Immune Health and Metabolism Mediated by Gut Microbe Akkermansia muciniphila

by Noelle Patno, PhD

Introduction

Recent findings show that not only respiratory disease but also hypertension and diabetes are prevalent comorbidities associated with COVID-19 infection.¹ In fact, multiple meta-analyses indicate that individuals with high blood pressure, diabetes, or cardiovascular diseases have a higher risk for the COVID-19 disease.^2–4 Metabolic disease and the immune response to infections are closely tied together in the gut, from which digestion and defense originate, as the oral route into the intestine is one major way that the body encounters food and foreign substances through the intestine. Key microbial species in the intestinal microbiome have been associated with both metabolic disorders and immunological responses.

One key popular species, Akkermansia muciniphila, has been observed at higher levels in the intestinal microbiome to be associated with better metabolic health as well as being related to inflammatory and immune mechanisms for overall immune health. The species is reduced in microbiomes of the obese^5,6 and those with glucose regulation impairment,⁷ type 2 diabetes,^5,6 as well as high blood pressure.⁸ In addition, A. muciniphila levels are significantly lower in samples from inflammatory bowel disease (IBD) patients^9,10 and are protective in preclinical models against progression of colitis,¹¹ including the promotion of wound healing in the intestinal mucosa,¹² which is needed to heal ulcerated tissue in IBD. Thus, A. muciniphila may be a key species for microbiome therapy to support intestinal metabolic and immune responses.

What does research suggest?

Research suggests that A. muciniphila participates in mechanisms that improve immune response related to metabolism. Higher endotoxin levels and the serum inflammatory marker high-sensitivity C-reactive protein (hs-CRP) are associated with significantly lower levels of A. muciniphila in nonalcoholic steatohepatitis patients.¹³ Animal models have shown how A. muciniphila affects glucose metabolism through underlying inflammatory response modulation, specifically, the immune system cytokine interferon gamma (IFN-y).¹⁴ Recently, A. muciniphila has been shown to induce the intestinal immune response specifically through T cell responses in mice.¹⁵ Glucose metabolism and inflammation become dysregulated during cancer as well, another situation in which A. muciniphila levels are relevant. Specifically, A. muciniphila increases the response against tumor growth during anti-PD-1 immunotherapy in cancer patients.¹⁶ Multiple studies now have shown that higher A. muciniphila is associated with beneficial response during cancer treatment.¹⁷

In an in vitro study with peripheral blood mononuclear cells (PBMCs), components from A. muciniphila modulated the cytokine response,¹⁸ suggesting that it could balance the gut ecosystem, which may be involved in how the host would respond to cytokine storm, an uncontrolled release of proinflammatory cytokines.¹⁹ Compared to other bacteria in the study, A. muciniphila’s induction was shown to be lower in inflammatory potential compared to other studied microbes.¹⁸ Many other in vitro and preclinical studies have demonstrated that the bacteria also induces anti- or proinflammatory responses depending on the context of the situation, and overall, A. muciniphila shows a protective role in intestinal immunity.²⁰ One key preclinical study²¹ suggested that a certain threshold of A. muciniphila was likely protective for these intestinal barrier effects to support intestinal immune responses.

To therapeutically increase A. muciniphila in the intestine, dietary modifications have demonstrated some efficacy. A healthy lifestyle approach, including dietary modification and fiber increases, has been beneficial.²² Metformin treatment in diabetes has resulted in an increase in A. muciniphila.^23,24  Multiple supplementary strategies have been explored in preclinical research to increase A. muciniphila.²⁰ Use of probiotics to modulate A. muciniphila is an emerging area of research. One clinical trial showed that daily consumption of 10 billion CFU of probiotic Bifidobacterium lactis B420 resulted in higher levels of A. muciniphila in the gut in a large scale, randomized, placebo-controlled trial.²⁵ In that same probiotic supplementation trial, probiotic B420 consumption was associated with a reduction in caloric intake, maintenance of body weight, and a reduction in waist circumference, while the placebo group gained weight during the six-month trial.²⁶ Thus, the B. lactis B420 probiotic supplementation trial associated A. muciniphila increases with beneficial metabolic effects as well.  

