Akkermansia muciniphila

Akkermansia muciniphila
Scientific classification
Kingdom:
Bacteria
Phylum:
Verrucomicrobia
Class:
Verrucomicrobiae
Order:
Verrucomicrobiales
Family:
Akkermansiaceae
Genus:
Akkermansia
Species:
A. muciniphila
Binomial name
Akkermansia muciniphila
Derrien et al 2004

Akkermansia muciniphila is a species of human intestinal mucin-degrading bacterium, the type species for a new genus, Akkermansia, proposed in 2004 by Muriel Derrien and Willem de Vos.[1][2]: 1474  Extensive research is being undertaken to understand its association with obesity, type 2 diabetes, and inflammation.[3][4][5][6][7]

Biology and Biochemistry

A. muciniphila is a Gram-negative, strictly anaerobic, non-motile, non-spore-forming, oval-shaped bacterium. Its type strain is MucT (=ATCC BAA-835T =CIP 107961T).[2] A. muciniphila is able to use mucin as its sole source of carbon and nitrogen, is culturable under anaerobic conditions on medium containing gastric mucin, and is able to colonize the gastrointestinal tracts of a number of animal species.[2][8]

Recently, A. muciniphila strain Urmite became the first (evidently) unculturable bacterial strain to be sequenced in its entirety entirely from a human stool sample.[9]

Human metabolism

A. muciniphila is believed to have anti-inflammatory effects in humans, and studies have shown inverse relationships between A. muciniphila colonization and inflammatory conditions such as appendicitis or inflammatory bowel disease (IBD). In one study, reduced levels of A. muciniphila correlated with increased severity of appendicitis. In a separate study, IBD patients were found to have lower levels A. muciniphila in their intestinal tract than individuals without IBD.[8]

Researchers have discovered that A. muciniphila could be used to combat obesity and type 2 diabetes.[10] The first study was carried out with mice, overfed to contain three times more fat than their lean cousin. The obese mice were then fed the bacteria, which were shown to reduce the fat burden of the mice by half without any change to the mice's diet. This effect was associated with a restoration of a proper gut barrier function, which means the absence of leakage of inflammatory bacterial compounds in the blood. Interestingly, in the same study, the authors found that if the bacteria was killed by very high temperature (autoclaving), the bacteria was unable to improve the metabolic response.[11] A study published in June 2015 showed an association between A. muciniphila abundance, insulin sensitivity, and healthier metabolic status in overweight/obese adults. The healthier subjects were those with high A. muciniphila abundance and gut microbial richness. In addition, this study showed that having higher abundance of A. muciniphila at baseline was associated with greater clinical benefits after weight loss.[6] The bacterium is naturally present in the human digestive tract at 3-5%, but has been seen to fall with obesity.[12]

In August 2015, additional research demonstrated that dietary fats influence the growth of Akkermansia muciniphilia relative to other bacterium in the dietary tract. Researchers conducted a study in which mice were fed diets which varied in fat composition but were otherwise identical: one group received lard, while the other received fish oil. After 11 weeks, the group receiving a fish oil diet had increased levels of A. muciniphila and bacterium of genus Lactobacillus, while the group receiving a lard diet had decreased levels of A. muciniphila and Lactobacillus. Additionally, fecal material from mice on the fish oil diet or the lard based diet was transplanted into a new group of mice which had their native gut flora eradicated by antibiotics. All of these mice were then fed a lard based diet. Despite receiving the same lard-based diet for 3 weeks, recipients of transplants from lard-fed donor mice showed increased levels of Lactobacillus and increased levels of inflammation, while recipients of transplants from fish oil-fed donors showed increased levels of A. muciniphila and decreased levels of inflammation. Researchers concluded that the increase in A. muciniphila corresponded to a reduction in inflammation, indicating a link between dietary fats, gut flora composition, and inflammation levels.[5] In 2017, it was discovered that pasteurizing (70 °C 30min) the bacteria increased the beneficial effects of the bacteria by a mechanism likely associated with the presence of a protein present on the outer membrane of Akkermansia muciniphila and called Amuc_1100.[13] Then in 2019, the same team of Belgian researchers from the UCLouvain tested for the first time in humans the impact of an oral supplementation with either A. muciniphila alive or pasteurized versus a placebo for 3 months. In this double-blind placebo-controlled proof-of-concept study, they found that the overweight or obese insulin resistant subjects displayed an improved metabolism with lower blood insulin, lower insulin resistance, lower inflammation and better cardiometabolic profile.[14] More recently, they have linked this effect with the possible increased production of some endocannabinoids acting on the receptor PPAR-a.[15]

Effects in cancer immunotherapy treatment

One study looked at 249 patients with lung or kidney cancer, A. muciniphila was in 69% of patients that did respond compared with just a third of those who did not. Boosting levels of A. muciniphila in mice seemed to also boost their response to immunotherapy.[16]

