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Obesity and insulin resistance are associated with dysbiosis of the gut microbiota and impaired intestinal barrier function. Herein, we report that Bofutsushosan (BFT), a Japanese herbal medicine, Kampo, which has been clinically used for constipation in Asian countries, ameliorates glucose metabolism in mice with diet–induced obesity. A 16S rRNA sequence analysis of fecal samples showed that BFT dramatically increased the relative abundance of Verrucomicrobia, which was mainly associated with a bloom of Akkermansia muciniphila (AKK). BFT decreased the gut permeability as assessed by FITC-dextran gavage assay, associated with increased expression of tight-junction related protein, claudin-1, in the colon. The BFT treatment group also showed significant decreases of the plasma endotoxin level and expression of the hepatic lipopolysaccharide-binding protein. Antibiotic treatment abrogated the metabolic effects of BFT. Moreover, many of these changes could be reproduced when the cecal contents of BFT-treated donors were transferred to antibiotic-pretreated high fat diet-fed mice. These data demonstrate that BFT modifies the gut microbiota with an increase in AKK, which may contribute to improving gut barrier function and preventing metabolic endotoxemia, leading to attenuation of diet-induced inflammation and glucose intolerance. Understanding the interaction between a medicine and the gut microbiota may provide insights into new pharmacological targets to improve glucose metabolism.

Alginate oligosaccharides are associated with some beneficial health effects. Gut microbiota is one of the most recently identified factors in the development of several metabolic diseases induced by high-fat diet. Our objective was to evaluate how alginate oligosaccharides impact on high-fat diet‑induced features of metabolic disorders and whether this impact is related to modulations in the modulation of the gut microbiota. C57BL/6J mice were fed with chow diet, high-fat diet, or high-fat diet supplemented with alginate oligosaccharides for 10 weeks. Alginate oligosaccharide treatment improved lipid metabolism, such as reducing levels of TG and LDL-C and inhibiting expression of lipogenesis genes. Alginate oligosaccharide administration reduced the levels of fasting blood glucose and increased the levels of serum insulin. Alginate oligosaccharide treatment was found to lower the expression of markers of inflammation, including IL1β and CD11c. Alginate oligosaccharide treatment modulated gut microbial communities and markedly prompted the growth of Akkermansia muciniphila, Lactobacillus reuteri, and Lactobacillus gasseri. Additionally, alginate oligosaccharide intervention significantly increased concentrations of short-chain fatty acids, such as acetic acid, propionic acid, and butyric acid, as well as decreased levels of endotoxin. Alginate oligosaccharides exert beneficial effects via alleviating metabolic metrics induced by high-fat diet, which is associated with increase in A. muciniphila, L. reuteri, and L. gasseri, as well as the release of microbiota-dependent short-chain fatty acids and inhibition of endotoxin levels.

Torularhodin, a unique carotenoid, confers beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the precise mechanism underlying its therapeutic effects remains unknown. Here, we report that torularhodin alleviates NAFLD in male mice by modulating the gut microbiota. Additionally, transplanting fecal microbiota from torularhodin-treated mice to germ-free mice also improves NAFLD. Mechanistically, torularhodin specifically enriches the abundance of Akkermansia muciniphila , which alleviates NAFLD by promoting the synthesis of adenosylcobalamin. Utilizing a human gastrointestinal system and a colonic organoid model, we further demonstrate that adenosylcobalamin confers protective effects against NAFLD through reducing ceramides, a well-known liver damaging compound, and this effect is mediated by inhibition of the hypoxia-inducible factor 2α pathway. Notably, we construct electrospun microsphere-encapsulated torularhodin, which facilitates the slow release of torularhodin in the colon. Together, our findings indicate the therapeutic potential of microbial utilization of carotenoids, such as torularhodin, for treating NAFLD. Nonalcoholic fatty liver disease (NAFLD) has limited dietary treatment options. Here, the authors show that torularhodin, a microbial carotenoid, alleviates NAFLD by enriching Akkermansia muciniphila and promoting adenosylcobalamin synthesis, which reduces ceramides via HIF-2α inhibition.

Over the past decade, there has been increasing evidence highlighting the implication of the gut microbiota in a variety of brain disorders such as depression, anxiety, and schizophrenia. Studies have shown that depression affects the stability of gut microbiota, but the impact of antidepressant treatments on microbiota structure and metabolism remains underexplored. In this study, we investigated the in vitro antimicrobial activity of antidepressants from different therapeutic classes against representative strains of human gut microbiota. Six different antidepressants: phenelzine, venlafaxine, desipramine, bupropion, aripiprazole and ( S )-citalopram have been tested for their antimicrobial activity against 12 commensal bacterial strains using agar well diffusion, microbroth dilution method, and colony counting. The data revealed an important antimicrobial activity (bacteriostatic or bactericidal) of different antidepressants against the tested strains, with desipramine and aripiprazole being the most inhibitory. Strains affiliating to most dominant phyla of human microbiota such as Akkermansia muciniphila, Bifidobacterium animalis and Bacteroides fragilis were significantly altered, with minimum inhibitory concentrations (MICs) ranged from 75 to 800 μg/mL. A significant reduction in bacterial viability was observed, reaching 5 logs cycle reductions with tested MICs ranged from 400 to 600 μg/mL. Our findings demonstrate that gut microbiota could be altered in response to antidepressant drugs.

