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Akkermansia muciniphila ( A. muciniphila ) is a 'star strain' that has attracted much attention in recent years. A. muciniphila can effectively regulate host metabolism, significantly affect host immune function, and play an important role in balancing host health and disease. As one of the organs most closely related to the gut (the two can communicate through the hepatic portal vein and bile duct system), liver is widely affected by intestinal microorganisms. A growing body of evidence suggests that A. muciniphila may alleviate liver-related diseases by improving the intestinal barrier, energy metabolism and regulating inflammation through its protein components and metabolites. This paper systematically reviews the key roles of A. muciniphila and its derivatives in maintaining liver health and improving liver disease.

Due to its physiological benefits from in vitro and in vivo points of view, Akkermansia muciniphila, a common colonizer in the human gut mucous layer, has consistently been identified as an option for the next-generation probiotic. A. muciniphila is a significant bacterium that promotes host physiology. However, it also has a great deal of potential to become a probiotic due to its physiological advantages in a variety of therapeutic circumstances. Therefore, it can be established that the abundance of A. muciniphila in the gut environment, which is controlled by many genetic and dietary variables, is related to the biological behaviors of the intestinal microbiota and gut dysbiosis/eubiosis circumstances. Before A. muciniphila is widely utilized as a next-generation probiotic, regulatory obstacles, the necessity for significant clinical trials, and the sustainability of manufacturing must be eliminated. In this review, the outcomes of recent experimental and clinical reports are comprehensively reviewed, and common colonization patterns, main factors involved in the colonization of A. muciniphila in the gut milieu, their functional mechanisms in establishing homeostasis in the metabolic and energy pathways, the promising delivery role of microencapsulation, potential genetic engineering strategies, and eventually safety issues of A. muciniphila have been discussed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Akkermansia muciniphila (AKK) bacteria improve the functions of theere intestinal and blood-brain barriers (BBB) via their extracellular vesicles (AmEvs). However, their role in postoperative cognitive dysfunction (POCD) and its underlying mechanisms remain unclear. To investigate, we used C57BL/6 J mice divided into five groups: Sham, POCD, POCD+Akk, POCD+Evs, and POCD+Evs + PLX5622. POCD was induced through intestinal ischemia-reperfusion (I/R). The mice's cognitive function was assessed using behavioral tests, and possible mechanisms were explored by examining gut and BBB permeability, inflammation, and microglial function. Toll-like receptor (TLR) 2/4 pathway-related proteins were also investigated both in vitro and in vivo. PLX5622 chow was employed to eliminate microglial cells. Our findings revealed a negative correlation between AKK abundance and POCD symptoms. Supplementation with either AKK or AmEvs improved cognitive function, improved the performance of the intestinal barrier and BBB, and decreased inflammation and microglial activation in POCD mice compared to controls. Moreover, AmEvs treatment inhibited TLR2/4 signaling in the brains of POCD mice and LPS-treated microglial cells. In microglial-ablated POCD mice, however, AmEvs failed to protect BBB integrity. Overall, AmEvs is a potential therapeutic strategy for managing POCD by enhancing gut and BBB integrity and inhibiting microglial-mediated TLR2/4 signaling., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xiang Gao reports financial support was provided by Fujian Science and Technology Plan Project (2020J01342)., (Copyright © 2023. Published by Elsevier B.V.)

Scope: Akkermansia muciniphila (A. muciniphila) are Gram negative commensal bacteria, degrading mucin in the intestinal mucosa, modulating intestinal permeability and inflammation in the digestive tract, liver, and blood. Some components can promote the relative abundance of A. muciniphila in the gut microbiota, but lower levels of A. muciniphila are more commonly found in people with obesity, diabetes, metabolic syndromes, or inflammatory digestive diseases. Over-intake of ethanol can also induce a decrease of A. muciniphila, associated with dysregulation of microbial metabolite production, impaired intestinal permeability, induction of chronic inflammation, and production of cytokines., Methods and Results: Using a PRISMA search strategy, a review is performed on the bacteriological characteristics of A. muciniphila, the factors capable of modulating its relative abundance in the digestive tract and its probiotic use in alcohol-related liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, hepatic transplantation, partial hepatectomy)., Conclusion: Several studies have shown that supplementation with A. muciniphila can improve ethanol-related hepatic pathologies, and highlight the interest in using this bacterial species as a probiotic., (© 2023 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

Gut - brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. Symptoms of IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxiety-like behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.

In the previous study, we found that the oral sodium valproate (SVP) increased the relative abundance of Akkermansia muciniphila (A. muciniphila) in rats, and plasma aspartate transaminase (AST) and alanine aminotransferase (ALT) activities were positively correlated with A. muciniphila levels. This study aimed to further investigate the role of A. muciniphila in SVP-induced hepatotoxicity by orally supplementing rats with the representative strain of A. muciniphila, A. muciniphila MucT. Additionally, the fresh faeces were incubated anaerobically with SVP to investigate the effect of SVP on faecal A. muciniphila in the absence of host influence. Results showed that A. muciniphila MucT ameliorated the hepatotoxicity and upregulation of A. muciniphila induced by SVP. SVP also induced a noteworthy elevation of A. muciniphila level in vitro, supporting the observation in vivo. Therefore, we speculate that A. muciniphila MucT may be a potential therapeutic strategy for SVP-induced hepatotoxicity. In addition, the increased A. muciniphila induced by SVP may differ from A. muciniphila MucT, but further evidence is needed. These findings provide new insights into the relationships between A. muciniphila and SVP-induced hepatotoxicity, highlighting the potential for different A. muciniphila strains to have distinct or even opposing effects on SVP-induced hepatotoxicity., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objectives: A better understanding of host-microbe interactions as a cross-talk between the gastrointestinal (GI) tract and the gut microbiota can help treat and prevent GI disorders by improving the maintenance of GI homeostasis. The gut microbiota can affect signaling molecules, such as serotonin, which regulates endocrine systems through the GI tract. Moreover, studying the effects of gut microbiota in the small intestine on the human GI tract health is pivotal., Methods: Male C57BL/6J mice (n = 30, 10 mice per group) were orally gavaged with 200 μL of PBS (control group); mice in group II were orally gavaged with 109 colony-forming units (CFU)/200 μL of viable A. muciniphila, suspended in PBS (A. muciniphila group); and mice in group III were orally gavaged with 10 μg of protein/200 μL of EVs (A. muciniphila-EV group) once daily for four weeks. The gene expression of serotonin system-related genes (Slc6a4, Tph1, Mao, Htr3, Htr4, and Htr7) was examined by quantitative real-time PCR (qPCR) method., Results: Based on the results, A. muciniphila significantly affected the mRNA expression of genes related to the serotonin system (Tph1, Mao, Htr3B, and Htr7) in the duodenum and (Htr3B, Htr4 and Htr7) in the ileum of mice (P < 0.05). Moreover, A. muciniphila-derived EVs affected the expression of major genes related to the serotonin system (Tph1, slc6a4a, Mao, Htr3B, Htr4, and Htr7) in the duodenum and ileum of mice (P < 0.05)., Conclusions: The present findings may pave the way for further investigation of the effects of strain-specific probiotics on the serotonergic system, which is currently in its infancy., Competing Interests: Declaration of competing interest The authors declare no competing both financial and non-financial interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Preeclampsia (PE) is known as a metabolism-related complication of pregnancy related to gut dysbiosis including the decreased abundance of Akkermansia muciniphila (A. muciniphila). However, the modulatory role of A. muciniphila as a supplement for PE remains ambiguous. This study investigated the effect of A. muciniphila administration on PE-like mice and its underlying mechanisms. A total of twenty-four C57BL/6 mice were randomly assigned into three groups. PE-like symptoms were induced by continuous injection of L-NAME intraperitoneally from gestational day (GD) 11 to GD18 combined with oral administration of pasteurized A. muciniphila during GD14-18 or not. Mice were sacrificed at GD19 to collect for further evaluation. Decreased A. muciniphila was observed in a successfully established PE-like model than normotensive pregnant control (NP), inversely correlated to increased systolic blood pressure blood and 24-h proteinuria. After supplementing with A. muciniphila, mice showed significantly minimized blood pressure and protein expression in urine, increased number of pups and weight of both embryos and placentas. In addition, colonies of bacteria, inflammatory cytokines (TNF-α and IL-6), and metabolic products of lipids including TC, FC, and TG were alleviated by A. muciniphila in the placentas. Among proteins linked with bowel barrier functions, diminished 2-AG and growing ZO-1 and occludin were attributable to A. muciniphila. Also, enhanced Treg/Th17 ratios were found in the intestines of mice treated with A. muciniphila. A. muciniphila facilitated alleviating PE-like symptoms and was beneficial as a novel probiotic therapeutic agent for PE., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, is a chronic relapsing gastrointestinal inflammatory disease mediated by dysregulated immune responses to resident intestinal microbiota. Current conventional approaches including aminosalicylates, corticosteroids, immunosuppressive agents, and biological therapies are focused on reducing intestinal inflammation besides inducing and maintaining disease remission, and managing complications. However, these therapies are not curative and are associated with various limitations, such as drug resistance, low responsiveness and adverse events. Recent accumulated evidence has revealed the involvement of mucin-degrading bacterium Akkermansia muciniphila ( A. muciniphila ) in the regulation of host barrier function and immune response, and how reduced intestinal colonisation of probiotic A. muciniphila can contribute to the process and development of inflammatory bowel diseases, suggesting that it may be a potential target and promising strategy for the therapy of inflammatory bowel disease. In this review, we summarise the current knowledge of the role of A. muciniphila in IBD, especially focusing on the related mechanisms, as well as the strategies based on supplementation with A. muciniphila , probiotics and prebiotics, natural diets, drugs, and herbs to promote its colonisation in the gut, and holds promise for A. muciniphila -targeted and -based therapies in the treatment of inflammatory bowel disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zheng, Han, Yuan, Xing, Zhang, Sun, Liu, Li and Mao.)

