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Periods of fasting and refeeding may reduce cardiometabolic risk elevated by Western diet. Here we show in the substudy of NCT02099968, investigating the clinical parameters, the immunome and gut microbiome exploratory endpoints, that in hypertensive metabolic syndrome patients, a 5-day fast followed by a modified Dietary Approach to Stop Hypertension diet reduces systolic blood pressure, need for antihypertensive medications, body-mass index at three months post intervention compared to a modified Dietary Approach to Stop Hypertension diet alone. Fasting alters the gut microbiome, impacting bacterial taxa and gene modules associated with short-chain fatty acid production. Cross-system analyses reveal a positive correlation of circulating mucosa-associated invariant T cells, non-classical monocytes and CD4 + effector T cells with systolic blood pressure. Furthermore, regulatory T cells positively correlate with body-mass index and weight. Machine learning analysis of baseline immunome or microbiome data predicts sustained systolic blood pressure response within the fasting group, identifying CD8 + effector T cells, Th17 cells and regulatory T cells or Desulfovibrionaceae, Hydrogenoanaerobacterium, Akkermansia , and Ruminococcaceae as important contributors to the model. Here we report that the high-resolution multi-omics data highlight fasting as a promising non-pharmacological intervention for the treatment of high blood pressure in metabolic syndrome patients. Nutritional modification including fasting has been shown to reduce cardiometabolic risk linked to western diet. Here the authors show implementation of fasting resulted in alterations to the intestinal microbiota, and circulating immune cells, improving blood pressure and body weight in patients with metabolic syndrome.

Akkermansia muciniphila is a gut bacterium that colonizes the gut mucosa, has a role in maintaining gut health and shows promise for potential therapeutic applications. The discovery of A. muciniphila as an important member of our gut microbiome, occupying an extraordinary niche in the human gut, has led to new hypotheses on gut health, beneficial microorganisms and host–microbiota interactions. This microorganism has established a unique position in human microbiome research, similar to its role in the gut ecosystem. Its unique traits in using mucin sugars and mechanisms of action that can modify host health have made A. muciniphila a subject of enormous attention from multiple research fields. A. muciniphila is becoming a model organism studied for its ability to modulate human health and gut microbiome structure, leading to commercial products, a genetic model and possible probiotic formulations. This Review provides an overview of A. muciniphila and Akkermansia genus phylogeny, ecophysiology and diversity. Furthermore, the Review discusses perspectives on ecology, strategies for harnessing beneficial effects of A. muciniphila for human mucosal metabolic and gut health, and its potential as a biomarker for diagnostics and prognostics. In this Review, Belzer and colleagues explore the diversity of the gut bacterium Akkermansia muciniphila , its biological functions and interactions with the host, diet and other members of the microbiota, as well as its association with health and disease and its potential in various applications.

Background Several studies have shown that probiotics have beneficial effects on weight control and metabolic health. In addition to probiotics, recent studies have investigated the effects of paraprobiotics and postbiotics. Therefore, we evaluated the preventive effects of live and pasteurized Akkermansia muciniphila MucT ( A. muciniphila ) and its extracellular vesicles (EVs) on HFD-induced obesity. Results The results showed that body weight, metabolic tissues weight, food consumption, and plasma metabolic parameters were increased in the HFD group, whereas A. muciniphila preventive treatments inhibited these HFD. The effects of pasteurized A. muciniphila and its extracellular vesicles were more noticeable than its active form. The HFD led to an increase in the colonic, adipose tissue, and liver inflammations and increased the expression of genes involved in lipid metabolism and homeostasis. Nevertheless, these effects were inhibited in mice that were administered A. muciniphila and its EVs. The assessment of the gut microbiota revealed significant differences in the microbiota composition after feeding with HFD. However, all treatments restored the alterations in some bacterial genera and closely resemble the control group. Also, the correlation analysis indicated that some gut microbiota might be associated with obesity-related indices. Conclusions Pasteurized A. muciniphila and its EVs, as paraprobiotic and postbiotic agents, were found to play a key role in the regulation of metabolic functions to prevent obesity, probably by affecting the gut-adipose-liver axis. Graphical Abstract