Conclusion

Higher levels of A. muciniphila in stool samples are associated with better metabolic profiles as well as underlying immune mechanisms, while lower levels are associated with metabolic diseases and inflammatory bowel diseases. Thus, increasing this beneficial bacteria may be an approach to reduce the risk of negative health outcomes in diabetic, obese, and hypertensive patients who are also more susceptible to immunological insults.

Citations

1. Yang J et al. Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis. International Journal of Infectious Diseases. 2020;94:91-95.
2. Wang B et al. Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis. Aging (Albany NY). 2020;12(7):6049-6057.
3. Emami A et al. Prevalence of underlying diseases in hospitalized patients with COVID-19: a systematic review and meta-analysis. Arch Acad Emerg Med. 2020;8(1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096724/. Accessed April 27, 2020.
4. Li B et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020:1-8.
5. Dao MC et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426-436.
6. Yassour M et al. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med. 2016;8.
7. Zhang X et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One. 2013;8(8):e71108.
8. Sun S et al. Gut microbiota composition and blood pressure. Hypertension. 2019;73(5):998-1006.
9. Png CW et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105(11):2420-2428.
10. Rajilić-Stojanović M et al. Phylogenetic analysis of dysbiosis in ulcerative colitis during remission. Inflamm Bowel Dis. 2013;19(3):481-488.
11. Kang C et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One. 2013;8(10):e76520.
12. Alam A et al. The microenvironment of injured murine gut elicits a local pro-restitutive microbiota. Nat Microbiol. 2016;1:15021.
13. Ozkul C et al. Determination of certain bacterial groups in gut microbiota and endotoxin levels in patients with nonalcoholic steatohepatitis. Turk J Gastroenterol. 2017;28(5):361-369.
14. Greer RL et al. Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism. Nat Commun. 2016;7:13329.
15. Ansaldo E et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science. 2019;364(6446):1179-1184.
16. Routy B et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.
17. Zhang T et al. Akkermansia muciniphila is a promising probiotic. Microb Biotechnol. 2019;12(6):1109-1125.
18. Ottman N et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS One. 2017;12(3):e0173004.
19. Tisoncik JR et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76(1):16-32.
20. Xu Y et al. Function of Akkermansia muciniphila in obesity: Interactions with lipid metabolism, immune response and gut systems. Front Microbiol. 2020;11:219.
21. Schneeberger M et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep. 2015;5:16643.
22. Verhoog S et al. Dietary factors and modulation of bacteria strains of Akkermansia muciniphila and Faecalibacterium prausnitzii: A systematic review. Nutrients. 2019;11(7):1565.
23. de la Cuesta-Zuluaga J et al. Metformin is associated with higher relative abundance of mucin-degrading akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017;40(1):54-62.
24. Lee H et al. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes. 2018;9(2):155-165.
25. Hibberd AA et al. Probiotic or synbiotic alters the gut microbiota and metabolism in a randomised controlled trial of weight management in overweight adults. Benef Microbes. 2019;10(2):121-135.
26. Stenman LK et al. Probiotic with or without fiber controls body fat mass, associated with serum zonulin, in overweight and obese adults—randomized controlled trial. EBioMedicine. 2016;13:190-200.

Noelle Patno, PhD received her PhD in Molecular Metabolism and Nutrition and Masters in Translational Science from the University of Chicago, studying the role of microbial components in intestinal epithelial cell survival related to inflammatory bowel disease. Prior to her graduate studies, Dr. Patno received a chemical engineering degree from Stanford University and worked as an engineer. She has personal experience and interest in preventive nutrition and nutritional therapies for chronic disease, and her current role involves researching and developing probiotics, prebiotics, and other nutritional programs for the promotion of digestive and overall health.