Effects in ALS in a mouse model

Researchers discovered that a mouse model of Amyotrophic lateral sclerosis suffers from an abnormal gut microbiome, and that supplementing these mice with Akkermansia muciniphila improved their symptoms, slowed the progression of their disease, and increased their survival.[17] Moreover, they found that A. muciniphila produce the vitamin nicotinamide, which when injected into the diseased mice improved their motor symptoms, although it did not increase their lifespan as the bacteria had.[17] They also found lower levels of nicotinamide in the circulation and the cerebrospinal fluid (CSF) of a small sample human ALS patients compared to their family members, and lower levels of A. muciniphila in their stool.[17] In addition, ALS patients with lower levels of nicotinamide in their blood tended to have worse symptoms than patients with higher levels.[17]

References

  1. ↑ de Vos, W.M. (2017). "Microbe Profile: Akkermansia muciniphila: a conserved intestinal symbiont that acts as the gatekeeper of our mucosa". Microbiology. 1635 (5): 646–648. doi:10.1099/mic.0.000444. PMID 28530168.
  2. 1 2 3 Derrien, M. (2004). "Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium". International Journal of Systematic and Evolutionary Microbiology. 54 (5): 1469–1476. doi:10.1099/ijs.0.02873-0. PMID 15388697.
  3. ↑ Everard, Amandine; Belzer, Clara; Geurts, Lucie; Ouwerkerk, Janneke P.; Druart, Céline; Bindels, Laure B.; Guiot, Yves; Derrien, Muriel; Muccioli, Giulio G.; Delzenne, Nathalie M.; de Vos, Willem M.; Cani, Patrice D. (28 May 2013). "Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity". Proceedings of the National Academy of Sciences of the United States of America. 110 (22): 9066–9071. Bibcode:2013PNAS..110.9066E. doi:10.1073/pnas.1219451110. PMC 3670398. PMID 23671105.
  4. ↑ "Intestinal bacterium Akkermansia curbs obesity". ScienceDaily. May 15, 2013.
  5. 1 2 Caesar, Robert; Tremaroli, Valentina; Kovatcheva-Datchary, Petia; Cani, Patrice D.; Bäckhed, Fredrik (2015). "Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling". Cell Metabolism. 22 (4): 658–668. doi:10.1016/j.cmet.2015.07.026. PMC 4598654. PMID 26321659. Mice that received microbiota from a lard-fed donor showed increased adiposity and inflammation, together with a significant increase in Lactobacillus, compared to mice that received microbiota from a fish-oil-fed donor. Therefore, these data do not provide evidence for a role of Lactobacillus in reducing inflammation. However, we found that the enrichment of Akkermansia co-occurred with partial protection against adiposity and inflammation in mice transplanted with fish-oil microbiota and fed a lard diet, highlighting Akkermansia as a potential mediator of the improved inflammatory and metabolic phenotype of mice fed fish oil.
  6. 1 2 Dao, Maria Carlota; Everard, Amandine; Aron-Wisnewsky, Judith; Sokolovska, Nataliya; Prifti, Edi; Verger, Eric O; Kayser, Brandon D; Levenez, Florence; Chilloux, Julien; Hoyles, Lesley; Dumas, Marc-Emmanuel; Rizkalla, Salwa W; Doré, Joel; Cani, Patrice D; Clément, Karine; Clément, K (March 2016). "Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology". Gut. 65 (3): 426–436. doi:10.1136/gutjnl-2014-308778. PMID 26100928.
  7. ↑ Derrien, Muriel; Belzer, Clara; de Vos, Willem M. (2016-02-11). "Akkermansia muciniphila and its role in regulating host functions". Microbial Pathogenesis. 106: 171–181. doi:10.1016/j.micpath.2016.02.005. hdl:10138/236401. PMID 26875998.
  8. 1 2 van Passel, Mark W. J.; Kant, Ravi; Zoetendal, Erwin G.; Plugge, Caroline M.; Derrien, Muriel; Malfatti, Stephanie A.; Chain, Patrick S. G.; Woyke, Tanja; Palva, Airi; de Vos, Willem M.; Smidt, Hauke (3 March 2011). "The Genome of Akkermansia muciniphila, a Dedicated Intestinal Mucin Degrader, and Its Use in Exploring Intestinal Metagenomes". PLOS ONE. 6 (3): e16876. Bibcode:2011PLoSO...616876V. doi:10.1371/journal.pone.0016876. PMC 3048395. PMID 21390229.
