NLRP6-associated host microbiota composition impacts in the intestinal barrier to systemic dissemination of Brucella abortus

Abstract

Brucella abortus is a Gram-negative bacterium responsible for a worldwide zoonotic infection—Brucellosis, which has been associated with high morbidity rate in humans and severe economic losses in infected livestock. The natural route of infection is through oral and nasal mucosa but the invasion process through host gut mucosa is yet to be understood. Studies have examined the role of NLRP6 (NOD-like receptor family pyrin domain-containing-6 protein) in gut homeostasis and defense against pathogens. Here, we investigated the impact of gut microbiota and NLRP6 in a murine model of Ba oral infection. Nlrp6-/- and wild-type (WT) mice were infected by oral gavage with Ba and tissues samples were collected at different time points. Our results suggest that Ba oral infection leads to significant alterations in gut microbiota. Moreover, Nlrp6-/- mice were more resistant to infection, with decreased CFU in the liver and reduction in gut permeability when compared to the control group. Fecal microbiota transplantation from WT and Nlrp6-/- into germ-free mice reflected the gut permeability phenotype from the donors. Additionally, depletion of gut microbiota by broad-spectrum-antibiotic treatment prevented Ba replication in WT while favoring bacterial growth in Nlrp6-/-. Finally, we observed higher eosinophils in the gut and leukocytes in the blood of infected Nlrp6-/- compared to WT-infected mice, which might be associated to the Nlrp6-/- resistance phenotype. Altogether, these results indicated that gut microbiota composition is the major factor involved in the initial stages of pathogen host replication and partially also by the resistance phenotype observed in Nlrp6 -/- mice regulating host inflammation against Ba infection.

Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis

“…19 However, it is unclear if the interplay between genetic alterations and gut dysbiosis plays a role in colorectal tumourigenesis. Here, we demonstrated that Sqle transgene expression in mice induces gut dysbiosis, characterised by the enrichment of several pathogenic bacteria including D. fairfieldensis, R. erythropolis, B. abortus and C. muridarum, that are associated with various pathologies [25][26][27] ; while potential protective bacteria with anti-inflammatory and antitumour properties, S. violaceusniger and Pseudomonas sp Leaf58, were depleted. [28][29][30] Transplantation of Sqle tg stool to GF mice significantly promoted the proliferation of the colonic epithelial cells as compared with wild-type mice, implying that Sqle-induced gut dysbiosis plays a casual role in CRC.…”

Fecal and vaginal microbiota of vaccinated and non-vaccinated pregnant elk challenged with Brucella abortus

“…While brucellosis is widely associated with abortion and reproductive problems in large animals, previous work has reported that brucellosis infection induces changes in the gut microbiota of mice ( 31 , 32 ). Therefore, we hypothesized that B. abortus infection might induce changes in the fecal and vaginal microflora of elk; we also hypothesized that these microbial communities might be affected by vaccination of elk with RB51.…”

Molecular Foundations of Inflammatory Diseases: Insights into Inflammation and Inflammasomes

“…Interestingly, investigations involving bone marrow chimeras have revealed that while colitis severity appears to be associated with NLRP6 function in the epithelial cell compartment, higher carcinogenesis in NLRP6-deficient mice has been associated with the hematopoietic cell compartment. Compared to wild-type animals, mice deficient in NLRP6 have a considerably different commensal microbiome composition; therefore, the gut microbiota directly affects the pathophysiology of a disease [58]. The chemokine CCL5, which stimulates inflammation and epithelial cell proliferation through the IL-6 pathway, is expressed by the microbiota and is linked to both colitis and colitis-associated carcinogenesis [59][60][61].…”