A high-fat (HF) diet reduces resistance to the foodborne pathogen Listeria monocytogenes . We demonstrate that short-term gavage with A. muciniphila increases resistance to oral and systemic L. monocytogenes infection in mice fed a HF diet. A. muciniphila reduced inflammation in the gut and liver of mice fed a high-fat diet prior to infection and reduced inflammatory cell infiltration in the ileum to levels similar to mice fed a low-fat (LF) diet. Akkermansia administration had minimal impacts upon the microbiota and microbial metabolites and did not affect individual taxa or impact the Bacteroidetes to Firmicutes ratio. In summary, A. muciniphila increased resistance to L. monocytogenes infection in mice fed a HF diet by moderating immune/physiological effects through specific interaction between A. muciniphila and the host gut.

Although gut microbiota has been linked to cancer, little is known about the crosstalk between gut- and intratumoral-microbiomes. The goal of this study was to determine whether gut Akkermansia muciniphila (Akk) is involved in the regulation of intratumoral microbiome and metabolic contexture, leading to an anticancer effect on lung cancer. We evaluated the effects of gut endogenous or gavaged exogenous Akk on the tumorigenesis using the Lewis lung cancer mouse model. Feces, blood, and tumor tissue samples were collected for 16S rDNA sequencing. We then conducted spatially resolved metabolomics profiling to discover cancer metabolites in situ directly and to characterize the overall Akk-regulated metabolic features, followed by the correlation analysis of intratumoral bacteria with metabolic network. Our results showed that both endogenous and exogenous gavaged Akk significantly inhibited tumorigenesis. Moreover, we detected increased Akk abundance in blood circulation or tumor tissue by 16S rDNA sequencing in the Akk gavaged mice, compared with the control mice. Of great interest, gavaged Akk may migrate into tumor tissue and influence the composition of intratumoral microbiome. Spatially resolved metabolomics analysis revealed that the gut-derived Akk was able to regulate tumor metabolic pathways, from metabolites to enzymes. Finally, our study identified a significant correlation between the gut Akk-regulated intratumoral bacteria and metabolic network. Together, gut-derived Akk may migrate into blood circulation, and subsequently colonize into lung cancer tissue, which contributes to the suppression of tumorigenesis by influencing tumoral symbiotic microbiome and reprogramming tumoral metabolism, although more studies are needed.

The gastrointestinal tract is the main target of cadmium toxicity. However, whether Akkermansia muciniphila (A. muciniphila), which has been reported to be the next generation of promising probiotics, can alleviate cadmium-induced intestinal damage has not been investigated. In this study, we found that compared to the cadmium exposure group, mice gavaged with A. muciniphila showed less severe intestinal mucosal damage, with improved bodyweight, colon length, a decline in inflammation, and significantly increased glutathione and goblet cell numbers. Meanwhile, melatonin was interestingly found to be strikingly increased after A. muciniphila treatment. We then demonstrated that melatonin also could ameliorate the intestinal mucosal damage caused by cadmium through scavenging reactive oxygen species (ROS) and increasing the number of goblet cells. Furthermore, mice treated with inhibitors had a low level of melatonin and could not reproduce the beneficial effects of the A. muciniphila. Our results implied that the regulation of melatonin production by A. muciniphila is associated with an increase in enterochromaffin cells number, which determine melatonin secretion. This study indicated that the A. muciniphila-melatonin axis reduces cadmium-induced damage by increasing the goblet cells and scavenging the ROS, which may guide the prevention of the toxic effects of heavy metals., Competing Interests: Declaration of competing interest There are no conflicts of interest concerning financial, professional or personal related to this manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Social hierarchy governs the physiological and biochemical behaviors of animals. Intestinal radiation injuries are common complications connected with radiotherapy. However, it remains unclear whether social hierarchy impacts the development of radiation-induced intestinal toxicity. Dominant mice exhibited more serious intestinal toxicity following total abdominal irradiation compared with their subordinate counterparts, as judged by higher inflammatory status and lower epithelial integrity. Radiation-elicited changes in gut microbiota varied between dominant and subordinate mice, being more overt in mice of higher status. Deletion of gut microbes by using an antibiotic cocktail or restructuring of the gut microecology of dominant mice by using fecal microbiome from their subordinate companions erased the difference in radiogenic intestinal injuries. Lactobacillus murinus and Akkermansia muciniphila were both found to be potential probiotics for use against radiation toxicity in mouse models without social hierarchy. However, only Akkermansia muciniphila showed stable colonization in the digestive tracts of dominant mice, and significantly mitigated their intestinal radiation injuries. Our findings demonstrate that social hierarchy impacts the development of radiation-induced intestinal injuries, in a manner dependent on gut microbiota. The results also suggest that the gut microhabitats of hosts determine the colonization and efficacy of foreign probiotics. Thus, screening suitable microbial preparations based on the gut microecology of patients might be necessary in clinical application.

Ever since Akkermansia muciniphila was discovered and characterized two decades ago, numerous studies have shown that the lack or decreased abundance of this commensal bacterium was linked with multiple diseases (such as obesity, diabetes, liver steatosis, inflammation and response to cancer immunotherapies). Although primarily based on simple associations, there are nowadays an increasing number of studies moving from correlations to causality. The causal evidence derived from a variety of animal models performed in different laboratories and recently was also recapitulated in a human proof-of-concept trial. In this Review, we cover the history of the discovery of A. muciniphila and summarize the numerous findings and main mechanisms of action by which this intestinal symbiont improves health. A comparison of this microorganism with other next-generation beneficial microorganisms that are being developed is also made., (© 2022. Springer Nature Limited.)

