Skate-Skin Mucin, Rich in Sulfated Sugars and Threonine, Promotes Proliferation of Akkermansia muciniphila in Feeding Tests in Rats and In Vitro Fermentation Using Human Feces

Dietary factors, affect Akkermansia muciniphila (AM) abundance in the colon, have attracted attention, driven by the inverse correlation between AM abundance and metabolic disorders. We prepared skate-skin mucin (SM), porcine stomach mucin (PM), and rat gastrointestinal mucin (RM). SM contained more sulfated sugars and threonine than PM or RM. Rats were fed a control diet or diets including SM, PM, or RM (15 g/kg), or SM (12 g/kg) from five different threonine contents for 14 d. Cecal total bacteria and AM were less and more numerous, respectively, in SM-fed rats than the others, but SM did not affect microbial species-richness. Low-threonine SM did not induce AM proliferation. The in vitro fermentation with human feces showed that the rate of AM increase was greater with SM than PM. Collectively, heavy SM sulfation facilitates a priority supply of SM-derived amino sugars and threonine that promotes AM proliferation in rats and human feces.

Akkermansia Muciniphila induces chronic extramedullary hematopoiesis through cooperative IL-1R and TLR signals

Bacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to spleen, which is termed as extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria, particularly the microbiota, regulates not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbial species on hematopoietic pathology remains largely unknown. Here we found that systemic injection of Akkermansia muciniphila (A. m.), a mucin-degrading bacterium abundantly existing in the human gut rapidly activates BM myelopoiesis, and induces a slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we termed chronic EMH. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) partially diminished A. m.-induced chronic EMH, while additional pharmacological inhibition of the interleukin-1 receptor (IL-1R) completely alleviated splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated innate immune signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders.

Active or Autoclaved Akkermansia muciniphila Relieves TNF-α-Induced Inflammation in Intestinal Epithelial Cells Through Distinct Pathways

Intestinal inflammation is a major threat to the health and growth of young animals such as piglets. As a next-generation probiotics, limited studies have shown that Akkermansia muciniphila could alleviate inflammation of intestinal epithelial cells (IECs). In this study, a TNF-α-induced inflammatory model of IPEC-J2 cells, the intestinal porcine enterocytes, was built to evaluate the effects of active or inactive A. muciniphila on the inflammation of IECs. The viability of IPEC-J2 cells was the highest when treated with active (108 copies/mL) or inactive (109 copies/mL) A. muciniphila for 7.5 h (P < 0.01). Treated with 20 ng/mL of TNF-α and followed by a treatment of A. muciniphila, the mRNA level of proinflammatory cytokines (IL-8, IL-1β, IL-6 and TNF-α) was remarkably reduced (P < 0.05) along with the increased mRNA level of tight junction proteins (ZO-1 and Occludin, P < 0.05). Flow cytometry analysis showed that active or inactive A. muciniphila significantly suppressed the rate of the early and total apoptotic of the inflammatory IPEC-J2 cells (P < 0.05). According to results of transcriptome sequencing, active and inactive A. muciniphila may decline cell apoptosis by down-regulating the expression of key genes in calcium signaling pathway, or up-regulating the expression of key genes in cell cycle signaling pathway. And the bacterium may alleviate the inflammation of IECs by down-regulating the expression of PI3K upstream receptor genes. Our results indicate that A. muciniphila may be a promising NGP targeting intestinal inflammation.

The Synbiotic Combination of Akkermansia muciniphila and Quercetin Ameliorates Early Obesity and NAFLD through Gut Microbiota Reshaping and Bile Acid Metabolism Modulation

Gut microbiota plays a key role in obesity and non-alcoholic fatty liver disease (NAFLD), so synbiotics could be a therapeutic alternative. We aim to evaluate a nutritional intervention together with the administration of the bacteria Akkermansia muciniphila and the antioxidant quercetin in an in vivo model of early obesity and NAFLD. 21-day-old rats were fed with control or high-fat diet for six weeks. Then, all animals received control diet supplemented with/without quercetin and/or A. muciniphila for three weeks. Gut microbiota, NAFLD-related parameters, circulating bile acids (BAs) and liver gene expression were analyzed. The colonization with A. muciniphila was associated with less body fat, while synbiotic treatment caused a steatosis remission, linked to hepatic lipogenesis modulation. The synbiotic promoted higher abundance of Cyanobacteria and Oscillospira, and lower levels of Actinobacteria, Lactococcus, Lactobacillus and Roseburia. Moreover, it favored elevated unconjugated hydrophilic BAs plasma levels and enhanced hepatic expression of BA synthesis and transport genes. A. muciniphila correlated with circulating BAs and liver lipid and BA metabolism genes, suggesting a role of this bacterium in BA signaling. Beneficial effects of A. muciniphila and quercetin combination are driven by gut microbiota modulation, the shift in BAs and the gut-liver bile flow enhancement.

