A Korean study led by Seoul National University (SNU) scientists is the first to demonstrate that the human intestinal mucin-degrading bacterium, Akkermansia muciniphila, secretes a glucagon-like peptide-1 (GLP-1)-inducing protein, which significantly improved glucose homeostasis and ameliorated metabolic disease in mice.
Reported in the April 5, 2021, edition of Nature Microbiology, these findings support extensive earlier research showing that A. muciniphila may have anti-inflammatory effects in humans and might be used to combat metabolic diseases including obesity and type 2 diabetes, the prevalence of which has recently reached epidemic proportions.
"Although there are a number of effective treatment options available for metabolic diseases, there remains a need for improved new treatments with better efficacy, safety and different routes of administration, such as oral uptake," said study leader GwangPyo Ko, a professor in the Department of Environmental Health Sciences of the Graduate School of Public Health at SNU.
Human gut microbiota are known to regulate a range of metabolic functions, including intestinal barrier homeostasis, glucose homeostasis and energy absorption.
Several preclinical and clinical studies have also shown that abundant A. muciniphila correlates with metabolic disorders, including obesity and type 2 diabetes.
Dietary supplementation with viable or pasteurized A. muciniphila has been shown to ameliorate metabolic endotoxemia and improve gut-barrier function, thereby improving the systemic metabolic profile.
Furthermore, A. muciniphila has been shown to reduce intestinal energy absorptive capacity under cold conditions and its presence correlates with fat browning, while pasteurized A. muciniphila has direct effects on host energy expenditure.
However, there has been little reported evidence regarding the molecular mechanisms involved in the beneficial effects of A. muciniphila, including on specific host cellular components or bacterial proteins.
Notably, there has been little investigation of the relationship between A. muciniphila and host adipose tissue depots, particularly brown adipose tissue (BAT), which mediates non-shivering thermogenesis.
The gut microbiota are known to modulate the host immune system through microbially derived metabolites or cell membrane components.
For example, bacterial metabolites such as short-chain fatty acids (SCFAs) regulate appetite by stimulating release of gut hormones, such as GLP-1, and activating enteric neuronal signaling, contributing to energy homeostasis.
Although A. muciniphila is known to affect gut hormone-releasing L cells, evidence of the bioactive molecule of A. muciniphila involved in GLP-1 secretion is lacking.
Thus A. muciniphila correlates with metabolic diseases and has had reported beneficial effects on host metabolism, but the molecular mechanisms involved have not been identified.
In their new Nature Microbiology study, the authors showed that A. muciniphila increased thermogenesis and GLP-1 secretion in high-fat-diet (HFD)-induced mice via induction of uncoupling protein 1 (UCP-1) in BAT and systemic GLP-1 secretion.
"Akkermansia administration significantly increased GLP-1 secretion and thermogenesis," Ko told BioWorld Science.
"We believe that GLP-1 induction was achieved via intercellular adhesion molecule 2 (ICAM-2) and calcium signaling, whereas UCP-1 induction is believed to be a response to combined signaling by the newly identified protein P9 and IL-6."
The research team had used rapid protein liquid chromatography (LC) and LC coupled to mass spectrophotometric analysis to identify P9, an 84 kDa protein secreted by A. muciniphila.
Using L cells and HFD-fed mice, the researchers then demonstrated that purified P9 alone was sufficient to induce GLP-1 secretion and BAT thermogenesis.
These are important findings, "as A. muciniphila has been strongly indicated to be beneficial for metabolic diseases," Ko told BioWorld Science.
"Our study has discovered the molecular mechanism whereby A. muciniphila improves the metabolic diseases, and discovered new ICAM-2 receptor, which has never been reported at all as related to metabolic diseases," he said.
Oral administration of P9 per se is sufficient to induce GLP-1 and BAT thermogenesis and strongly suggests there should be a new way to treat metabolic diseases such as obesity, diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
In a ligand-receptor capture analysis, the authors then found that P9 interacts with ICAM-2, whereas IL-6 deficiency was shown to abrogate the effects of P9 in glucose homeostasis and downregulate ICAM-2 expression.
"We believe that this is a novel discovery, especially as the function of ICAM-2 receptor was previously poorly studied, but our data suggest that IL-6 can increase the expression of ICAM-2," Ko said.
Together, these findings show that the interactions between P9 and ICAM-2 potentially could be targeted by therapeutics for metabolic diseases, including obesity and type 2 diabetes.
"We believe that in future we can extrapolate and develop these findings to improve metabolic diseases treatments without significant side effects, with ICAM-2 being a new novel target for treating metabolic diseases," said Ko.
For example "we believe that oral administration of P9 could be a new approach for the treatment of metabolic diseases, while ICAM-2 as a novel target could be expandable to a number of different options including small molecules, biologics etc.," he said.
Meanwhile, "we have achieved protein crystallization of P9, solved its structure and are currently developing novel drug candidates based on structure and different diseases models controlling immunometabolism."