Akkermansia muciniphila is an intestinal symbiont known to improve the gut barrier function in mice and humans. Various cell envelope components have been identified to play a critical role in the immune signaling of A. muciniphila, but the chemical composition and role of peptidoglycan (PG) remained elusive. Here, we isolated PG fragments from A. muciniphila MucT (ATCC BAA-835), analyzed their composition and evaluated their immune signaling capacity. Structurally, the PG of A. muciniphila was found to be noteworthy due of the presence of some nonacetylated glucosamine residues, which presumably stems from deacetylation of N-acetylglucosamine. Some of the N-acetylmuramic acid (MurNAc) subunits were O-acetylated. The immunological assays revealed that muropeptides released from the A. muciniphila PG could both activate the intracellular NOD1 and NOD2 receptors to a comparable extent as muropeptides from Escherichia coli BW25113. These data challenge the hypothesis that non-N-acetylattion of PG can be used as a NOD-1 evasion mechanism. Our results provide new insights into the diversity of cell envelope structures of key gut microbiota members and their role in steering host-microbiome interactions., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Muscular atrophy is a muscle disease in which muscle mass and strength decrease due to aging, injury, metabolic disorders, or chronic conditions. Proteins in muscle tissue are degraded by the ubiquitin-proteasome pathway, and atrophy accelerates this pathway. Akkermansia muciniphila and Faecalibacterium prausnitzii strains are effective agents against metabolic and inflammatory diseases in next-generation probiotic research. In this study, we evaluated the efficacy of A. muciniphila strain EB-AMDK19 and F. prausnitzii strain EB-FPDK11 in a mouse model of muscular atrophy, since atrophy inhibits energy metabolism and immune activation. After oral administration of each strain for 4 weeks, the hind legs of the mice were fixed with a plaster cast to immobilize them for a week. As a result, the administration of EB-AMDK19 and EB-FPDK11 strains improved grip strength but did not increase muscle mass. At the molecular level, A. muciniphila and F. prausnitzii treatments decreased the expression levels of ubiquitin-proteasome genes, atrogin-1 , MuRF , and cathepsin L . They increased the expression level of the mitochondrial biogenesis regulatory gene, PGC-1α . The effect of the strains was confirmed by a decrease in myostatin. Furthermore, A. muciniphila and F. prausnitzii modulated the immune function by enhancing ZO-1 and inhibiting IL-6 . In particular, EB-AMDK19 promoted the expression of IL-10 , an anti-inflammatory cytokine. These results suggest that A. muciniphila and F. prausnitzii may have beneficial effects on muscular atrophy, verified by newly isolated EB-AMDK19 and EB-FPDK11 as potential next-generation probiotics.

Gut microbiota are reported to be associated with many diseases, including cancers. Several bacterial taxa have been shown to be associated with cancer development or response to treatment. However, longitudinal microbiota alterations during the development of cancers are relatively unexplored. To better understand how microbiota changes, we profiled the gut microbiota composition from prostate cancer-bearing mice and control mice at five different time points. Distinct gut microbiota differences were found between cancer-bearing mice and control mice. Akkermansiaceae was found to be significantly higher in the first three weeks in cancer-bearing mice, which implies its role in the early stage of cancer colonization. We also found that Bifidobacteriaceae and Enterococcaceae were more abundant in the second and last sampling week, respectively. The increments of Akkermansiaceae , Bifidobacteriaceae and Enterococcaceae were previously found to be associated with responses to immunotherapy, which suggests links between these bacteria families and cancers. Additionally, our function analysis showed that the bacterial taxa carrying steroid biosynthesis and butirosin and neomycin biosynthesis were increased, whereas those carrying naphthalene degradation decreased in cancer-bearing mice. Our work identified the bacteria taxa altered during prostate cancer progression and provided a resource of longitudinal microbiota profiles during cancer development in a mouse model.

Bacteria of the phylum Verrucomicrobia are ubiquitous in marine environments and can be found as free-living organisms or as symbionts of eukaryotic hosts. Little is known about host-associated Verrucomicrobia in the marine environment. Here we reconstructed two genomes of symbiotic Verrucomicrobia from bacterial metagenomes derived from the Atlanto-Mediterranean sponge Petrosia ficiformis and three genomes from strains that we isolated from offshore seawater of the Eastern Mediterranean Sea. Phylogenomic analysis of these five strains indicated that they are all members of Verrucomicrobia subdivision 4, order Opitutales. We compared these novel sponge-associated and seawater-isolated genomes to closely related Verrucomicrobia. Genomic analysis revealed that Planctomycetes-Verrucomicrobia microcompartment gene clusters are enriched in the genomes of symbiotic Opitutales including sponge symbionts but not in free-living ones. We hypothesize that in sponge symbionts these microcompartments are used for degradation of l-fucose and l-rhamnose, which are components of algal and bacterial cell walls and therefore may be found at high concentrations in the sponge tissue. Furthermore, we observed an enrichment of toxin-antitoxin modules in symbiotic Opitutales. We suggest that, in sponges, verrucomicrobial symbionts utilize these modules as a defence mechanism against antimicrobial activity deriving from the abundant microbial community co-inhabiting the host., (© 2020 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Verrucomicrobia affiliated with " Candidatus Udaeobacter" belong to the most abundant soil bacteria worldwide. Although the synthesis of antibiotics presumably evolved in soil, and environmental pollution with antimicrobials increases, the impact of these complex molecules on " Ca Udaeobacter" remains to be elucidated. In this study, we demonstrate that " Ca. Udaeobacter" representatives residing in grassland as well as forest soil ecosystems show multidrug resistance and even take advantage of antibiotics release. Soils treated with up to six different antibiotics exhibited a higher " Ca. Udaeobacter" abundance than corresponding controls after 3, 8, and 20 days of incubation. In this context, we provide evidence that " Ca. Udaeobacter" representatives may utilize nutrients which are released due to antibiotic-driven lysis of other soil microbes and thereby reduce energetically expensive synthesis of required biomolecules. Moreover, genomic analysis revealed the presence of genes conferring resistance to multiple classes of antibiotics and indicated that " Ca. Udaeobacter" representatives most likely oxidize the trace gas H 2 to generate energy. This energy might be required for long-term persistence in terrestrial habitats, as already suggested for other dominant soil bacteria. Our study illustrates, for the first time, that globally abundant " Ca. Udaeobacter" benefits from release of antibiotics, which confers advantages over other soil bacteria and represents a so-far overlooked fundamental lifestyle feature of this poorly characterized verrucomicrobial genus. Furthermore, our study suggests that " Ca. Udaeobacter" representatives can utilize H 2 as an alternative electron donor. IMPORTANCE Soil bacteria have been investigated for more than a century, but one of the most dominant terrestrial groups on Earth, " Candidatus Udaeobacter," remains elusive and largely unexplored. Its natural habitat is considered a major reservoir of antibiotics, which directly or indirectly impact phylogenetically diverse microorganisms. Here, we found that " Ca. Udaeobacter" representatives exhibit multidrug resistance and not only evade harmful effects of antimicrobials but even benefit from antibiotic pressure in soil. Therefore, " Ca. Udaeobacter" evidently affects the composition of soil resistomes worldwide and might represent a winner of rising environmental pollution with antimicrobials. In addition, our study indicates that " Ca. Udaeobacter" representatives utilize H 2 and thereby contribute to global hydrogen cycling. The here-reported findings provide insights into elementary lifestyle features of " Ca. Udaeobacter," potentially contributing to its successful global dissemination., (Copyright © 2020 Willms et al.)

