Unraveling the gut-Lung axis: Exploring complex mechanisms in disease interplay

The link between gut and lung starts as early as during organogenesis. Even though they are anatomically distinct, essential bidirectional crosstalk via complex mechanisms supports GLA. Emerging studies have demonstrated the association of gut and lung diseases via multifaceted mechanisms. Advancements in omics and metagenomics technologies revealed a potential link between gut and lung microbiota, adding further complexity to GLA. Despite substantial studies on GLA in various disease models, mechanisms beyond microbial dysbiosis regulating the interplay between gut and lung tissues during disease conditions are not thoroughly reviewed. This review outlines disease specific GLA mechanisms, emphasizing research gaps with a focus on gut-to-lung direction based on current GLA literature. Moreover, the review discusses potential gut microbiota and their products like metabolites, immune modulators, and non-bacterial contributions as a basis for developing treatment strategies for lung diseases. Advanced experimental methods, modern diagnostic tools, and technological advancements are also highlighted as crucial areas for improvement in developing novel therapeutic approaches for GLA-related diseases. In conclusion, this review underscores the importance of exploring additional mechanisms within the GLA to gain a deeper understanding that could aid in preventing and treating a wide spectrum of lung diseases

Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons

Abstract The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. While regulatory T (Treg) and B (Breg) cells, as the main elements of immune homeostasis, contribute to the control of hyperinflammation during COVID-19 infection, we hypothesized change in their levels in relation to disease severity and the presence of autoantibodies (auto-Abs) to type I IFNs. Cytometric analysis of blood of 62 COVID-19 patients with different severities revealed an increased proportion of conventional (cTreg; CD25+FoxP3+) and unconventional (uTreg; CD25-FoxP3+) Tregs, as well as the LAG3+ immune suppressive form of cTreg/uTreg, in the blood of severe COVID-19 cases compared to the milder, non-hospitalized cases. The increase in blood levels of cTreg/uTreg, but not LAG3+ cTreg/uTreg subtypes, was even higher among patients with severe COVID-19 and auto-Abs to type I IFNs. Regarding Bregs, compared to the milder, non-hospitalized cases, the proportion of IL-35+ and IL-10+ Bregs was elevated in the blood of severe COVID-19 patients, and to a higher extent in those with auto-Abs to type I IFNs. Moreover, blood levels of cTreg, LAG3+ cTreg/uTreg, and IL-35+ and IL-10+ Breg subtypes were associated with lower blood levels of proinflammatory cytokines such as IL-6, IL-17, TNFα, and IL-1β. Interestingly, patients who were treated with either tocilizumab and/or a high dose of Vitamin D had higher blood levels of these regulatory cells and better control of the proinflammatory cytokines. These observations suggest that perturbations in the levels of immunomodulatory Tregs and Bregs occur in COVID-19, especially in the presence of auto-Abs to type I IFNs