Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus1. The gut microbiota is a new key contributor involved in the onset of obesity-related disorders2. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension3–8. Since the administration of A. muciniphila has never been investigated in humans, we conducted a randomized, double-blind, placebo-controlled pilot study in overweight/obese insulin-resistant volunteers; 40 were enrolled and 32 completed the trial. The primary end points were safety, tolerability and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass). Secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010 A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated. Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62 ± 7.02%, P = 0.002), and reduced insulinemia (−34.08 ± 7.12%, P = 0.006) and plasma total cholesterol (−8.68 ± 2.38%, P = 0.02). Pasteurized A. muciniphila supplementation slightly decreased body weight (−2.27 ± 0.92 kg, P = 0.091) compared to the placebo group, and fat mass (−1.37 ± 0.82 kg, P = 0.092) and hip circumference (−2.63 ± 1.14 cm, P = 0.091) compared to baseline. After three months of supplementation, A. muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (clinical trial no. NCT02637115) shows that the intervention was safe and well tolerated and that supplementation with A. muciniphila improves several metabolic parameters. Supplementation with Akkermansia muciniphila, a gut microbe previously associated with metabolic health in preclinical models, is safe and well tolerated in humans and may improve metabolic parameters in overweight and obese patients.

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Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.

The microbiome has received increasing attention over the last 15 years. Although gut microbes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obesity, diabetes, and liver diseases but also cancer and even neurodegenerative diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the number of publications focusing on the gut microbiota was, remarkably, 12 900, which represents four-fifths of the total number of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a critical analysis of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with the protection or the onset of a disease. In fact, environmental factors such as dietary habits, drug treatments, intestinal motility and stool frequency and consistency are all factors that influence the composition of the microbiota and should be considered. The cases of the bacteria Prevotella copri and Akkermansia muciniphila will be discussed as key examples.

https://gut.bmj.com/content/gutjnl/67/9/1716.full.pdf

Human gut microbiome: hopes, threats and promises

The microbiota plays a central role in human health and disease by shaping immune development, immune responses and metabolism, and by protecting from invading pathogens. Technical advances that allow comprehensive characterization of microbial communities by genetic sequencing have sparked the hunt for disease-modulating bacteria. Emerging studies in humans have linked the increased abundance of Prevotella species at mucosal sites to localized and systemic disease, including periodontitis, bacterial vaginosis, rheumatoid arthritis, metabolic disorders and low-grade systemic inflammation. Intriguingly, Prevotella abundance is reduced within the lung microbiota of patients with asthma and chronic obstructive pulmonary disease. Increased Prevotella abundance is associated with augmented T helper type 17 (Th17) -mediated mucosal inflammation, which is in line with the marked capacity of Prevotella in driving Th17 immune responses in vitro. Studies indicate that Prevotella predominantly activate Toll-like receptor 2, leading to production of Th17-polarizing cytokines by antigen-presenting cells, including interleukin-23 (IL-23) and IL-1. Furthermore, Prevotella stimulate epithelial cells to produce IL-8, IL-6 and CCL20, which can promote mucosal Th17 immune responses and neutrophil recruitment. Prevotella-mediated mucosal inflammation leads to systemic dissemination of inflammatory mediators, bacteria and bacterial products, which in turn may affect systemic disease outcomes. Studies in mice support a causal role of Prevotella as colonization experiments promote clinical and inflammatory features of human disease. When compared with strict commensal bacteria, Prevotella exhibit increased inflammatory properties, as demonstrated by augmented release of inflammatory mediators from immune cells and various stromal cells. These findings indicate that some Prevotella strains may be clinically important pathobionts that can participate in human disease by promoting chronic inflammation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/imm.12760

The immune response to Prevotella bacteria in chronic inflammatory disease

Metabolic disorders associated with obesity and cardiometabolic disorders are worldwide epidemic Among the different environmental factors, the gut microbiota is now considered as a key player interfering with energy metabolism and host susceptibility to several non-communicable diseases Among the next-generation beneficial microbes that have been identified, Akkermansia muciniphila is a promising candidate Indeed, A muciniphila is inversely associated with obesity, diabetes, cardiometabolic diseases and low-grade inflammation Besides the numerous correlations observed, a large body of evidence has demonstrated the causal beneficial impact of this bacterium in a variety of preclinical models Translating these exciting observations to human would be the next logic step and it now appears that several obstacles that would prevent the use of A muciniphila administration in humans have been overcome Moreover, several lines of evidence indicate that pasteurization of A muciniphila not only increases its stability but more importantly increases its efficacy This strongly positions A muciniphila in the forefront of next-generation candidates for developing novel food or pharma supplements with beneficial effects Finally, a specific protein present on the outer membrane of A muciniphila, termed Amuc_1100, could be strong candidate for future drug development In conclusion, as plants and its related knowledge, known as pharmacognosy, have been the source for designing drugs over the last century, we propose that microbes and microbiomegnosy, or knowledge of our gut microbiome, can become a novel source of future therapies

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Next-generation beneficial microbes : The case of Akkermansia muciniphila

Research into the role of the gut microbiome in modulating brain function has rapidly increased over the past 10 years, albeit chiefly in animal models. Increasing clinical and preclinical evidence implicates the microbiome as a possible key susceptibility factor for neurological disorders, including Alzheimer's disease, autism spectrum disorder, multiple sclerosis, Parkinson's disease, and stroke. Cross-sectional clinical studies are bolstering the concept of altered microbial composition contributing to the pathophysiology of such diseases. However, the field is nascent, and interpretation of such data is often difficult given that the composition of the microbiome is influenced by various factors such as diet and exercise. Longitudinal studies and randomised controlled trials in humans are needed to find out if targeting the microbiome can yield novel therapeutic strategies. Systems biology approaches will also be important in integrating such data with genomic and metabolomic datasets from clinical cohorts with neurological disease to help guide individual treatment selection.

The gut microbiome in neurological disorders.

Recently, the potential role of gut microbiome in metabolic diseases has been revealed, especially in cardiovascular diseases. Hypertension is one of the most prevalent cardiovascular diseases worldwide, yet whether gut microbiota dysbiosis participates in the development of hypertension remains largely unknown. To investigate this issue, we carried out comprehensive metagenomic and metabolomic analyses in a cohort of 41 healthy controls, 56 subjects with pre-hypertension, 99 individuals with primary hypertension, and performed fecal microbiota transplantation from patients to germ-free mice. Compared to the healthy controls, we found dramatically decreased microbial richness and diversity, Prevotella-dominated gut enterotype, distinct metagenomic composition with reduced bacteria associated with healthy status and overgrowth of bacteria such as Prevotella and Klebsiella, and disease-linked microbial function in both pre-hypertensive and hypertensive populations. Unexpectedly, the microbiome characteristic in pre-hypertension group was quite similar to that in hypertension. The metabolism changes of host with pre-hypertension or hypertension were identified to be closely linked to gut microbiome dysbiosis. And a disease classifier based on microbiota and metabolites was constructed to discriminate pre-hypertensive and hypertensive individuals from controls accurately. Furthermore, by fecal transplantation from hypertensive human donors to germ-free mice, elevated blood pressure was observed to be transferrable through microbiota, and the direct influence of gut microbiota on blood pressure of the host was demonstrated. Overall, our results describe a novel causal role of aberrant gut microbiota in contributing to the pathogenesis of hypertension. And the significance of early intervention for pre-hypertension was emphasized.

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Kelda Auguste

Papers

Gut microbiota dysbiosis contributes to the development of hypertension.

Additional file 11: Table S17. of Gut microbiota dysbiosis contributes to the development of hypertension