Despite the relevance of complex root microbial communities for plant health, growth and productivity, the molecular basis of these plant-microbe interactions is not well understood. Verrucomicrobia are cosmopolitans in the rhizosphere, nevertheless their adaptations and functions are enigmatic since the proportion of cultured members is low. Here we report four cultivated Verrucomicrobia isolated from rice, putatively representing four novel species, and a novel subdivision. The aerobic strains were isolated from roots or rhizomes of Oryza sativa and O. longistaminata. Two of them are the first cultivated endophytes of Verrucomicrobia, as validated by confocal laser scanning microscopy inside rice roots after re-infection under sterile conditions. This extended known verrucomicrobial niche spaces. Two strains were promoting root growth of rice. Discovery of root compartment-specific Verrucomicrobia permitted an across-phylum comparison of the genomic conformance to life in soil, rhizoplane or inside roots. Genome-wide protein domain comparison with niche-specific reference bacteria from distant phyla revealed signature protein domains which differentiated lifestyles in these microhabitats. Our study enabled us to shed light into the dark microbial matter of root Verrucomicrobia, to define genetic drivers for niche adaptation of bacteria to plant roots, and provides cultured strains for revealing causal relationships in plant-microbe interactions by reductionist approaches.

The trace amounts (0.53 ppmv) of atmospheric hydrogen gas (H 2 ) can be utilized by microorganisms to persist during dormancy. This process is catalyzed by certain Actinobacteria, Acidobacteria, and Chloroflexi, and is estimated to convert 75 × 10 12  g H 2 annually, which is half of the total atmospheric H 2 . This rapid atmospheric H 2 turnover is hypothesized to be catalyzed by high-affinity [NiFe] hydrogenases. However, apparent high-affinity H 2 oxidation has only been shown in whole cells, rather than for the purified enzyme. Here, we show that the membrane-associated hydrogenase from the thermoacidophilic methanotroph Methylacidiphilum fumariolicum SolV possesses a high apparent affinity (K m(app)  = 140 nM) for H 2 and that methanotrophs can oxidize subatmospheric H 2 . Our findings add to the evidence that the group 1h [NiFe] hydrogenase is accountable for atmospheric H 2 oxidation and that it therefore could be a strong controlling factor in the global H 2 cycle. We show that the isolated enzyme possesses a lower affinity (K m  = 300 nM) for H 2 than the membrane-associated enzyme. Hence, the membrane association seems essential for a high affinity for H 2 . The enzyme is extremely thermostable and remains folded up to 95 °C. Strain SolV is the only known organism in which the group 1h [NiFe] hydrogenase is responsible for rapid growth on H 2 as sole energy source as well as oxidation of subatmospheric H 2 . The ability to conserve energy from H 2 could increase fitness of verrucomicrobial methanotrophs in geothermal ecosystems with varying CH 4 fluxes. We propose that H 2 oxidation can enhance growth of methanotrophs in aerated methane-driven ecosystems. Group 1h [NiFe] hydrogenases could therefore contribute to mitigation of global warming, since CH 4 is an important and extremely potent greenhouse gas.

The white leg Litopenaeus vannamei shrimp is of importance to the eastern Pacific fisheries and aquaculture industry but suffer from diseases such as the recently emerged early mortality syndrome. Many bacterial pathogens have been identified but the L. vannamei microbiota is still poorly known. Using a next-generation sequencing (NGS) approach, this work evaluated the impact of the inclusion in the diet of mannan oligosaccharide, (MOS, 0.5% w/w), over the L. vannamei microbiota and production behavior of L. vannamei under intensive cultivation in Ecuador. The MOS supplementation lasted for 60 days, after which the shrimp in the ponds were harvested, and the production data were collected. MOS improved productivity outcomes by increasing shrimp survival by 30%. NGS revealed quantitative differences in the shrimp microbiota between MOS and control conditions. In the treatment with inclusion of dietary MOS, the predominant phylum was Actinobacteria (28%); while the control group was dominated by the phylum Proteobacteria (30%). MOS has also been linked to an increased prevalence of Lactococcus- and Verrucomicrobiaceae-like bacteria. Furthermore, under the treatment of MOS, the prevalence of potential opportunistic pathogens, like Vibrio, Aeromonas, Bergeyella and Shewanella, was negligible. This may be attributable to MOS blocking the adhesion of pathogens to the surfaces of the host tissues. Together, these findings point to the fact that the performance (survival) improvements of the dietary MOS may be linked to the impact on the microbiota, since bacterial lines with pathogenic potential towards shrimps were excluded in the gut.

Data regarding Akkermansia muciniphila viability under stress remains scarce despite its beneficial potential. Therefore, the main goal was to assess A. muciniphila culturability when exposed to different temperatures, atmospheres and gastrointestinal simulated conditions. Cultivable cell numbers A. muciniphila remain high after refrigerated and room temperatures oxygen exposure, and gastrointestinal passage., Competing Interests: Declaration of competing interest The authors of paper entitled “Uncovering Akkermansia muciniphila resilience or susceptibility to different temperatures, atmospheres and gastrointestinal conditions " submitted to the Anaerobe, do not have any actual or potential conflict of interest including financial, personal or other relationships with other people or organizations within that could inappropriately influence, or be perceived to influence this work., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The prevalence of obesity and diabetes, and their complicating mental disorders, severely affect public health. This study aimed to investigate the long-term effects of an Akkermansia muciniphila subtype (A. muciniphila sub ) on high-fat diet-induced obesity and diabetes, and to evaluate whether this subtype can alleviate their complicated mental disorders. Whole genome sequencing and short chain fatty acid production analysis in supernatant of pure culture were performed. Female adult C57BL/6 mice were fed a high-fat diet or a normal chow diet and were gavaged with A. muciniphila sub or phosphate-buffered saline daily for 10 months. Body weight, food consumption and blood glucose were measured. At the end of the treatment period, all mice were subjected to the Y-maze test, sucrose preference test, analyses of serum, fecal microbiota analysis and histological examination. This A. muciniphila sub had 278 unique genes compared to the type strain (A. muciniphila ATCC BAA-835) and produced short chain fatty acids both. A. muciniphila sub administration significantly reduced body weight gain and improved the spatial memory of high-fat diet-fed mice. A. muciniphila sub increased Nissl bodies in neurons of the hippocampus, and restored the high-fat diet-inhibited tryptophan metabolism. The high-fat diet led to decreased serum 5-hydroxytryptamine and induced depression, which were not alleviated by A. muciniphila sub . A. muciniphila sub increased the relative fecal abundance of Bifidobacterium, and was negatively correlated with the fecal abundance of Bacteroides. The present study demonstrated the beneficial effects of this A. muciniphila sub on body weight, blood glucose control and the alleviation of the memory decay caused by a high-fat diet in mice., Competing Interests: Declaration of competing interest The authors declare that no conflicts of interest exist., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To investigate the effects of Akkermansia muciniphila ( A. muciniphila ) on the proliferation, apoptosis and insulin secretion of rat pancreatic islet cell tumor cells (INS-1)., Methods: INS-1 cells were divided into three groups, normal, repair, and protect groups, and subsequently every group was subjected with A. muciniphila metabolites, live A. muciniphila orpasteurized A. muciniphila for 48 h. A group that did not treat with anything was set as blank control. After intervention, the cell viability was determined by MTT method, the insulin secretion level stimulated by glucose was determined by ELISA, the expressions of the genes involved in insulin secretion and apoptosis were tested by qRT-PCR, and the expression of apoptosis related protein Bax was evaluated by Western blot., Results: There was no significant change in INS-1 cell morphology after co-incubation with 3 types of A. Muciniphila interventions for 48 h. The proliferative activity of INS-1 cells was decreased in the repair group that treated with live A. muciniphila than that of control ( P <0.005). A. muciniphila intervention had no effect on insulin secretion in INS-1 cells in normal, repair or protection group ( P >0.05). A. muciniphila secretions promoted the expression of glucose transporter 2 ( Glut 2) in 3 groups and the expression of glucokinase ( GCK ) in repair group ( P <0.05). The expression of Bax of the INS-1 cell in the normal group was decreased after intervented with 3 kinds of A. muciniphila intervention materials ( P <0.001).The expression of Bax gene of the INS-1 cell in the repair group that treated with dead A. muciniphila was decreased ( P <0.05). The expression of Bax protein of INS-1 cells that treated with A. muciniphila interventions was decreased., Conclusion: A. muciniphila can promote the expression of insulin secretion-related genes in INS-1 cells, inhibit the expression of apoptotic genes and apoptosis protein Bax.This research provides a new direction for applying A. muciniphila in improving type 2 diabetes., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Obesity is one of the most serious public health challenges in the world. Obesity during early life has been associated with an increased risk of neurodevelopmental disorders, including deficits in learning and memory, yet the underlying mechanisms remain unclear. Here, we show that early life high-fat diet (HFD) feeding impairs hippocampus-dependent contextual/spatial learning and memory, and alters the gut microbiota, particularly by depleting Akkermansia muciniphila (A. muciniphila), in mice. Transplantation of the HFD microbiota confers hippocampus-dependent learning and memory deficits to mice fed a chow diet. Oral treatment of HFD-fed mice with the gut commensal A. muciniphila corrects gut permeability, reduces hippocampal microgliosis and proinflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6) expression, and restores neuronal development and synapse plasticity, thus ameliorates defects in learning and memory. Interestingly, treatment of mice with lipopolysaccharide (LPS) mimics HFD-induced hippocampus-dependent cognitive impairment in chow-fed mice. In line with these findings, pharmacologic blockade of Toll-like receptor 4 (TLR4) signalling or antibiotics treatment both effectively prevent hippocampus-dependent learning and memory deficits in HFD-fed mice. Collectively, our findings demonstrate an unexpected pivotal role of gut microbiota in HFD-induced cognitive deficits and identify a potential probiotic therapy for obesity associated with cognitive dysfunction during early life.