In gut, Akkermansia muciniphila ( A. muciniphila ) probably exerts its probiotic activities by the positive modulation of mucus thickness and gut barrier integrity. However, the potential mechanisms between A. muciniphila and mucin balance have not been fully elucidated. In this study, we cultured the bacterium in a BHI medium containing 0% to 0.5% mucin, and transcriptome and gas chromatography mass spectrometry (GC–MS) analyses were performed. We found that 0.5% (m/v) mucin in a BHI medium induced 1191 microbial genes to be differentially expressed, and 49 metabolites to be changed. The metabolites of sorbose, mannose, 2,7-anhydro-β-sedoheptulose, fructose, phenylalanine, threonine, lysine, ornithine, asparagine, alanine and glutamic acid were decreased by 0.5% mucin, while the metabolites of leucine, valine and N-acetylneuraminic acid were increased. The association analysis between transcriptome and metabolome revealed that A. muciniphila gave strong responses to energy metabolism, amino sugar and nucleotide sugar metabolism, and galactose metabolism pathways to adapt to high mucin in the medium. This finding showed that only when mucin reached a certain concentration in a BHI medium, A. muciniphila could respond to the culture environment significantly at the level of genes and metabolites, and changed its metabolic characteristics by altering the effect on carbohydrates and amino acids.

Several studies have reported that the host-microbe interactions in the gut modulate the host serotonin or 5-hydroxytryptamine (5-HT) system. Here, we evaluated the effects of Akkermansia muciniphila and its extracellular vesicles (EVs) on genes pertaining to the serotonergic system in the colon and hippocampus of mice. Male C57BL/6J mice were administered viable A. muciniphila and its EVs for 4 weeks. The serotonin levels in the colon, hippocampus, and serum of mice, as well as the human colon carcinoma cells (Caco-2), were measured by ELISA assays. Also, the effects of A. muciniphila and its EVs on the expression of serotonin system genes in the colon and hippocampus were examined. A. muciniphila and its EVs may have a biological effect on the induction of serotonin levels in the colon and hippocampus of mice. Also, EVs increased the serotonin level in the Caco-2 cell line. In contrast, both treatments decreased the serotonin level in the serum. Both the bacterium and its EVs had significant effects on the mRNA expression of genes, involved in serotonin signaling/metabolism in the colon and hippocampus of mice. Moreover, A. muciniphila and its EVs affected the mRNA expression of inflammatory cytokines ( Il-10 and Tnf -α) in the colon, however, there is no significant difference in inflammatory cell infiltrate in the histopathology of the colon. The presence of A. muciniphila and its EVs in the gut promotes serotonin concentration, they also affect serotonin signaling/metabolism through the gut-brain axis and may be considered in new therapeutic strategies to ameliorate serotonin-related disorders.

Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila, a gut probiotic, ameliorates systemic inflammation by tightening the intestinal barrier. In this study, fractured mice intragastrically administrated with A. muciniphila were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muciniphila at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis, and can be stimulated by PDGF-BB. Moreover, A. muciniphila treatment significantly reduced gut permeability and inflammation at the early stage. Dextran sulfate sodium (DSS) was used to disrupt the gut barrier to determine its role in fracture healing and whether A. muciniphila still can stimulate bone fracture healing. As expected, A. muciniphila evidently improved gut barrier, reduced inflammation and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muciniphila reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB+ preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidence for the involvement of type H vessels in fracture healing and suggests the potential of A. muciniphila as a promising strategy for bone healing. This article has an associated First Person interview with the first author of the paper.

An accumulating body of evidence suggests that the bacterium Akkermansia muciniphila exhibits positive systemic effects on host health, mainly by improving immunological and metabolic functions, and it is therefore regarded as a promising potential probiotic. Recent clinical and preclinical studies have shown that A. muciniphila plays a vital role in a variety of neuropsychiatric disorders by influencing the host brain through the microbiota-gut-brain axis (MGBA). Numerous studies observed that A. muciniphila and its metabolic substances can effectively improve the symptoms of neuropsychiatric disorders by restoring the gut microbiota, reestablishing the integrity of the gut mucosal barrier, regulating host immunity, and modulating gut and neuroinflammation. However, A. muciniphila was also reported to participate in the development of neuropsychiatric disorders by aggravating inflammation and influencing mucus production. Therefore, the exact mechanism of action of A. muciniphila remains much controversial. This review summarizes the proposed roles and mechanisms of A. muciniphila in various neurological and psychiatric disorders such as depression, anxiety, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, strokes, and autism spectrum disorders, and provides insights into the potential therapeutic application of A. muciniphila for the treatment of these conditions.

