Obesity, a complex syndrome recognized as a major public health issue in the 21st century, is associated with a range of chronic diseases. The gut microbiota, a diverse community of microorganisms residing in the intestine, plays a pivotal role in regulating host metabolism. Among these microorganisms, Akkermansia muciniphila has emerged as a bacterium of interest due to its potential role in modulating obesity and related metabolic disorders.
Obesity and the Gut Microbiota
Disparity in energy consumption and energy expenditure often leads to weight gain and adiposity. Obesity is associated with the prevalence of many chronic diseases, such as cardiovascular disorders, certain tumors, type 2 diabetes, elevated blood pressure, stroke, osteoarthritis, gallbladder disease, and psychosocial issues. Overweight and obesity were estimated to cause 3.4 million deaths globally in 2010, and have affected more than 671 million in 2016. The prevalence of obesity has tripled between 1975 and 2016 according to the WHO. Rural areas have experienced the highest increase compared to cities, indicating dramatic changes in lifestyle. Overconsumption of animal products, refined grains, and added sugars, especially in sweetened beverages, is considered a primary driver. Macronutrients, including carbohydrates and proteins, can also significantly influence the gut microbiota composition.
The human gut microbiota comprises tens of trillions of microorganisms, representing over 1000 different species of bacteria and at least 3 million genes. The distribution and composition of the gut microbiota vary across different anatomical sites of the intestine and are affected by intrinsic and extrinsic factors, including lifestyle, diet, and health status. The colon is the most inhabited site, containing approximately 107 to 108 cells of Clostridium Type IV and XIV, Bacteroidetes, Bifidobacterium, and Enterobacteriaceae. The gut microbiota composition exhibits strong associations with obesity and metabolic syndrome, and the ratio of Firmicutes to Bacteroides appears to be crucial. An increased ratio of Firmicutes to Bacteroides in adults has been correlated with increased BMI.
Akkermansia Muciniphila: A Next-Generation Probiotic
Mucin, a protective barrier against xenobiotics in the intestine, plays a significant role in the microbiota adhesion to the intestinal layers. Bacteria capable of degrading mucin are more likely to survive the changing microenvironment of the intestine. Akkermansia muciniphila is one of the early occupants of the intestinal tract, reaching concentrations of 108 cells/gram or more than 1% of total fecal microbes. It can use mucin as its sole source of carbon and nitrogen, making it a "next-generation probiotic." Knowledge about A. muciniphila has grown significantly since its first isolation in 2004. As the only member of the Verrucomicrobia phylum in the gut of mammals, it is easily detected using 16S rRNA gene sequencing.
Abundant evidence suggests that the abundance of Akkermansia in the gut correlates with host health and disease status. Its numbers as a beneficial microorganism decrease with aging. A. muciniphila has been shown to modulate the endocannabinoid (eCB) system, an essential regulatory system involved in glucose and energy metabolism in the context of obesity, type 2 diabetes, and inflammation. Human and animal trials have demonstrated a positive correlation between A. muciniphila intervention and improvements in obesity and metabolic disorders. Supplementation with A. muciniphila and strategies that increase its abundance in the gut microbiota may offer a beneficial approach to obesity management.
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Clinical Trials and Interventional Studies
To evaluate the role of A. muciniphila in obesity and lipid parameters in obese and non-obese populations, a systematic review of clinical trials and controlled interventional studies was conducted. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA 2009). The search strategy involved no filters or limitations. The criterion to explain the "clinical trial" was based on animal experiments that may have been planned for an intervention (which may involve control or other placebo groups), and with purpose to determine the effect of ingesting A. muciniphila on metabolic syndrome, lipid profile, and fat mass and obesity.
The search included studies that met the following selection criteria: (1) animal model, (2) involvement of a control group, and (3) treatment or intervention with A. muciniphila supplementation. Exclusion criteria included: (1) not an original paper, (2) lack of comparison intervention, and (3) human studies and animals with pathologies. Data extracted from each article included author, publication year, sample size and animal species, study design, duration and dose of ingestion of A. muciniphila, control, and the outcomes related to obesity and metabolic syndrome. The Modified Downs and Black checklist was used to assess the quality and risk of bias in the studies.