We aimed to evaluate colonisation patterns of Akkermansia muciniphila in a Greek adult population and to investigate model-adjusted associations of A. muciniphila with host adiposity and cardiometabolic markers. Participants (n=125) underwent anthropometric, dietary, physical activity and lifestyle evaluation. Blood sampling for determination of blood lipid indices, glucose metabolism, adiponectin, lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), inflammation and oxidative stress parameters was also performed. Stool A. muciniphila presence and levels were determined by quantitative PCR and subjects were grouped based on bimodal distribution of levels (Low vs High). A. muciniphila was detected in 88.6% of participants. Overweight/obese (OW/OB) subjects were more prone in low bimodal levels of A. muciniphila compared to normal-weight (NW) individuals (58.75 vs 27.59%, P =0.004), with a 4-time greater likelihood after multi-adjusted logistic regression analysis ( P =0.016). Levels of A. muciniphila were negatively associated with total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio (log 10 :-0.009±0.004, P =0.033), whereas detection of this bacterium was negatively associated with both TC/HDL-C ratio (log 10 : -0.049±0.023, P =0.036) and low-density lipoprotein cholesterol/HDL-C ratio (-0.407±0.176, P =0.023). Furthermore, low bimodal levels of A. muciniphila were positively associated with fasting blood glucose (log 10 : 0.018±0.009, P =0.037). In terms of inflammation markers, levels of A. muciniphila were positively associated with soluble cluster of differentiation-14 (sCD14) (log 10 : 0.012±0.004, P =0.003) and faecal detection of this bacterium had a positive association with anti-inflammatory interleukin 10 levels (log 10 : 0.325±0.131, P =0.015). In addition, A. muciniphila levels were positively associated with total adiponectin (log 10 : 0.046±0.015, P =0.002), whereas low bimodal levels of A. muciniphila had an inverse relationship with this blood marker (log 10 : -0.131±0.053, P =0.016). In conclusion, we confirmed the previously reported association of A. muciniphila with metabolic health for the first time in a Greek urban population; furthermore, we shed some light to novel atherosclerotic risk markers with rather unexplored connections with A. muciniphila colonisation patterns in human subjects.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.

Akkermansia muciniphila is potential probiotic in that its type strain ATCC BAA-835 has beneficial effects upon obesity and diabetes. However, whether A. muciniphila can improve inflammatory bowel diseases (IBD), which is a form of chronic intestinal dysbiosis, is unknown. Hence, we used an isolated murine A. muciniphila strain (designated 139) and A. muciniphila type strain ATCC, to investigate their anti-inflammatory properties in cell models and in Dextran Sulfate Sodium (DSS)-induced chronic colitis of mice. In vitro , the two A. muciniphila strains exerted similar anti-inflammatory properties as they both reduced IL-8 production by TNF-α-stimulated HT-29 cells. However, neither of the strains showed capacity to increase the differentiation of regulatory T (Treg)-cells from CD4+ T cell populations significantly. In vivo , both A. muciniphila strains exerted anti-inflammatory effects on chronic colitis as they improved clinical parameters including spleen weight, colon inflammation index, and colon histological score. They also down-regulated the expression of the pro-inflammatory cytokines including TNF-α and IFN-γ in the colon of mice. However, the anti-inflammatory effects of strain ATCC were stronger than strain 139 in that ATCC significantly reduced spleen weight, colon inflammation index, and fecal lipocalin-2 content in mice with chronic colitis, while strain 139 was not. Dysbiosis of the gut microbiota was observed in mice with chronic colitis. Both A. muciniphila strains facilitated the normalization of the gut microbiota. The specific capacity of strain ATCC to modulate the differentiation of Tregs as well as increase production of short chain fatty acids, demonstrated strain-specific characteristics for these two A. muciniphila strains. This study suggests the potential beneficial effect of A. muciniphila on IBD and the importance of the future study of the function of A. muciniphila at the strain-level.

Introduction and Objectives: The amounts of Akkermansia muciniphila and Faecalibacterium prausnitzii in gut microbiota are reduced in patients with allergic diseases compared to healthy controls. We aimed to quantify levels of A. muciniphila and F. prausnitzii amounts using real-time quantitative PCR (qPCR) in the gut microbiota of children with allergic asthma and in healthy controls., Materials and Methods: In total, 92 children between the ages of three and eight who were diagnosed with asthma and 88 healthy children were included in the study and bacterial DNA was isolated from the stool samples using the stool DNA isolation Kit. qPCR assays were studied with the microbial DNA qPCR Kit for A. muciniphila and microbial DNA qPCR Kit for F. prausnitzii., Results: Both bacterial species showed a reduction in the patient group compared to healthy controls. A. muciniphila and F. prausnitzii were found to be 5.45±0.004, 6.74±0.01 and 5.71±0.002, 7.28±0.009 in the stool samples of the asthma and healthy control groups, respectively., Conclusions: F. prausnitzii and A. muciniphila may have induced anti-inflammatory cytokine IL-10 and prevented the secretion of pro-inflammatory cytokines like IL-12. These findings suggest that A. muciniphila and F. prausnitzii may suppress inflammation through its secreted metabolites., (Copyright © 2019 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Alterations to the gut microbiota have been previously suggested to be tightly linked to chronic systemic inflammation, which is a major contributing factor to complications and disease progression in chronic kidney disease (CKD). Nevertheless, the effect of gut dysbiosis on the pathogenesis and/or production of inflammatory factors in CKD has not been extensively studied to date. In the present study, we conducted 16S ribosomal DNA pyrosequencing using fecal microbiota samples and analyzed the production of serum inflammatory factors in 50 patients with CKD and 22 healthy control (HC) subjects. The results revealed that compared to the HC subjects, patients with CKD exhibited a significant reduction in the richness and structure of their fecal microbiota. At the phylum level, compared to the HC group, patients with CKD also presented reduced abundance of Actinobacteria but increased abundance of Verrucomicrobia. Moreover, the genera Lactobacillus, Clostridium IV, Paraprevotella, Clostridium sensu stricto, Desulfovibrio , and Alloprevotella were enriched in the fecal samples of patients with CKD, while Akkermansia and Parasutterella were enriched in those of the HC subjects. The abundance of Akkermansia in the CKD group was significantly lower than that in the HC group (3.08 vs. 0.67%); this decrease in the abundance of Akkermansia , an important probiotic, in patients with CKD is a striking discovery as it has not been previously reported. Finally, we analyzed whether these changes to the fecal microbiota correlated with CKD clinical characteristics and/or the production of known inflammatory factors. Altered levels of the microbiota genera Parasutterella, Lactobacillus, Paraprevotella, Clostridium sensu stricto , and Desulfovibrio were shown to be correlated with CKD disease-severity indicators, including the estimated glomerular filtration rate. Most notably, Akkermansia was significantly negatively correlated with the production of interleukin-10. The results of the present study suggest that microbiota dysbiosis may promote chronic systemic inflammation in CKD. Furthermore, they support that modifying the gut microbiota, especially Akkermansia , may be a promising potential therapeutic strategy to attenuate the progression of, and/or systemic inflammation in, CKD.

