COVID-19 disease severity is linked to host immunity as well as lung and gut dysbiosis: a narrative review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a high pathogenesis and coronavirus disease 2019 (COVID-19) has a high mortality rate of 12–45% among cases with pneumonia requiring intensive care unit admission. Radiological findings of COVID-19 pneumonia can differ with differing host immunity, even though it is the same disease caused by the same pathogen. There are several theories that COVID-19 patients show different radiological patterns and outcomes by age. Not only viral pathogenesis but also dysfunction of monocytes with aging as well as lung and gut dysbiosis could contribute to the high mortality rate in elderly patients.

Monocytes play an essential role in the more severe COVID-19 disease that occurs in the elderly. Aging has been reported to be characterised by substantial dysregulation of various cellular functions in monocytes and macrophages. Monocytes isolated from the elderly show increased basal cytokine production compared with monocytes from younger people [1]. In addition, monocytes in the elderly also exhibit impaired phagocytosis and decreased expression of the human leukocyte antigen-DR isotype (HLA-DR). Downregulation of HLA-DR in monocytes and other antigen-presenting cells can suppress the transition to an adaptive immune response during acute infection and thus exacerbate the disease. In fact, in an observational study of 54 individuals with COVID-19, Giamarellos-Bourboulis et al. found evidence of severe immune dysregulation caused by monocyte dysfunction in all patients [2]. We speculate that monocyte dysfunction may contribute to the severity of more disorders of COVID-19 in the elderly.

The severity of COVID-19 disease is strongly correlated with gut and lung dysbiosis. The gut microbiome of COVID-19 patients has a significant reduction in bacterial diversity, a significantly higher relative abundance of opportunistic pathogens such as Streptococcus, Rothia, Veillonella and Actinomyces, and a lower abundance of bacteria that are beneficial symbionts compared with controls. Moreover, it has been reported that the disease severity of COVID-19 is correlated with a predominance of opportunistic pathogens and inversely with beneficial commensals.

There are several reports regarding the correlation between dysbiosis of the lung microbiome and COVID-19. Gaibani et al. performed a study comparing the lung microbiome between COVID-19 patients who were critically ill and COVID-19-negative patients with pneumonia using bronchoalveolar lavage samples. COVID-19 patients had a lower microbial diversity with a significantly higher relative abundance of Pseudomonas spp. compared with COVID-19-negative pneumonia patients. In contrast, the lung microbiome in COVID-19-negative pneumonia patients was mainly characterised by the enrichment of Haemophilus influenzae, Veillonella dispar, Granulicatella spp., Porphyromonas spp. and Streptococcus spp. [3]. Several studies have already reported that respiratory virus infections can alter the lung microbial composition and total bacterial load. Commensal bacteria mainly characterise the microbial composition in healthy persons (Prevotella spp., Veillonella spp., Streptococcus spp. and Tropheryma whipplei), which are involved in the maintenance of host immune homeostasis. Thus, it is reasonable that viral infection-induced alteration of the microbial composition and total bacterial load can contribute to disease severity in patients with respiratory viral infections.

Recent studies have shown that the gut microbiome composition differs significantly in patients with COVID-19 compared with non-COVID-19 individuals [4]. Moreover, plasma concentrations of inflammatory cytokines, chemokines and tissue damage markers are correlated with the gut microbiota composition. Yeoh et al. also assessed which species specifically were enriched or depleted in COVID-19 patients correlating with concentrations of inflammatory markers. The results showed that Bifidobacterium adolescentis, Eubacterium rectale and Faecalibacterium prausnitzii, with know immunomodulatory roles in the human gastrointestinal system, are negatively correlated with concentrations of inflammatory markers among patients. Conversely, Bacteroides dorei and Akkermansia muciniphila were positively correlated with interleukin 1-beta (IL-1β), interleukin 6 (IL-6) and C-X-C motif ligand 8 (CXCL8) [4].

The lung microbiome has several roles in viral immunity. First, microbiota dwelling on the respiratory surface can act as a barrier, therefore preventing viral attachment to host cells. Second, it primes lung immunity, which will fight against viral infection, and exposure to a diverse range of microbiota may build a wider immunity. Focusing on alteration of the microbiota, a reduction in faecal bifidobacteria has often been noted for age-related gut dysbiosis. Besides, a reduction in butyrate-producing organisms from the Clostridium cluster XIVa as well as anti-inflammatory organisms such as Faecalibacterium prausnitzii and Akkermansia muciniphila have been reported [5]. In summary, lung and gut dysbiosis affect the disease severity of COVID-19 and its prognosis. The lung and gut microbiome may soon be a potential therapeutic target for COVID-19.

In conclusion, viral immunity affected by lung and gut dysbiosis and age-associated monocyte dysfunction could affect disease severity in humans. We hypothesise that radiological findings and prognosis of COVID-19 differ by age group.