Gut microbe emerges as a promising tool in the fight against COVID-19

Can a gut microbe protect your lungs from COVID-19? New research uncovers how Akkermansia muciniphila primes powerful immune responses against the virus.

Study: Akkermansia Muciniphila Primes Lung-Resident Antiviral Immunity via the Gut–Lung Axis During SARS-CoV-2 Infection. Image Credit: TopMicrobialStock / Shutterstock

*Important notice: Preprints with The Lancet / SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Akkermansia muciniphila is a commensal bacterium found in the human gastrointestinal tract. It has demonstrated preclinical efficacy to improve several human diseases, including diabetes and obesity. A recent study, led by researchers at Yonsei University, Korea, revealed a novel role of this bacterium in shaping lung-specific antiviral immunity in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study is currently available as a preprint* via Preprints with The Lancet at the Social Science Research Network (SSRN).

Background

The human gut microbiota plays a crucial role in maintaining intestinal barrier integrity and regulating immune, neurological, and metabolic functions. The gut-lung axis is a bidirectional network that connects the gastrointestinal system with the respiratory system via various signaling pathways, immune cell trafficking, and microbial metabolites. This network has gained significant attention during the coronavirus disease 2019 (COVID-19) pandemic as a major determinant of disease severity and outcomes.

SARS-CoV-2, the causative pathogen of the COVID-19 pandemic, is known to negatively impact the composition and diversity of the gut microbiota, leading to disruptions in intestinal barrier integrity, alterations in gut-derived metabolites, the translocation of microbial organisms into the bloodstream, and hyperactivation of immune and inflammatory responses. These are major hallmarks of severe COVID-19.

Therapeutic strategies targeting the gut microbiota, such as short-chain fatty acid (SCFA) supplementation, probiotics, and fecal microbiota transplantation, have shown promising outcomes in restoring microbial homeostasis and modulating immune responses in various infectious diseases.

Considering potential therapeutic implications of gut microbiota, the current study was designed to investigate the effects of SARS-CoV-2 variants on gut microbiota composition and host immune responses. The study also examined the therapeutic potential of the gut microbial community, with a specific focus on Akkermansia muciniphila. This bacterium degrades mucin and is often enriched in patients with COVID-19.

The study

The study was conducted on K18-hACE2 transgenic mice (overexpressing human ACE2 under a cytokeratin promoter), which develop neuroinvasion and lethal pathology not fully representative of human COVID-19. The mice were infected with either the original Wuhan strain or the omicron variant of SARS-CoV-2, and fecal samples were collected at multiple time points to examine the dynamics of gut microbiota.

The immunomodulatory role of Akkermansia muciniphila in SARS-CoV-2 infection was assessed in antibiotic-pretreated mice (creating a pseudo-germ-free model), which was generated by pretreating the mice with broad-spectrum antibiotics before administering the bacterium. The antibiotic pretreatment resulted in depletion of the gut microbiota.

Importantly, Akkermansia muciniphila was administered prophylactically (before infection). The prophylactic efficacy of Akkermansia muciniphila was determined by monitoring weight loss, lung pathology, immune cell phenotypes, and cytokine profiles.

Key findings

The study findings revealed that the ancestral Wuhan strain and the omicron variant of SARS-CoV-2 have significantly distinct effects on gut microbiota dynamics, with the Wuhan strain inducing more pronounced and persistent dysbiosis and increasing the abundance of Akkermansia muciniphila, whereas Omicron caused only transient changes. The Wuhan infection was also associated with specific upregulation of lipid metabolism-related pathways (carotenoid/steroid biosynthesis).

A strong positive association was observed between Akkermansia muciniphila abundance and SARS-CoV-2 infection-related consequences, including weight loss and reduced body temperature, in the study. Given these findings, gut microbiota profiling of five independent COVID-19 patient cohorts was carried out in the study.

The findings revealed that patients with mild COVID-19 have a significantly higher abundance of Akkermansia muciniphila than those with moderate-to-severe COVID-19, though with notable inter-individual variability in severe cases. This suggests that the expansion of Akkermansia muciniphila in response to SARS-CoV-2 infection may represent a host-compensatory response, highlighting a novel role of this bacterium as a promising prophylactic candidate.

Prophylactic efficacy of Akkermansia muciniphila

The analysis of immune response in antibiotic-pretreated mice treated with Akkermansia muciniphila revealed significantly enhanced lung-specific antiviral immune responses, characterized by expansion and activation of tissue-resident memory T cells, increased cytokine production, enhanced polyfunctional T cell responses (IFN-γ/TNF-α), and formation of inducible bronchus-associated lymphoid tissue, which is a type of organized lymphoid tissue that triggers immune responses in the lungs and helps clear infection.

Mechanistically, this involved A. muciniphila‘s microbial antigens (Amuc_1434/1100) suppressing PD-L1, phospholipids activating the TLR2-TLR1 signaling pathway, and metabolites modulating the AhR pathways. The Akkermansia muciniphila treatment also conferred significant protection against SARS-CoV-2 infection, mitigating weight loss and improving lung histopathology.

Study significance

The study highlights the role of Akkermansia muciniphila as a potent biomarker of SARS-CoV-2-induced gut microbiota alteration as well as a promising biotherapeutic candidate for COVID-19.

According to the study findings, Akkermansia muciniphila can substantially increase lung-specific antiviral immunity by modulating the gut-lung axis. Specifically, the findings suggest that Akkermansia muciniphila primes distal mucosal immunity via a coordinated network of microbial antigens, lipids, enzymes, and metabolites, in addition to colonize in the gut.

Akkermansia muciniphila, as a bacterium that degrades mucin, is known to exacerbate intestinal inflammation by disrupting the mucus barrier. However, it has also been documented that the bacterium plays a crucial role in promoting the production of certain cytokines that are essential for mucosal tissue repair and immune regulation. The current study findings support these beneficial impacts of Akkermansia muciniphila and endorse its utility as a novel microbiota-targeted prophylactic intervention against SARS-CoV-2 and other respiratory infections.

The study used K18-hACE2 transgenic mice for experimental purposes. These mice exhibit neurotropism and lethality patterns differing from human cases, limiting clinical extrapolation. Furthermore, the study used antibiotic-treated mice as a pseudo-germ-free model (lacking true germ-free immunological naivety), which can potentially affect the colonization efficiency and immunomodulatory functions of Akkermansia muciniphila. Future studies should consider these factors while investigating the immunomodulatory mechanisms of this bacterium and should evaluate therapeutic (post-infection) administration.

*Important notice: Preprints with The Lancet / SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.