Scope: Modulation of intestinal microbiota has emerged as a new therapeutic approach for non-alcoholic fatty liver disease (NAFLD). Herein, it is addressed whether gut microbiota modulation by quercetin and intestinal microbiota transplantation can influence NAFLD development., Methods and Results: Gut microbiota donor mice are selected according to their response to high-fat diet (HFD) and quercetin in terms of obesity and NAFLD-related biomarkers. Germ-free recipients displayed metabolic phenotypic differences derived from interactions between microbiota transplanted, diets, and quercetin. Based on the evaluation of hallmark characteristics of NAFLD, it is found that gut microbiota transplantation from the HFD-non-responder donor and the HFD-fed donor with the highest response to quercetin results in a protective phenotype against HFD-induced NAFLD, in a mechanism that involves gut-liver axis alteration blockage in these receivers. Gut microbiota from the HFD-responder donor predisposed transplanted germ-free mice to NAFLD. Divergent protective and deleterious metabolic phenotypes exhibited are related to definite microbial profiles in recipients, highlighting the predominant role of Akkermansia genus in the protection from obesity-associated NAFLD development., Conclusions: The results provide scientific support for the prebiotic capacity of quercetin and the transfer of established metabolic profiles through gut microbiota transplantation as a protective strategy against the development of obesity-related NAFLD., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Infection and dysbiosis present a close relationship with metabolic diseases although the influence of apical periodontitis (AP) in this context needs further investigation. This study evaluated the influence of AP in a rat model of metabolic syndrome induced by 10% fructose supplementation., Methods: Male Wistar rats were used. Animals that received a high-fructose diet (HFD, n = 30) or filtered water (control, n = 30) were subdivided into the following groups: (1) without induction of AP (no AP, n = 10 each), (2) with AP induction 2 weeks before euthanasia (AP 14 days, n = 10 each), and (3) with AP induction 4 weeks before euthanasia (AP 28 days, n = 10 each)., Results: HFD triggered metabolic syndrome, as indicated by the induction of overweight and hyperglycemia, besides polydipsia, regardless of the AP induction. Serum or intestinal tumor necrosis factor, interleukin 1 beta, and interleukin 6 levels were undetectable, regardless of the experimental group. Serum leptin and adiponectin levels were significantly elevated in the HFD group without AP induction. The intestinal levels of leptin were significantly increased in the groups with 28 days of AP induction despite HFD. A significant elevation of liver glutathione levels was observed in animals submitted to HFD and AP for 14 days. AP induction (14 or 28 days) led to pulp and periapical tissue inflammation without any influence of HFD. Either HFD or AP induction led to dysbiosis, as indicated by a significant reduction of fecal A. muciniphila expression., Conclusions: We provide novel evidence that AP can have systemic impacts on metabolic disorders, likely by modulating intestinal metabolism and microbiota., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Akkermansia muciniphila is a common member of the intestinal microbiota of healthy human individuals. Its abundance is negatively associated with inflammatory bowel disease and metabolic disorders and the oral administration of A. muciniphila improves the symptoms of metabolic disease in mice. Therefore, A. muciniphila is a promising candidate for the treatment of type-2 diabetes and obesity. However, some studies using animal models of intestinal inflammation reported that A. muciniphila may exacerbate gut inflammation. Because of these contradictory reports the present study aimed to clarify the role of A. muciniphila in the development of intestinal inflammation and the conditions promoting it. For this purpose, the short-term colitogenic potential of A. muciniphila strain ATCC BAA-835 was investigated in colitis-prone, gnotobiotic IL-10-deficient (Il10 -/- ) mice. Il10 -/- mice mono-associated with A. muciniphila showed no signs of intestinal inflammation based on body-weight change, histopathological scoring and inflammatory markers. Additional association of the mice with the colitogenic Escherichia coli strain NC101 led to cecal but not colonic inflammation. However, the severity of the inflammation did not exceed that observed in mice mono-associated with E. coli NC101. Il10 -/- mice colonized with a simplified human intestinal microbiota showed increased histopathology, but no increase in inflammatory markers. Furthermore, co-colonization with A. muciniphila did not modify histopathology. The turnover of intestinal mucus was similar in all groups despite the mucus-degrading property of A. muciniphila. Overall, the data do not support a short-term pro-inflammatory effect of A. muciniphila strain ATCC BAA-835 in the Il10 -/- mouse model for inflammatory bowel disease.

Impaired intestinal barrier function occurs before type 1 diabetes (T1D) onset with a possible contribution of microbial translocation. Breastfeeding is associated with enhanced mucosal intestinal integrity and T1D protection. Our aim was to study the potential of human milk (HM) to prevent diabetes onset and modulate the translocation of gut bacteria susceptible to breastfeeding or associated to diabetes onset. We show that HM intake can prevent T1D in nonobese diabetic mice independently of bifidobacteria colonization. Prior to diabetes onset, HM mice harbored splenic bacterial counts and plasma lipopolysaccharides level similar to control mice but exhibited a reduced expansion of Anaerotruncus sp. in pancreas and Lactobacillus johnsonii and Barnesiella in Peyer's patches (PP). Surprisingly, pancreas and PP bacterial expansion did not correlate with their own gut localization but with ileal Escherichia coli and cecal HM-susceptible bacteria (the promoted L. murinus and Bacteroides vulgatus, and the repressed B. fragilis and E. coli), respectively. Besides, higher colonic B. vulgatus counts induced by HM intake were associated with low islet infiltration and pancreatic E. coli expansion. On another hand, splenic dendritic cells (DCs) were identified as negative covariate of PP Barnesiella, suggesting a possible HM contribution to preserving splenic DCs through the reduction of Barnesiella translocation. Fecal B. vulgatus also negatively correlated with PP Barnesiella expansion, indicating that the mouse coprophagic behavior likely added to HM effect. Our findings provide evidence that HM has a multilevel impact and cooperates with some gut bacteria for controlling bacterial translocation at the earliest stage of insulitis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Interest in manipulating the gut microbiota to treat disease has led to a need for understanding how organisms can establish themselves when introduced into a host with an intact microbial community. Here, we employ the concept of orthogonal niche engineering: a resource typically absent from the diet, seaweed, creates a customized niche for an introduced organism. In the short term, co-introduction of this resource at 1% in the diet along with an organism with exclusive access to this resource, Bacteroides plebeius DSM 17135, enables it to colonize at a median abundance of 1% and frequently up to 10 or more percent, both on pulsed and constant seaweed diets. In a two-month follow-up after the initial treatment period, B. plebeius stops responding to seaweed in mice initially on the constant seaweed diet, suggesting treatment regime will affect controllability. These results offer potential for diet-based intervention to introduce and control target organisms., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aimed to investigate how Akkermansia muciniphila can implicate type 2 diabetes mellitus and the mechanisms underlying the effects A. muciniphila on type 2 diabetes mellitus. Normal and streptozotocin-induced diabetic Sprague-Dawley rats were orally administered with A. muciniphila and solvent. After 4 weeks of treatment, diabetic rats orally administered with live or pasteurized A. muciniphila exhibited significant increase in the blood concentration of high-density lipoprotein, and decrease in the hepatic glycogen, serum plasminogen activator inhibitor-1, tumor necrosis factor-α, lipopolysaccharide, malondialdehyde and total glucagon-like peptide-1. Moreover, diabetic rats orally administered with A. muciniphila showed significantly increased species alpha diversity and gene function in gut microbes. These results indicated that A. muciniphila can improve liver function, reduce gluco/lipotoxicity, alleviate oxidative stress, suppress inflammation and normalize intestine microbiota of the host animal, thereby ameliorating type 2 diabetes mellitus. Akkermansia muciniphila might be considered as one of the ideal new probiotics used in the management of type 2 diabetes mellitus in future.