The gut microbiome influences neurological disorders through bidirectional communication between the gut and the brain, i.e., the gut-brain axis. Artemisia asiatica ex , an extract of Artemisia asiatica Nakai (Stillen®, DA-9601) has been reported to improve depression by increasing brain-derived neurotropic factor. Therefore, we hypothesized that DA-9601 can be a potential therapeutic candidate for Alzheimer’s disease (AD) acting through the gut-brain axis. Four groups of Tg2576 mice were used as the animal model for AD: wild type mice (n = 6), AD mice (n = 6), and DA-9601-administered AD mice given dosages of 30mg/kg/day (DA_30mg; n = 6) or 100mg/kg/day (DA_100mg; n = 6). Microglial activation, blood‒brain barrier integrity, amyloid beta accumulation, cognitive behavior, and changes in the gut microbiome were analyzed. DA-9601 improved the cognitive behavior of mice (DA_30mg **p<0.01; DA_100mg **p<0.01) and reduced amyloid beta accumulation (DA_30mg ***p<0.001; DA_100mg **p<0.01). Increased Iba-1 and upregulation of claudin-5 (DA_30mg *p<0.05) and occludin (DA_30mg **p<0.01; DA_100mg ***p<0.001) indicated altered microglial activation and improved blood‒brain barrier integrity. Akkermansia muciniphila was dramatically increased by DA-9601 administration (DA_30mg 47%; DA_100mg 61%). DA-9601 improved AD pathology with Akkermansia muciniphila dominance in the gut microbiome in a mouse model of AD, inferring that DA-9601 can affect AD through the gut-brain axis.

Background Phytohormones have garnered considerable interest as potential modulators of the gut-bone axis. Denosumab (Deno), a widely utilized therapeutic agent for postmenopausal osteoporosis, has not been previously investigated for its effects on gut health. The objective of this study was to assess the efficacy of isoflavones (SI), naringin (Nar), and Deno in the management of postmenopausal osteoporosis by targeting the gut-bone axis. Methods The postmenopausal osteoporosis model in mice was established via bilateral oophorectomy. Subsequently, mice in the Deno group received subcutaneous injections of Deno at a dosage of 10 mg/kg, administered twice weekly. In contrast, mice in the SI and Nar groups were subjected to oral gavage with 200 mg/kg/day of SI and Nar, respectively. The treatment period for all groups lasted for 8 weeks. Upon the conclusion of the experiment, a thorough evaluation of the effects of SI, Nar, and Deno on bone and gut health in mice was conducted through immunological, pathological, imaging, and multi-omics methodologies. Results Deno, SI, and Nar significantly alleviated the physical symptoms in postmenopausal mice. However, only SI and Nar significantly modulated the gut microbiota. Akkermansia was significantly enriched after the gavage of SI and Nar. Akkermansia has the capacity to not only augment bone mass and alleviate strength deterioration via extracellular vesicles, but it also influences bone metabolism by diminishing inflammation and modulating lipid metabolism . Notably, no significant changes in the gut microbiota were observed in the Deno group, which may be attributed to the differences in the method of administration, as Deno was administered via subcutaneous injection rather than gavage. Conclusion SI and Nar may influence the gut–bone axis through Akkermansia and have the potential of alternative treatment options for postmenopausal osteoporosis. Although the gut microbiota is not significantly affected by the subcutaneous administration of Deno, the long-term management of postmenopausal osteoporosis and the exploration of various management models warrant additional scrutiny. Furthermore, this study has yet to establish a dose–response relationship, indicating that further research is essential to clarify the regulatory effects of varying doses of SI and Nar on postmenopausal osteoporosis especially the modulation of gut microbiota. Graphical Abstract