Evidence from Animal Studies
Ten studies investigated the effect of A. muciniphila supplementation on obesity parameters and metabolic disorder in C57BL/6J mice models. Yang et al. found that treatment with pasteurized A. muciniphila significantly decreased body weight gain, caloric intake, mesenteric fat weight, subcutaneous fat weight, epididymal fat weight, total fat, and energy efficiency in high-fat diet (HFD)-fed mice. The treatment with A. muciniphila upregulated the colonic gene expression of Glucagon-like peptide-1 (GLP-1) and Peptide YY(PYY), which are the intestinal hormones with appetite suppressing and anti-diabetic plus anti-obesity properties.
Everard et al. compared the effects of viable A. muciniphila administration with heat-killed A. muciniphila. Viable A. muciniphila normalized metabolic endotoxemia, fat storage, adipose tissue metabolism, and CD11c adipose tissue marker caused by diet. A. muciniphila treatment decreased body weight and improved body composition without changes in food intake. These effects were not observed after administration of heat-killed A. muciniphila.
Other trials found that pasteurized A. muciniphila significantly decreased body weight gain, total adiposity index, and fat mass gain without affecting accumulated food intake in HFD-fed mice. Fecal caloric content also significantly increased. Depommier et al. reported that five weeks of supplementation with A. muciniphila decreased body weight gain and significantly reduced fat mass as well as increased lean mass in mice fed with a normal diet (ND). Visceral fat weight, closely related to insulin resistance pathogenesis, was more clearly reduced.
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Plovier et al. found that daily treatment with A. muciniphila live cells reduced HFD-induced weight gain and fat mass gain. The same dose of pasteurized A. muciniphila gave a greater effect than unpasteurized culture, regardless of food consumption. Mice fed with pasteurized A. muciniphila had a higher fecal caloric content, implying that pasteurized culture administration reduces caloric absorption. Treatment with Amuc_1100*, the outer membrane protein of *A. muciniphila* produced in E. coli, resulted in lower body weight and fat mass gain compared to untreated HFD-fed mice, regardless of food consumption.
Wu et al. demonstrated that A. muciniphila GP01 treatment reduced food intake and body weight in both HFD and ND groups. Ashrafian et al. reported that obese mice treated with A. muciniphila-derived extracellular vehicles (EVs) demonstrated a substantial reduction in food consumption and a low level of body weight gain. Obese mice feeding with A. muciniphila live cells caused body and epididymal adipose tissue (EAT) weight loss, but had a lower impact on body weight and adipose weight than its EVs.
However, some studies reported contradictory results. Kim et al. and Deng et al. reported that no difference in weight gain was observed between groups treated and non-treated with A. muciniphila. Deng et al. showed that treatment with cells of strains GP01 and GP25 alleviated the effect of HFD on adipocyte size in inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT). A. muciniphila treatment greatly decreased the amount of unilocular adipocytes in HFD mice, alleviating the whitening of brown adipose tissue (BAT).
Akkermansia and Glucose Metabolism
In the HFD group, the fasting blood glucose level was significantly higher than in the normal fed group. However, this parameter was substantially depleted by the treatment of HFD-fed mice with A. muciniphila. The OGTT area under the curve (AUC), serum insulin level, homeostatic model assessment for Insulin Resistance (HOMA-IR), and hepatic gene expression of G6Pase (an enzyme involved in glucose production) were significantly higher than in the normal group. However, the HFD group treated with A. muciniphila significantly reduced the levels of these four parameters.
Human Studies and Considerations
While animal studies have shown promising results, the effects of A. muciniphila on obesity prevention in humans require further investigation. A study based on the American Gut Project (AGP) database of 10,534 subjects found a nonlinear association between Akkermansia and obesity risk. Higher abundance of Akkermansia was associated with a lower risk of obesity, independent of common confounders such as age, sex, smoking, alcohol consumption, diet, and country.
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Despite the potential benefits, it's important to consider that excessive enrichment of Akkermansia muciniphila in specific intestinal microenvironments may exacerbate local inflammation. Conditions like inflammatory bowel disease (IBD), Salmonella typhimurium infection, or post-antibiotic reconstitution may not benefit from Akkermansia supplementation. Furthermore, caution is advised when using Akkermansia in patients with endocrine and gynecological disorders such as polycystic ovary syndrome (PCOS) or endometriosis, as they have a higher risk of developing IBD. Neurological conditions such as Parkinsonâs disease or multiple sclerosis also exhibit increased Akkermansia municiphila abundance.
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