Objective: Alcoholic liver disease (ALD) is a global health problem with limited therapeutic options. Intestinal barrier integrity and the microbiota modulate susceptibility to ALD. Akkermansia muciniphila , a Gram-negative intestinal commensal, promotes barrier function partly by enhancing mucus production. The aim of this study was to investigate microbial alterations in ALD and to define the impact of A. muciniphila administration on the course of ALD., Design: The intestinal microbiota was analysed in an unbiased approach by 16S ribosomal DNA (rDNA) sequencing in a Lieber-DeCarli ALD mouse model, and faecal A. muciniphila abundance was determined in a cohort of patients with alcoholic steatohepatitis (ASH). The impact of A. muciniphila on the development of experimental acute and chronic ALD was determined in a preventive and therapeutic setting, and intestinal barrier integrity was analysed., Results: Patients with ASH exhibited a decreased abundance of faecal A. muciniphila when compared with healthy controls that indirectly correlated with hepatic disease severity. Ethanol feeding of wild-type mice resulted in a prominent decline in A. muciniphila abundance. Ethanol-induced intestinal A. muciniphila depletion could be restored by oral A. muciniphila supplementation. Furthermore, A. muciniphila administration when performed in a preventive setting decreased hepatic injury, steatosis and neutrophil infiltration. A. muciniphila also protected against ethanol-induced gut leakiness, enhanced mucus thickness and tight-junction expression. In already established ALD, A. muciniphila used therapeutically ameliorated hepatic injury and neutrophil infiltration., Conclusion: Ethanol exposure diminishes intestinal A. muciniphila abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. A. muciniphila promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from A. muciniphila supplementation., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Recent advancements suggest that in addition to its roles in developmental processes, transcription repressor hairy and enhancer of split 1 (Hes1) also acts as a key regulator of inflammatory responses. A healthy gut microbiota ecology is critical for establishment of tissue homeostasis. However, the role of epithelial Hes1 in regulating intestinal microbiota ecology and intestinal homeostasis remains unexplored. Here we show that epithelial Hes1 deficiency leads to intestinal microbial dysbiosis and disturbed homeostasis. Both inducible Hes1 deletion and intestinal epithelial cell (IEC)-intrinsic Hes1 deletion resulted in loss of Bacteroidetes in ileum and increase of Escherichia coli and Akkermansia muciniphila in colon. Loss of Bacteroidetes closely correlated with decreased expression of commensal-dependent antimicrobial genes, leading to impaired resistance against pathogenic bacterial colonization. Moreover, Hes1 deficiency enhanced susceptibility to Dextran sodium sulphate-induced intestinal inflammation. Of note, transfer of Hes1-deficient-mouse-derived fecal microbiota promoted intestinal inflammation. The increase of A. muciniphila in colon was associated with Hes1-deficiency-induced unbalanced mucosal microhabitats. Thus, our results support that IEC-intrinsic Hes1 maintains gut homeostasis by preventing microbial dysbiosis partially through regulating mucosal microhabitats.

The bacterial phylum Verrucomicrobia was formally described two decades ago and originally believed to be a minor member of many ecosystems; however, it is now recognized as ubiquitous and abundant in both soil and aquatic systems. Nevertheless, knowledge of the drivers of its relative abundance and within-phylum habitat preferences remains sparse, especially in lake systems. Here, we documented the distribution of Verrucomicrobia in 12 inland lakes in Southeastern Michigan, a Laurentian Great Lake (Lake Michigan), and a freshwater estuary, which span a gradient in lake sizes, depths, residence times, and trophic states. A wide range of physical and geochemical parameters was covered by sampling seasonally from the surface and bottom of each lake, and by separating samples into particle-associated and free-living fractions. On average, Verrucomicrobia was the 4th most abundant phylum (range 1.7-41.7%). Fraction, season, station, and depth explained up to 70% of the variance in Verrucomicrobia community composition and preference for these habitats was phylogenetically conserved at the class-level. When relative abundance was linearly modeled against environmental data, Verrucomicrobia and non-Verrucomicrobia bacterial community composition correlated to similar quantitative environmental parameters, although there were lake system-dependent differences and > 55% of the variance remained unexplained. A majority of the phylum exhibited preference for the particle-associated fraction and two classes (Opitutae and Verrucomicrobiae) were identified to be more abundant during the spring season. This study highlights the high relative abundance of Verrucomicrobia in north temperate lake systems and expands insights into drivers of within-phylum habitat preferences of the Verrucomicrobia.

Bacteriostatic properties of a potential anti-obesity agent cinnamaldehyde (CMN) may present untoward effects on the resident gut microbiota. Here, we evaluated whether the combination of Isomalto-oligosaccharides (IMOs) with CMN prevents unwanted effects of CMN on gut microbiota and associated metabolic outcomes in HFD-fed mice. Male Swiss albino mice divided into four groups (n = 10), were fed on normal chow, or HFD (58% fat kcal), HFD + CMN (10 mg kg -1 ) and HFD + CMN (10 mg kg -1 ) + IMOs (1 g kg -1 ) for 12 weeks. Effects on HFD-induced biochemical, histological, inflammatory and genomic changes in the gastrointestinal tract, liver, and visceral white adipose tissue were studied. Cosupplementation of CMN with IMOs potentiates its preventive action against HFD-induced increase in serum LPS and abundances of selected LPS producing bacteria (Enterobacteriaceae, Escherichia Coli, Cronobacter sp, Citrobacter sp., Klebsiella sp., Salmonella sp.). CMN and IMOs co-administration prevented HFD-induced decrease in selected beneficial gut bacterial abundances (Bifidobacteria, Roseburia sp., Akkermansia muciniphila, Feacalibacterium sp.). CMN's effects against HFD-induced increase in gut permeability, histological and inflammatory changes in the colon were further augmented by cosupplementation of IMOs. Similar effects were observed in hepatic inflammatory markers. Cosupplementation of CMN with IMOs and CMN alone administration prevented HFD-induced changes in peripheral hormones and lipid metabolism-related parameters. This study provides evidence that coadministration of IMOs with CMN potentiates its anti-obesity effect and limits the side effects of CMN on gastrointestinal flora. Further, this study gives us important direction for the development of a concept-based novel class of functional foods/nutraceuticals for improved metabolic health. © BioFactors, 43(6):821-835, 2017., (© 2017 International Union of Biochemistry and Molecular Biology.)