Background Altered gut microbiota has emerged as a major contributing factor to the etiology of chronic conditions in humans. Antibiotic exposure, historically dating back to the mass production of penicillin in the early 1940s, has been proposed as a primary contributor to the cumulative alteration of microbiota over generations. However, the mechanistic link between the antibiotics-altered microbiota and chronic conditions remains unclear. Results In this study, we discovered that variants of the key beneficial gut microbe, Akkermansia muciniphila , were selected upon exposure to penicillin. These variants had mutations in the promoter of a TEM-type β-lactamase gene or pur genes encoding the de novo purine biosynthesis pathway, and they exhibited compromised abilities to mitigate host obesity in a murine model. Notably, variants of A. muciniphila are prevalent in the human microbiome worldwide. Conclusions These findings highlight a previously unknown mechanism through which antibiotics influence host health by affecting the beneficial capacities of the key gut microbes. Furthermore, the global prevalence of A. muciniphila variants raises the possibility that these variants contribute to global epidemics of chronic conditions, warranting further investigations in human populations. 58AjLUkmnEy4EafSRrEqX8 Video Abstract

A novel homogeneous polysaccharide named GEP-1 was isolated and purified from Gastrodia elata (G. elata) by hot-water extraction, ethanol precipitation, and membrane separator. GEP-1, which has a molecular weight of 20.1 kDa, contains a polysaccharide framework comprised of only glucose. Methylation and NMR analysis showed that GEP-1 contained 1,3,6-linked-α-Glcp, 1,4-linked-α-Glcp, 1,4-linked-β-Glcp and 1,4,6-linked-α-Glcp. Interestingly, GEP-1 contained citric acid and repeating p-hydroxybenzyl alcohol as one branch. Furthermore, a bioactivity test showed that GEP-1 could significantly promote the growth of Akkermansia muciniphila (A. muciniphila) and Lacticaseibacillus paracasei (L.paracasei) strains. These results implied that GEP-1 might be useful for human by modulating gut microbiota.

Imbalanced nutrition, such as a high-fat/high-carbohydrate diet, is associated with negative effects on human health. The composition and metabolic activity of the human gut microbiota are closely related to the type of diet and have been shown to change significantly in response to changes in food content and food supplement administration. Alkylresorcinols (ARs) are lipophilic molecules that have been found to improve lipid metabolism and glycemic control and decrease systemic inflammation. Furthermore, alkylresorcinol intake is associated with changes in intestinal microbiota metabolic activity. However, the exact mechanism through which alkylresorcinols modulate microbiota activity and host metabolism has not been determined. In this study, alterations in the small intestinal microbiota (SIM) and the large intestinal microbiota (LIM) were investigated in mice fed a high-fat diet with or without pentadecylresorcinol (C15) supplementation. High-throughput sequencing was applied for jejunal and colonic microbiota analysis. The results revealed that C15 supplementation in combination with a high-fat diet could decrease blood glucose levels. High-throughput sequencing analysis indicated that C15 intake significantly increased (p < 0.0001) the abundance of the probiotic bacteria Akkermansia muciniphila and Bifidobacterium pseudolongum in both the small and large intestines and increased the alpha diversity of LIM (p < 0.05), but not SIM. The preliminary results suggested that one of the mechanisms of the protective effects of alkylresorcinol on a high-fat diet is the modulation of the content of SIM and LIM and metabolic activity to increase the probiotic bacteria that alleviate unhealthy metabolic changes in the host.

The past two decades of research have raised gut microbiota composition as a contributing factor to the development of obesity, and higher abundance of certain bacterial species has been linked to the lean phenotype, such as Akkermansia muciniphila . The ability of pre- and probiotics to affect metabolic health could be via microbial community alterations and subsequently changes in metabolite profiles, modulating for example host energy balance via complex signaling pathways. The aim of this mice study was to determine how administration of a prebiotic fiber, polydextrose (PDX) and a probiotic Bifidobacterium animalis ssp. lactis 420 (B420), during high fat diet (HFD; 60 kcal% fat) affects microbiota composition in the gastrointestinal tract and adipose tissue, and metabolite levels in gut and liver. In this study C57Bl/6J mice (N = 200) were split in five treatments and daily gavaged: 1) Normal control (NC); 2) HFD; 3) HFD + PDX; 4) HFD + B420 or 5) HFD + PDX + B420 (HFD+S). At six weeks of treatment intraperitoneal glucose-tolerance test (IPGTT) was performed, and feces were collected at weeks 0, 3, 6 and 9. At end of the intervention, ileum and colon mucosa, adipose tissue and liver samples were collected. The microbiota composition in fecal, ileum, colon and adipose tissue was analyzed using 16S rDNA sequencing, fecal and liver metabolomics were performed by nuclear magnetic resonance (NMR) spectroscopy. It was found that HFD+PDX intervention reduced body weight gain and hepatic fat compared to HFD. Sequencing the mice adipose tissue (MAT) identified Akkermansia and its prevalence was increased in HFD+S group. Furthermore, by the inclusion of PDX, fecal, lleum and colon levels of Akkermansia were increased and liver health was improved as the detoxification capacity and levels of methyl-donors were increased. These new results demonstrate how PDX and B420 can affect the interactions between gut, liver and adipose tissue.