Akkermansia muciniphila and influenza virus

In the last decade, Akkermansia muciniphila has emerged as a next-generation beneficial microorganism in a wide reach of health conditions. Now, new research advances a role for this relatively recently discovered microbe in combatting an influenza virus, a cause of infections and deaths worldwide.

Akkermansia muciniphila, in brief

Widely distributed in human intestines, but also detected in the respiratory tract, application of specific strains of A. muciniphila in mice models has shown benefit in a range of diseases and disorders:

• Inflammatory bowel disease
• Atherosclerosis
• Liver inflammation
• Metabolic diseases

Studies in humans are beginning. A proof-of-concept study conducted in 2020 showed that supplementation with live and pasteurized forms of A. muciniphila in overweight and obese human volunteers was safe and well tolerated; several metabolic parameters were also improved.

A. muciniphila and influenza viruses

As is true with other viruses, influenza infection can alter the structure of the gut microbiota (based on research in animal models). For example, influenza A viruses have been shown to provoke the quantitative depletion of the small intestinal microbiota and may exacerbate secondary Salmonella infection.

Conversely, changes in the gut microbiota can also visibly affect the outcome of influenza A infection. In addition, oral probiotics have significantly improved influenza symptoms by regulating the  immune response.

And though there are links between A. muciniphila and influenza virus infections — specifically emerging viruses such as H7N9 (a novel avian-origin influenza A) — the relationship is complicated.

Indeed, abundances of several gut microbes were significantly altered following H7N9 infection. 

Researchers recently observed that A. muciniphila was up-regulated more significantly in the mice that died of H7N9 influenza virus infection suggesting that A. muciniphila is related to H7N9 pathogenicity. This seemingly adverse finding clashed with the characterization of A. muciniphila as a probiotic organism with great potential as described above.

A follow-up study further evaluated the effects of oral administration of A. muciniphila on the pathogenicity of the H7N9 influenza virus in mice and analyzed the probable mechanisms underlying these effects. Here’s what was found:

• H7N9 influenza virus infection significantly altered the composition of gut microbiota in mice.
• The H7N9 infection group was enriched in A. muciniphila.  
• Oral administration of A. muciniphila improved clinical symptoms of H7N9 infection. A. muciniphila increased the survival rate of mice and alleviated mouse weight loss; moreover, pasteurized A. muciniphila displayed better protective effects against H7N9 infection than viable A. muciniphila. Details here. 
• Oral administration of A. muciniphila significantly improved the immune responses in H7N9-infected mouse lungs. These results indicated that A. muciniphila can improve the innate immune response to H7N9 infection, such as the anti-viral interferon-g production, suggesting that the anti-influenza role of A. muciniphila may depend on its anti-inflammatory and immunoregulatory capacity.
• Oral administration of pasteurized A. muciniphila suppressed the proliferation of H7N9 virus in vivo and improved lung pathology.A. muciniphila is known to induce intestinal adaptive immune responses. In this mouse study, the lungs of the control group showed more severe inflammatory cell infiltration, alveolar atrophy, and fibrosis than either the A. muciniphila or the pasteurized A. muciniphila groups.
• Oral administration of pasteurized A. muciniphila improved immune responses in H7N9-infected lungs. Results showed some enhanced effect of pasteurized A. muciniphila leading the researchers to speculate that the anti-influenza role of A. muciniphila mainly depends on its anti-inflammatory and immunoregulatory capacities.

Thus — surprisingly — this study confirmed that A. muciniphila does not aggravate but instead reduces the severity of H7N9 infection.

Pasteurization

Notably, pasteurization of A. muciniphila enhanced the capacity of the organism to reduce the severity of influenza infection.

The reason for this interesting phenomenon — also observed in several other diseases — remains elusive. However, the change of certain cytokines in pasteurized A. muciniphila group (such as IL-6, TNF-α, and IFN-β) was more significant. It was suggested that the beneficial effects of A. muciniphila could be due to some of its components but not to its proliferation in the gut.

Benefits of pasteurization also extend to advantages in the manufacturing and storage for supplementation as parabiotics (i.e. non-viable ‘probiotics’).

The authors cautioned that their study only demonstrates the anti-influenza effects of A. muciniphila in mice. And as always, results are strain-specific. Nevertheless, A. muciniphila may improve host defense against the influenza virus, most likely due to its anti-inflammatory and immunoregulatory properties.

Takeaway

“The current study not only enriches our understanding of the interactions between influenza virus infection and the gut microbiota, but also identified a novel anti-influenza microbe, thereby laying the foundation for the development of anti-influenza probiotics. For example, it can be used as a preventive agent before infection or can be used continuously after infection to reduce inflammatory storms during the influenza season.”

Key references

Ansaldo, Eduard et al. “Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis.” Science (New York, N.Y.) vol. 364,6446 (2019): 1179-1184. doi:10.1126/science.aaw7479

Depommier, Clara et al. “Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.” Nature medicine vol. 25,7 (2019): 1096-1103. doi:10.1038/s41591-019-0495-2

 Hu, Xiaotong et al. “Akkermansia muciniphila Improves Host Defense Against Influenza Virus Infection.” Frontiers in microbiology vol. 11 586476. 2 Feb. 2021, doi:10.3389/fmicb.2020.586476 Plovier, Hubert et al. “A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.” Nature medicine vol. 23,1 (2017): 107-113. doi:10.