Akkermansia muciniphila - mucosal-immunology-lab/bacterial-database GitHub Wiki
| Bacterial Information | Value |
|---|---|
| Taxonomy level | Species |
| NCBI Taxonomy ID | 239935 |
| Phylum | Verrucomicrobiota |
| Family | Akkermansiaceae |
| Genus | Akkermansia |
| Gram stain | Gram-negative |
| Oxygen requirements | Strictly anaerobic |
| Spore-forming | No |
| Motile | No |
| Image |  |
Cells are oval-shaped, non-motile, and stain Gram-negative. They are strictly anaerobic and chemo-organotrophic, as well as being mucolytic in pure culture. A recent study has however shown good survival upon exposure to atmospheric oxygen, so it could be classed as aerotolerant (Reunanen 2015).
A. muciniphila possess all characteristics of the genus. The long axis of single cells is 0.6 – 1.0μm depending on growth substrate. Cells occur single, in pairs, in short chains, and in aggregates. Growth occurs at 20 – 40°C (optimum, 37°C) and at pH 5.5 – 8.0 (optimum, 6.5).
They are able to grow on gastric mucin, brain-heart infusion and Columbia media, and on N-acetylglucosamine, N-acetylgalactosamine and glucose when these three sugars are in the presence of (each at 2g/L) peptone, yeast extract, casitone and tryptone. Cellobiose, lactose, galactose, xylose, fucose, rhamnose, maltose, succinate, acetate, fumarate, butyrate, lactate, casitone, Casamino acids, tryptone, peptone, yeast extract, proline, glycine, aspartate, serine, threonine, and glutamate do not support growth. A. muciniphila are also capable of using mucin as a source of carbon, nitrogen, and energy. Mucin fermentation is able to release free sulfate. In mucin media, cells are covered with filaments. Growth occurs without vitamins. Colonies appear white with a diameter of 0.7mm in soft agar mucin medium. It’s DNA G+C content is 47.6 mol%.
In addition to its mucin-degrading activity, A. muciniphila has been shown to have a role in stimulating mucin production (Shin 2014)(Lee 2014).
Akkermania muciniphila is an almost ubiquitously detected member of the mammalian gastrointestinal (GI) tract, and constitutes 1 to 4% of the human faecal microbiota (Collado 2007). It is routinely detected in mouse and rat faeces.
A. muciniphila reduces high-fat diet-induced body weight gain, fat mass gain, and glucose intolerance together with reinforcement of gut barrier function (Everard 2013)(Plovier 2016). Although killing the bacteria by using high pressure and temperature (i.e., autoclaving) completely abolished the effect of the bacteria (Everard 2013), it was found that pasteurising Akkermansia actually enhanced its beneficial effects as compared to the live bacteria (Plovier 2016).
Two proteins have been identified that may contribute to this effect: Amuc_1100 and P9 (Cani 2021):
- Amuc_1100 is a thermostable protein, highly expressed on the outer membrane (Plovier 2016), that activates Toll-like receptor 2 (TLR-2) and replicates most of the beneficial effects of the bacteria (Plovier 2016)(Wang 1988)(Wang 2021), suggesting that even dead, A. muciniphila can still improve host health.
- P9, and 84kDa protein, binds to specific proteins such as ICAM-2 to increase circulating glucagon-like peptide-1 (GLP-1) after glucose challenge (Yoon 2021); GLP-1 activates the GLP-1 receptor on pancreatic beta cells and neurons in the brain to stimulate insulin release, inhibit glucagon release, and subsequently lower blood glucose. In addition, it was found that Akkermansia increases IL-6 expression in the ileum and colon of mice (Yoon 2021). Given that IL-6 dose-dependently increases GLP-1 in vitro, it has been hypothesised that Akkermansia could also act through an IL-6-GLP-1-signaling axis; IL-6 knockout mice failed to respond to P9-induced GLP-1 secretion and a GLP-1 receptor antagonist abolished the effects of P9 on thermogenesis (Yoon 2021).
The combined effect of SCFAs produced by A. muciniphila (via GPR-41/43 on intestinal L cells), Amuc_1100 (via TLR-2 on macrophages/intestinal epithelial cells, and subsequent IL-6 production and stimulation of L cells), and P9 (via ICAM-2 on L cells) is to increase gut barrier immunity and thermogenesis, while decreasing body weight, fat mass, and blood glucose levels (Cani 2021).
Disease severity in adult asthma patients has been negatively correlated with faecal A. muciniphila levels (Michalovich 2019).
