phenomenon, such as maternal imprinting, in utero intestinal metabolome, and weaning reaction. We describe how the gut microbiota shapes both innate and adaptive immunity with emphasis on the metabolites short-chain fatty acids and secondary bile acids. We also comprehensively delineate how disruption in the microbiota–immune axis results in immune-mediated diseases, such as gastrointestinal infections, inflammatory bowel diseases, cardiometabolic disorders (e.g., cardiovascular diseases, diabetes, and hypertension), autoimmunity (e.g., rheumatoid arthritis), hypersensitivity (e.g., asthma and allergies), psychological disorders (e.g., anxiety), and cancer (e.g., colorectal and hepatic). We further encompass the role of fecal microbiota transplantation, probiotics, prebiotics, and dietary polyphenols in reshaping the gut microbiota and their therapeutic potential. Continuing, we examine how the gut microbiota modulates immune therapies, including immune checkpoint inhibitors, JAK inhibitors, and anti-TNF therapies. We lastly mention the current challenges in metagenomics, germ-free models, and microbiota recapitulation to a achieve fundamental understanding for how gut microbiota regulates immunity. Altogether, this review proposes improving immunotherapy efficacy from the perspective of microbiome-targeted interventions.

/pdf/crosstalk-between-gut-microbiota-and-host-immunity-impact-on-28czsdqd.pdf

Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy

Accumulating evidence indicates gut microbiota contributes to aging-related disorders. However, the exact mechanism underlying gut dysbiosis-related pathophysiological changes during aging remains largely unclear. In the current study, we first performed gut microbiota remodeling on old mice by fecal microbiota transplantation (FMT) from young mice, and then characterized the bacteria signature that was specifically altered by FMT. Our results revealed that FMT significantly improved natural aging-related systemic disorders, particularly exerted hepatoprotective effects, and improved glucose sensitivity, hepatosplenomegaly, inflammaging, antioxidative capacity and intestinal barrier. Moreover, FMT particularly increased the abundance of fecal A.muciniphila, which was almost nondetectable in old mice. Interestingly, A.muciniphila supplementation also exerted similar benefits with FMT on old mice. Notably, targeted metabolomics on short chain fatty acids (SCFAs) revealed that only acetic acid was consistently reversed by FMT. Then, acetic acid intervention exerted beneficial actions on both Caenorhabditis elegans and natural aging mice. In conclusion, our current study demonstrated that gut microbiota remodeling improved natural aging-related disorders through A.muciniphila and its derived acetic acid, suggesting that interventions with potent stimulative capacity on A. muciniphila growth and production of acetic acid was alternative and effective way to maintain healthy aging. DATA AVAILABILITY STATEMENT: The data of RNAseq and 16 S rRNA gene sequencing can be accessed in NCBI with the accession number PRJNA848996 and PRJNA849355. 

Gut microbiota remodeling improves natural aging-related disorders through Akkermansia muciniphila and its derived acetic acid.

ROS-triggered self-disintegrating and pH-responsive astaxanthin nanoparticles for regulating the intestinal barrier and colitis.

Traditional Chinese herbal medicine often exerts the therapeutic effect of “treating different diseases with the same method” in clinical practice; in other words, it is a kind of herbal medicine that can often treat two or even multiple diseases; however, the biological mechanism underlying its multi-path and multi-target pharmacological effects remains unclear. Growing evidence has demonstrated that gut microbiota dysbiosis plays a vital role in the occurrence and development of several diseases, and that the root cause of herbal medicine plays a therapeutic role in different diseases, a phenomenon potentially related to the improvement of the gut microbiota. We used local intestinal diseases, such as ulcerative colitis, and systemic diseases, such as type 2 diabetes, as examples; comprehensively searched databases, such as PubMed, Web of Science, and China National Knowledge Infrastructure; and summarized the related studies. The results indicate that multiple individual Chinese herbal medicines, such as Rhizoma coptidis (Huang Lian), Curcuma longa L (Jiang Huang), and Radix Scutellariae (Huang Qin), and Chinese medicinal compounds, such as Gegen Qinlian Decoction, Banxia Xiexin Decoction, and Shenling Baizhu Powder, potentially treat these two diseases by enriching the diversity of the gut microbiota, increasing beneficial bacteria and butyrate-producing bacteria, reducing pathogenic bacteria, improving the intestinal mucosal barrier, and inhibiting intestinal and systemic inflammation. In conclusion, this study found that a variety of traditional Chinese herbal medicines can simultaneously treat ulcerative colitis and type 2 diabetes, and the gut microbiota may be a significant target for herbal medicine as it exerts its therapeutic effect of “treating different diseases with the same method”.

