Probiotics regulating inflammation via NLRP3 inflammasome modulation: A potential therapeutic approach for COVID-19

Inflammasomes are cytoplasmic multiprotein complexes formed by the host’s immune system as a response to microbial infection and cellular damage. Many studies have revealed various regulators of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, while it has been recently shown that NLRP3 is implicated in COVID-19 pathogenesis. At the same time, probiotics counteract the inflammatory process and modulate cytokine release, thus influencing both innate and adaptive immune systems. Herein, we review the immunomodulatory potential of probiotics on the assembly of NLRP3 inflammasome, as well as the pathophysiological mechanisms supporting the use of probiotic bacteria for SARS-CoV-2 infection management, presenting evidence from preclinical studies of the last decade: in vivo, ex vivo, and mixed trials. Data show that probiotics intake is related to NLRP3 inflammasome attenuation and lower levels of inflammation markers, highlighting the beneficial effects of probiotics on inflammatory conditions. Currently, none of the ongoing clinical trials evaluating the effectiveness of probiotics intake in humans with COVID-19 has been completed. However, evidence from preclinical studies indicates that probiotics may block virus invasion and replication through their metabolites, bacteriocins, and their ability to block Angiotensin-Converting Enzyme 2 (ACE2), and by stimulating the immune response through NLRP3 inflammasome regulation. In this review, the beneficial effects of probiotics in the inflammatory process through NLRP3 inflammasome attenuation are presented. Furthermore, probiotics may target SARS-CoV-2 both by blocking virus invasion and replication and by stimulating the immune response through NLRP3 inflammasome regulation. Heterogeneity of the results—due to, among others, different bacterial strains and their metabolites, forms, dosage, and experimental designs—indicates the need for more extensive research. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Dimethyl itaconate induces long-term innate immune responses and confers protection against infection

Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced ex vivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context. Proteomic