Background: Akkermansia muciniphila is one of the most dominant bacteria that resides on the mucus layer of intestinal tract and plays key role in human health, however, little is known about its genomic content., Results: Herein, we for the first time characterized the genomic architecture of A. muciniphila based on whole-genome sequencing, assembling, and annotating of 39 isolates derived from human and mouse feces. We revealed a flexible open pangenome of A. muciniphila currently consisting of 5644 unique proteins. Phylogenetic analysis identified three species-level A. muciniphila phylogroups exhibiting distinct metabolic and functional features. Based on the comprehensive genome catalogue, we reconstructed 106 newly A. muciniphila metagenome assembled genomes (MAGs) from available metagenomic datasets of human, mouse and pig gut microbiomes, revealing a transcontinental distribution of A. muciniphila phylogroups across mammalian gut microbiotas. Accurate quantitative analysis of A. muciniphila phylogroups in human subjects further demonstrated its strong correlation with body mass index and anti-diabetic drug usage. Furthermore, we found that, during their mammalian gut evolution history, A. muciniphila acquired extra genes, especially antibiotic resistance genes, from symbiotic microbes via recent lateral gene transfer., Conclusions: The genome repertoire of A. muciniphila provided insights into population structure, evolutionary and functional specificity of this significant bacterium.

Akkermansia muciniphila is an intestinal bacterium that was isolated a decade ago from a human fecal sample. Its specialization in mucin degradation makes it a key organism at the mucosal interface between the lumen and host cells. Although it was isolated quite recently, it has rapidly raised significant interest as A. muciniphila is the only cultivated intestinal representative of the Verrucomicrobia, one of the few phyla in the human gut that can be easily detected in phylogenetic and metagenome analyses. There has also been a growing interest in A. muciniphila, due to its association with health in animals and humans. Notably, reduced levels of A. muciniphila have been observed in patients with inflammatory bowel diseases (mainly ulcerative colitis) and metabolic disorders, which suggests it may have potential anti-inflammatory properties. The aims of this review are to summarize the existing data on the intestinal distribution of A. muciniphila in health and disease, to provide insight into its ecology and its role in founding microbial networks at the mucosal interface, as well as to discuss recent research on its role in regulating host functions that are disturbed in various diseases, with a specific focus on metabolic disorders in both animals and humans., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Akkermansia muciniphila is an abundant inhabitant of the intestinal tract of humans and many other animals. It is the sole intestinal representative of the verrucomicrobia in human stools and depleted in adults suffering from obesity, diabetes and several other diseases. A. muciniphila degrades intestinal mucin into mainly propionic and acetic acid, and lives in symbiosis with its host, marked by signalling to immune and metabolic pathways, priming trophic chains and likely providing competitive exclusion at the host-microbe interface. Since its recent discovery, A. muciniphila has increasingly been studied and recognized as a true intestinal symbiont promoting beneficial interactions in the intestinal tract.

Dysfunction in host immune responses and pathologic alterations in the gut microbiota, referred to as dysbiosis, can both contribute to the development of inflammatory bowel disease (IBD). However, it remains unclear how specific changes in host immunity or the microbiota cause disease. We previously demonstrated that the loss of the innate immune receptor NLRP6 in mice resulted in impaired production of interleukin-18 (IL-18) and increased susceptibility to epithelial-induced injury. Here, we show that NLRP6 is important for suppressing the development of spontaneous colitis in the Il10 -/- mice model of IBD and that NLRP6 deficiency results in the enrichment of Akkermansia muciniphila. A. muciniphila was sufficient for promoting intestinal inflammation in both specific-pathogen-free and germ-free Il10 -/- mice. Our results demonstrate that A. muciniphila can act as a pathobiont to promote colitis in a genetically susceptible host and that NLRP6 is a key regulator of its abundance., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Obesity is a major global public health problem requiring multifaceted interventional approaches including dietary interventions with probiotic bacteria. High-throughput genome sequencing of microbial communities in the mammalian gastrointestinal system continues to present diverse protein function information to understand the bacterial determinants that influence obesity development. The goal of the research reported in this article was to identify biological processes in probiotic bacteria that could influence the mechanisms for the extraction of energy from diet in the human gastrointestinal system. Our research strategy of combining bioinformatics and visual analytics methods was based on the identification of operon gene arrangements in genomes of Lactobacillus species and Akkermansia muciniphila that include at least a gene for a universal stress protein. The two major findings from this research study are related to Lactobacillus plantarum and Akkermansia muciniphila bacteria species which are associated with weight-loss. The first finding is that Lactobacillus plantarum strains have a two-gene operon that encodes a universal stress protein for stress response and the membrane translocator protein (TSPO), known to function in mitochondrial fatty acid oxidation in humans. The second finding is the presence of a three-gene operon in Akkermansia muciniphila that includes a gene whose human mitochondrial homolog is associated with waist-hip ratio and fat distribution. From a public health perspective, elucidation of the bacterial determinants influencing obesity will help in educating the public on optimal probiotic use for anti-obesity effects.

Host mucin is the main constituent of the mucus layer that covers the gut epithelium of the host, and an important source of glycans for the bacteria colonising the intestine. Akkermansia muciniphila is a mucin-degrading bacterium, abundant in the human gut, that is able to produce acetate and propionate during this degradation process. A. muciniphila has been correlated with human health in previous studies, but a mechanistic explanation is lacking. In this study, the main site of colonisation was characterised alongside additional conditions, such as differences in colon pH, prebiotic supplementation and variable mucin supply. To overcome the limitations of in vivo studies concerning variations in mucin availability and difficult access to proximal regions of the colon, a dynamic in vitro gut model (SHIME) was used. In this model, A. muciniphila was found to colonise the distal colon compartment more abundantly than the proximal colon ((±8 log copies/ml compared to ±4 log copies/ml) and the preference for the distal compartment was found to be pH-dependent. The addition of mucin caused a specific increase of A. muciniphila (±4.5 log increase over two days), far exceeding the response of other bacteria present, together with an increase in propionate. These findings suggest that colonisation and mucin degradation by A. muciniphila is dependent on pH and the concentration of mucin. Our results revealed the preference of A. muciniphila for the distal colon environment due to its higher pH and uncovered the quick and stable response of A. muciniphila to mucin supplementation.

Abnormal shifts in the composition of gut microbiota contribute to the pathogenesis of metabolic diseases, including obesity and type 2 diabetes (T2DM). The crosstalk between gut microbes and the host affects the inflammatory status and glucose tolerance of the individuals, but the underlying mechanisms have not been elucidated completely. In this study, we treated the lean chow diet-fed mice with Akkermansia muciniphila, which is thought to be inversely correlated with inflammation status and body weight in rodents and humans, and we found that A. muciniphila supplementation by daily gavage for five weeks significantly alleviated body weight gain and reduced fat mass. Glucose tolerance and insulin sensitivity were also improved by A. muciniphila supplementation compared with the vehicle. Furthermore, A. muciniphila supplementation reduced gene expression related to fatty acid synthesis and transport in liver and muscle; meanwhile, endoplasmic reticulum (ER) stress in liver and muscle was also alleviated by A. muciniphila. More importantly, A. muciniphila supplementation reduced chronic low-grade inflammation, as reflected by decreased plasma levels of lipopolysaccharide (LPS)-binding protein (LBP) and leptin, as well as inactivated LPS/LBP downstream signaling (e.g. decreased phospho-JNK and increased IKBA expression) in liver and muscle. Moreover, metabolomics profiling in plasma also revealed an increase in anti-inflammatory factors such as α-tocopherol, β-sitosterol and a decrease of representative amino acids. In summary, our study demonstrated that A. muciniphila supplementation relieved metabolic inflammation, providing underlying mechanisms for the interaction of A. muciniphila and host health, pointing to possibilities for metabolic benefits using specific probiotics supplementation in metabolic healthy individuals., (© 2017 Society for Endocrinology.)