Daily oral gavage with A. muciniphila (~1 x 108 cells per dose) reduced airway inflammation in both acute (ovalbumin (OVA) or house dustmite (HDM)) and chronic (HDM for 3 weeks followed by a week of bacterial administration) mouse models of asthma (BALB/c mice; both wild-type and MyD88–/–)(Michalovich 2019).
-
In acute OVA-initiated disease:
- The A. muciniphila-treated group showed marked reduction in BAL eosinophils compared to OVA alone. Ex vivo lung cells also showed reduced IL-4 and IL-5 secretion.
- A. muciniphila treatment also resulted in altered lung tissue lymphocyte profiles: IL-4+ and IFN-γ+ lymphocytes were reduced, while IL-10+Foxp3+ (double-positive) lymphocytes were increased.
- Airway hyper-reactivity in response to methacholine was significantly reduced with A. muciniphila administration.
- Heat killed A. muciniphila or cell free supernatants from A. muciniphila cultures had no effect in the OVA model.
-
In acute HDM-induced disease:
- A. muciniphila treatment significantly reduced BAL inflammatory cell numbers, and was equally effective in both wild-type and MyD88–/– mice.
-
In the chronic HDM model:
- A. muciniphila administration reduced numbers of innate and adaptive immune cells compared to HDM: eosinophils, neutrophils, monocytes, CD8+ cells, NK cells, B cells, CD183+ cells, CD183–CD196– cells, and CD196+ cells.
- Re-challenged animals that received A. muciniphila during the resolution phase displayed reduced eosinophil response.
Of note, A. muciniphila numbers in faeces increased 1,000 – 10,000 times in HDM-exposed mice, but it was not detected in the BAL samples from exposed animals.
Reduction in A. muciniphila levels has been observed in ulcerative colitis (UC) and Crohn's disease (CD), both during clinically-active disease and remission (Png 2010)(Rajilić-Stojanović 2013).
A. muciniphila has the capacity to adhere to Caco2 and HT-20 in vitro and result in strengthening of the intestinal barrier (Reunanen 2015). It was also shown that cell concentrations of A. muciniphila 100-fold higher than Escherichia coli were required to elicit comparable production of IL-8 by enterocytes, highlighting a very low level of proinflammatory activity.
Mice fed a high fat diet (HFD), obese mice, and mice with type 2 diabetes-like symptoms all exhibit lower abundance of A. muciniphila (Kiilerich 2016)(Nobel 2015)(Cox 2014).
Levels of A. muciniphila in mice are inversely associated with inflammatory markers, lipid synthesis, and several plasma markers of insulin resistance, cardiovascular risk, and adiposity (Schneeberger 2015).
It has been observed by qPCR that compared to normal-weight pregnant women, overweight pregnant women have reduced numbers of Bifidobacterium, A. muciniphila, and an increase in Staphylococcus, Enterobacteriaceae, and Escherichia coli (Santacruz 2010).
A. muciniphila has been shown significantly decreased in obese children compared to normal weight children (ages 4-5), coinciding with increased Enterobacteriaceae levels (Karlsson 2012).
Oral gavage with A. muciniphila (~ 2.1 x 108 per 0.2mL dose) for 4 weeks in a HFD mouse model of obesity normalised diet-induced endotoxaemia (serum LPS levels), adiposity, and expression of adipose tissue marker CD11c. It also reduced animal body weight and improved body composition (i.e. fat mass/lean mass ratio) without changse in food intake (Everard 2013).
- In addition, treatment with A. muciniphila completely reversed diet-induced fasting hyperglycaemia via a mechanism that was associated with a 40% reduction in hepatic glucose-6-phosphatase mRNA expression, suggesting a reduction in gluconeogenesis.
- A. muciniphila also increased mRNA expression of markers for adipocyte differentiation and lipid oxidation without affecting those for lipogenesis suggesting a role in control of fat storage, adipose tissue metabolism, and glucose homeostasis.
-
A. muciniphila has been associated with decreased monoacylglycerol lipase expression and increased endocannabinoid (acylglycerols) content in the ileum, which corresponded with improved barrier function and decreased metabolic inflammation (Muccioli 2010). Levels of 2-phosphoglycerol, 2-oxoglutarate, and 2-arachidonoylglycerol were subsequently increased following oral gavage, supporting a link between A. muciniphila administration and intestinal levels of acylglycerols that are involved in glucose and intestinal homeostasis.
- It has been demonstrated previously that pharmacological inhibition of monoacylglycerol lipase reduced metabolic endotoxaemia and systemic inflammation, suggesting a direct link between acylglycerols and gut barrier function (Alhouayek 2011).
- Faecal IgA levels were unaffected by A. muciniphila treatment, suggesting gut barrier function is improved via another mechanism of epithelial signalling.