La cirugía bariátrica modifica la diversidad bacteriana y los metabolitos de la microbiota intestinal mejorando el perfil metabólico del huésped y contribuyendo a la reducción del peso

La obesidad es una enfermedad crónica multifactorial de características inflamatorias que afecta a ambos sexos y a todas las edades a nivel mundial, aumentando la morbilidad y mortalidad por diversas enfermedades. La obesidad se asocia a disbiosis de la microbiota intestinal, alterando con ello la absorción de nutrientes y el metabolismo energético. La cirugía bariátrica ha demostrado ser el mejor tratamiento para la obesidad mórbida y las enfermedades asociadas al sobrepeso. Los estudios de los efectos de la cirugía bariátrica sobre la microbiota intestinal, realizados en los últimos cinco años, se caracterizaron por tener poca cantidad de sujetos en las muestras, con seguimientos entre seis meses y un año, teniendo resultados heterogéneos. En general, la cirugía bariátrica produce cambios importantes en la microbiota intestinal, con aumento de los filos Proteobacteria, Fusobacteria y Verrucomicrobia; y disminución del filo Firmicutes. Akkermansia muciniphila puede ser una bacteria-clave asociada a los beneficios obtenidos por la cirugía. La diversidad bacteriana aumenta a partir de los seis meses de la cirugía, y la conformación final de la microbiota, luego de un periodo de adaptación, está asociado a un perfil metabólico bacteriano detox-redox con poca liberación de energía. No se ha demostrado ninguna relación de causalidad entre los cambios de la microbiota intestinal producidos por la cirugía y los efectos beneficiosos de la misma, aunque los estudios de trasplante de material fecal sugieren una verdadera transferencia fenotípica asociada al peso y al perfil metabólico. Conocer los mecanismos de esta relación microbiota-hospedero ayudaría a encontrar intervenciones terapéuticas con los mismos resultados que se obtienen con la cirugía. En conclusión, la cirugía bariátrica induce cambios importantes en la microbiota intestinal, donde los metabolitos bacterianos interactúan con el huésped mejorando el perfil metabólico y contribuyendo a la pérdida del peso.

The Prebiotic Effects of Oats on Blood Lipids, Gut Microbiota, and Short-Chain Fatty Acids in Mildly Hypercholesterolemic Subjects Compared With Rice: A Randomized, Controlled Trial

Phytochemicals derived from oats are reported to possess a beneficial effect on modulating dyslipidemia, specifically on lowering total and LDL cholesterol. However, deeper insights into its mechanism remain unclear. In this randomized controlled study, we assigned 210 mildly hypercholesterolemic subjects from three study centers across China (Beijing, Nanjing, and Shanghai) to consume 80 g of oats or rice daily for 45 days. Plasma lipid profiles, short chain fatty acids (SCFAs), and fecal microbiota were measured. The results showed that total cholesterol (TC) and non-high-density lipoprotein cholesterol (non-HDL-C) decreased significantly with both oats and rice intake after 30 and 45 days. The reduction in TC and non-HDL-C was greater in the participants consuming oats compared with rice at day 45 (p = 0.011 and 0.049, respectively). Oat consumption significantly increased the abundance of Akkermansia muciniphila and Roseburia, and the relative abundance of Dialister, Butyrivibrio, and Paraprevotella, and decreased unclassified f-Sutterellaceae. In the oat group, Bifidobacterium abundance was negatively correlated with LDL-C (p = 0.01, r = −0.31) and, TC and LDL-C were negatively correlated to Faecalibacterium prausnitzii (p = 0.02, r = −0.29; p = 0.03, r = −0.27, respectively). Enterobacteriaceae, Roseburia, and Faecalibacterium prausnitzii were positively correlated with plasma butyric acid and valeric acid concentrations and negatively correlated to isobutyric acid. HDL-C was negatively correlated with valeric acid (p = 0.02, r = −0.25) and total triglyceride (TG) was positively correlated to isovaleric acid (p = 0.03, r = 0.23). Taken together, oats consumption significantly reduced TC and LDL-C, and also mediated a prebiotic effect on gut microbiome. Akkermansia muciniphila, Roseburia, Bifidobacterium, and Faecalibacterium prausnitzii, and plasma SCFA correlated with oat-induced changes in plasma lipids, suggesting prebiotic activity of oats to modulate gut microbiome could contribute towards its cholesterol-lowering effect.