Microbiota, Immune Subversion, and Chronic Inflammation

Abstract

Several host-adapted pathogens and commensals have evolved mechanisms to evade the host innate immune system inducing a state of low-grade inflammation. Epidemiological studies have also documented the association of a subset of these microorganisms with chronic inflammatory disorders. In this review, we summarize recent studies demonstrating the role of the microbiota in chronic inflammatory diseases and discuss how specific microorganisms subvert or inhibit protective signaling normally induced by toll-like receptors (TLRs). We highlight our work on the oral pathogen Porphyromonas gingivalis and discuss the role of microbial modulation of lipid A structures in evasion of TLR4 signaling and resulting systemic immunopathology associated with atherosclerosis. P. gingivalis intrinsically expresses underacylated lipid A moieties and can modify the phosphorylation of lipid A, leading to altered TLR4 signaling. Using P. gingivalis mutant strains expressing distinct lipid A moieties, we demonstrated that expression of antagonist lipid A was associated with P. gingivalis-mediated systemic inflammation and immunopathology, whereas strains expressing agonist lipid A exhibited modest systemic inflammation. Likewise, mice deficient in TLR4 were more susceptible to vascular inflammation after oral infection with P. gingivalis wild-type strain compared to mice possessing functional TLR4. Collectively, our studies support a role for P. gingivalis-mediated dysregulation of innate and adaptive responses resulting in immunopathology and systemic inflammation. We propose that anti-TLR4 interventions must be designed with caution, given the balance between the protective and destructive roles of TLR signaling in response to microbiota and associated immunopathologies.

Systemic comorbidities associated with rosacea: a multicentric retrospective observational study

“…In the present study, the frequency of obesity was significantly higher in the rosacea group than in the control group, which probably accounts for the significantly higher frequency of metabolic and cardiovascular disorders in the rosacea group. Additionally, oral and gut microbiome dysbiosis are associated with systemic inflammation leading to atherosclerosis . An earlier study in 60 rosacea patients and 50 gender‐ and age‐matched controls observed that coronary artery disease risk factors were significantly more common in the rosacea patients than in the controls .…”

“…19 In the present study, the frequency of obesity was significantly higher in the rosacea group than in the control group, which probably accounts for the significantly higher frequency of metabolic and cardiovascular disorders in the rosacea group. Additionally, oral and gut microbiome dysbiosis are associated with systemic inflammation leading to 20 An earlier study in 60 rosacea patients and 50 gender-and age-matched controls observed that coronary artery disease risk factors were significantly more common in the rosacea patients than in the controls. 21 A nationwide casecontrol study conducted in Taiwan that included 33,553 rosacea patients and 67,106 age-and gender-matched controls noted that dyslipidemia, hypertension, and coronary artery disease were significantly associated with rosacea.…”

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

“…It could be argued that this is more reflective of the exposures of human infants. We have an increasing appreciation for the effects of the microbiome on the ability of the immune system to respond to challenge [40–42]. The microbiome established in newborns is the result of exposure in the birth canal as well as from environmental encounters in the first days of life.…”

Maternal modifiers of the infant gut microbiota: metabolic consequences

“…Strikingly, several of these host-adapted Gram-negative bacteria that express immune-evasive lipid A are associated with increased risk of autoimmune disease (Vatanen et al 2016), type I diabetes, atherosclerosis (Erridge et al 2007b; Slocum et al 2014), and allergic disorders in childhood and adulthood (Grönlund et al 2000; Ogra and Welliver 2008). A role of lipid A variants is to allow a bacterium to evade TLR4 and promote chronic inflammation and these variants appear to act through dysregulation of both innate and adaptive immune responses (Kramer and Genco 2017). …”