  9. ↑ Caputo, Aurélia; Dubourg, Grégory; Croce, Olivier; Gupta, Sushim; Robert, Catherine; Papazian, Laurent; Rolain, Jean-Marc; Raoult, Didier (2015). "Whole-genome assembly of Akkermansia muciniphila sequenced directly from human stool". Biology Direct. 10 (1): 5. doi:10.1186/s13062-015-0041-1. PMC 4333879. PMID 25888298.
  10. ↑ Cani, Patrice D.; de Vos, Willem M. (2017). "Next-Generation Beneficial Microbes: The Case of Akkermansia muciniphila". Frontiers in Microbiology. 8: 1765. doi:10.3389/fmicb.2017.01765. ISSN 1664-302X. PMC 5614963. PMID 29018410.
  11. ↑ Everard, Amandine; Belzer, Clara; Geurts, Lucie; Ouwerkerk, Janneke P.; Druart, Céline; Bindels, Laure B.; Guiot, Yves; Derrien, Muriel; Muccioli, Giulio G.; Delzenne, Nathalie M.; Vos, Willem M. de (2013-05-28). "Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity". Proceedings of the National Academy of Sciences. 110 (22): 9066–9071. Bibcode:2013PNAS..110.9066E. doi:10.1073/pnas.1219451110. ISSN 0027-8424. PMC 3670398. PMID 23671105.
  12. ↑ Owens, Brian (13 May 2013). "Gut microbe may fight obesity and diabetes". Nature. doi:10.1038/nature.2013.12975. S2CID 75514381.
  13. ↑ Plovier, Hubert; Everard, Amandine; Druart, Céline; Depommier, Clara; Van Hul, Matthias; Geurts, Lucie; Chilloux, Julien; Ottman, Noora; Duparc, Thibaut; Lichtenstein, Laeticia; Myridakis, Antonis (January 2017). "A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice". Nature Medicine. 23 (1): 107–113. doi:10.1038/nm.4236. hdl:10044/1/42901. ISSN 1546-170X. PMID 27892954. S2CID 205397880.
  14. ↑ Depommier, Clara; Everard, Amandine; Druart, Céline; Plovier, Hubert; Van Hul, Matthias; Vieira-Silva, Sara; Falony, Gwen; Raes, Jeroen; Maiter, Dominique; Delzenne, Nathalie M.; de Barsy, Marie (July 2019). "Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study". Nature Medicine. 25 (7): 1096–1103. doi:10.1038/s41591-019-0495-2. ISSN 1546-170X. PMC 6699990. PMID 31263284.
  15. ↑ Depommier, Clara; Vitale, Rosa Maria; Iannotti, Fabio Arturo; Silvestri, Cristoforo; Flamand, Nicolas; Druart, Céline; Everard, Amandine; Pelicaen, Rudy; Maiter, Dominique; Thissen, Jean-Paul; Loumaye, Audrey (January 2021). "Beneficial Effects of Akkermansia muciniphila Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists". Cells. 10 (1): 185. doi:10.3390/cells10010185. PMC 7832901. PMID 33477821.
  16. ↑ Routy, Bertrand; Le Chatelier, Emmanuelle; Derosa, Lisa; Duong, Connie P. M.; Alou, Maryam Tidjani; Daillère, Romain; Fluckiger, Aurélie; Messaoudene, Meriem; Rauber, Conrad; Roberti, Maria P.; Fidelle, Marine; Flament, Caroline; Poirier-Colame, Vichnou; Opolon, Paule; Klein, Christophe; Iribarren, Kristina; Mondragón, Laura; Jacquelot, Nicolas; Qu, Bo; Ferrere, Gladys; Clémenson, Céline; Mezquita, Laura; Masip, Jordi Remon; Naltet, Charles; Brosseau, Solenn; Kaderbhai, Coureche; Richard, Corentin; Rizvi, Hira; Levenez, Florence; Galleron, Nathalie; Quinquis, Benoit; Pons, Nicolas; Ryffel, Bernhard; Minard-Colin, Véronique; Gonin, Patrick; Soria, Jean-Charles; Deutsch, Eric; Loriot, Yohann; Ghiringhelli, François; Zalcman, Gérard; Goldwasser, François; Escudier, Bernard; Hellmann, Matthew D.; Eggermont, Alexander; Raoult, Didier; Albiges, Laurence; Kroemer, Guido; Zitvogel, Laurence (5 January 2018). "Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors". Science. 359 (6371): 91–97. Bibcode:2018Sci...359...91R. doi:10.1126/science.aan3706. PMID 29097494.
  17. 1 2 3 4 Blacher, Eran; Bashiardes, Stavros; Shapiro, Hagit; Rothschild, Daphna; Mor, Uria; Dori-Bachash, Mally; Kleimeyer, Christian; Moresi, Claudia; Harnik, Yotam; Zur, Maya; Zabari, Michal; Brik, Rotem Ben-Zeev; Kviatcovsky, Denise; Zmora, Niv; Cohen, Yotam; Bar, Noam; Levi, Izhak; Amar, Nira; Mehlman, Tevie; Brandis, Alexander; Biton, Inbal; Kuperman, Yael; Tsoory, Michael; Alfahel, Leenor; Harmelin, Alon; Schwartz, Michal; Israelson, Adrian; Arike, Liisa; Johansson, Malin E. V.; Hansson, Gunnar C.; Gotkine, Marc; Segal, Eran; Elinav, Eran (August 2019). "Potential roles of gut microbiome and metabolites in modulating ALS in mice". Nature. 572 (7770): 474–480. Bibcode:2019Natur.572..474B. doi:10.1038/s41586-019-1443-5. PMID 31330533. S2CID 198172518.

Further reading

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