Gut dysbiosis, namely dysregulation of the intestinal microbiota, and increased gut permeability lead to enhanced inflammation and are commonly seen in chronic conditions such as obesity and aging. In people living with HIV (PLWH), several lines of evidence suggest that a depletion of gut CD4 T-cells is associated with gut dysbiosis, microbial translocation and systemic inflammation. Antiretroviral therapy (ART) rapidly controls viral replication, which leads to CD4 T-cell recovery and control of the disease. However, gut dysbiosis, epithelial damage and microbial translocation persist despite ART, increasing risk of developing inflammatory non-AIDS comorbidities such as cardiovascular disease, diabetes mellitus, liver steatosis and cancer. In addition to ART, an emerging research priority is to discover strategies to improve the gut microbial composition and intestinal barrier function. Probiotic interventions have been extensively used with controversial benefits in humans. Encouragingly, within the last decade, the intestinal symbiotic bacterium has emerged as the \"sentinel of the gut.\" A lower abundance of has been shown in diabetic and obese people as well as in PLWH. Interventions with high levels of polyphenols such as tea or diets rich in fruit, the antibiotic vancomycin and the antidiabetic drug metformin have been shown to increase abundance, contributing to improved metabolic function in diabetic and obese individuals. We hypothesize that gut microbiota rich in can reduce microbial translocation and inflammation, preventing occurrences of non-AIDS comorbidities in PLWH. To this aim, we will discuss the protective effect of and its potential applications, paving the way toward novel therapeutic strategies to improve gut health in PLWH.

Akkermansia muciniphila , a microorganism ubiquitously colonizing the mucosal layer of the human gut, has garnered significant scientific interest as a promising candidate for probiotic therapeutics. Its persistent identification in both laboratory and living organism studies underscores its potential physiological benefits, positioning it as a bacterium of paramount importance in promoting host health. This review examines the diversity and abundance of gut microbiota members, emphasizing the identification of microbial species engaged in cross-feeding networks with A. muciniphila . Insightful exploration into the mechanisms of cross-feeding, including mucin-derived nutrient exchange and metabolite production, unveils the intricate dynamics shaping microbial community stability. Such interactions contribute not only to the availability of essential nutrients within the gut environment but also to the production of metabolites influencing microbial community dynamics and host health. In conclusion, the cumulative evidence from in vitro and in vivo perspectives substantiates the notion that A. muciniphila holds tremendous promise as a next-generation probiotic. By leveraging its unique physiological benefits, particularly in mucosal health and metabolic regulation, A. muciniphila stands poised to revolutionize the landscape of probiotic interventions for enhanced host well-being.

Akkermansia muciniphila (A. muciniphila), a mucin-degrading commensal bacterium predominant in the gut microbiota, establishes a multifaceted antioxidant defense system through its enzymatic machinery and bioactive metabolites. The bacterium maintains mucosal homeostasis via specialized mucinolytic enzymes while secreting functionally diverse components including SCFAs, outer membrane proteins (notably Amuc_1100), and extracellular vesicles (EVs). Mechanistically, Amuc_1100 enhances SOD activity and reduces oxidative damage markers such as MDA through TLR2/NF-κB pathway activation. SCFAs mediate systemic antioxidant responses via gut-organ axis communication, while EVs ameliorate intestinal barrier dysfunction through MAPK signaling pathway modulation. Clinically, A. muciniphila supplementation demonstrates therapeutic efficacy in improving insulin sensitivity in obese and type 2 diabetic patients, and shows potential in mitigating Parkinson's disease pathology by regulating α -synuclein oligomerization. Translational applications face several challenges, including strain-specific functional variations, host microenvironment dependencies, and potential risks of excessive mucin degradation. Recent advances in bioengineering approaches, particularly microencapsulation and biomimetic delivery systems, have significantly enhanced bacterial viability and targeted delivery. Future investigations should employ integrated multi-omics strategies to elucidate the intricate metabolic-immune-redox regulatory networks of A. muciniphila, facilitating its development as a precision therapeutic intervention.