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 obese5,6 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) patients9,10 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

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