/pdf/gut-microbiota-the-potential-key-target-of-tcms-therapeutic-1kofyxih.pdf

Gut Microbiota: The Potential Key Target of TCM’s Therapeutic Effect of Treating Different Diseases Using the Same Method—UC and T2DM as Examples

The present study aimed to determine if metformin exerts anti-inflammatory and mucus-protective effects via the gut microbiota. Metformin has extensive benefits including anti-inflammatory effects. Previous studies showed that metformin changed the gut microbiota composition and increases the number of goblet cells. Intestinal dysbiosis and goblet cell depletion are important features of ulcerative colitis (UC). The underlying mechanism and whether metformin can improve the mucus barrier in UC remain unclear. Metformin (400 mg/kg/day) was administered to mice with dextran sulfate sodium (DSS)-induced UC for 2 wk to investigate the effects of metformin on the intestinal mucus barrier. The gut microbiota was depleted, using antibiotics, to explore its role in the mucus-protecting effects of metformin. Akkermansia muciniphila (A. muciniphila), which was enriched in metformin-treated mice, was administered to mice to investigate the effects of the bacteria on UC and the mucus barrier. Metformin attenuated DSS-induced UC in mice, as evidenced by the alleviation of diarrhea, hematochezia, and the decrease in body weight. The expression of mucin2, a prominent mucus barrier protein, was increased in the metformin-treated group compared to the DSS-treated group. Furthermore, fecal 16S rRNA analysis showed that metformin treatment changed the gut microbiota composition by increasing the relative abundance of Lactobacillus and Akkermansia species while decreasing Erysipelatoclostridium at the genus level. Antibiotic treatment partly abolished the anti-inflammatory and mucus-protecting effects of metformin. Administration of A. muciniphila alleviated the colonic inflammation and mucus barrier disruption. Metformin alleviated DSS-induced UC in mice and protected against cell damage via affecting the gut microbiota, thereby providing a new mechanism for the therapeutic effect of metformin in patients with UC. This study also provides evidence that A. muciniphila as a probiotic has potential benefits for UC.

/pdf/metformin-exerts-anti-inflammatory-and-mucus-barrier-porh0l0cxv.pdf

Metformin Exerts Anti-inflammatory and Mucus Barrier Protective Effects by Enriching Akkermansia muciniphila in Mice With Ulcerative Colitis

Clostridioides difficile infection (CDI) is a common infection of the gastrointestinal tract. Typically, 20%-30% of CDI patients experience recurrent C. difficile infection (RCDI). Although the role of Th17 in infectious and inflammatory diseases including CDI has gained attention, reports on the correlation between Th17 and RCDI are scarce. In this study, CDI and RCDI mice models were challenged with C. difficile. Serum lactic acid dehydrogenase, inflammatory factor levels, reverse transcriptase-polymerase chain reaction, western blot analysis, hematoxylin and eosin staining, immunohistochemistry, flow cytometry analysis, and enzyme-linked immunosorbent assay were performed on the CDI, RCDI, and control group mice. The results showed more serious clinical manifestations in the RCDI group compared with those in the CDI group. More severe gut barrier disruption and higher degree of microbiota translocation were observed in the RCDI group compared with those in the CDI group. Moreover, extremely severe apoptosis was observed in HCT-116 cells incubated with the serum from RCDI mice model. In addition, higher levels of Th17 and IL-17 were detected in the blood or serum from the RCDI mouse model. Treatment with RORγt small molecule inhibitor SR1001 increased the expression of occludin, decreased the apoptotic rate of HCT-116 cells, and decreased the concentrations of Th17 and IL-17. Concisely, Th17 and IL-17 are potential indicators of RCDI and may serve as therapeutic targets for RCDI treatment. This study lays the foundation for future research on RCDI diagnosis and treatment.

Blockade of T helper 17 cell function ameliorates recurrent Clostridioides difficile infection in mice

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Metformin Exerts Anti-inflammatory and Mucus Barrier Protective Effects by Enriching Akkermansia muciniphila in Mice With Ulcerative Colitis

Blockade of T helper 17 cell function ameliorates recurrent Clostridioides difficile infection in mice