Colonization resistance against multi-drug-resistant bacteria: a narrative review.

Colonization resistance by gut microbiota is a fundamental phenomenon in infection prevention and control. Hospitalized patients may be exposed to multi-drug-resistant bacteria when hand hygiene compliance among healthcare workers is not adequate. An additional layer of defence is provided by the healthy gut microbiota, which helps clear the exogenous bacteria and acts as a safety net when hand hygiene procedures are not followed. This narrative review focuses on the role of the gut microbiota in colonization resistance against multi-drug-resistant bacteria, and its implications for infection control. The review discusses the underlying mechanisms of colonization resistance (direct or indirect), the concept of resilience of the gut microbiota, the link between the antimicrobial spectrum and gut dysbiosis, and possible therapeutic strategies. Antimicrobial stewardship is crucial to maximize the effects of colonization resistance. Avoiding unnecessary antimicrobial therapy, shortening the antimicrobial duration as much as possible, and favouring antibiotics with low anti-anaerobe activity may decrease the acquisition and expansion of multi-drug-resistant bacteria. Even after antimicrobial therapy, the resilience of the gut microbiota often occurs spontaneously. Spontaneous resilience explains the existence of a window of opportunity for colonization of multi-drug-resistant bacteria during or just after antimicrobial therapy. Strategies favouring resilience of the gut microbiota, such as high-fibre diets or precision probiotics, should be evaluated.

Boosting the IL-22 response using flagellin prevents bacterial infection in cigarette smoke-exposed mice.

The progression of chronic obstructive pulmonary disease (COPD), a lung inflammatory disease being the fourth cause of death worldwide, is marked by acute exacerbations. These episodes are mainly caused by bacterial infections, frequently due to Streptococcus pneumoniae. This susceptibility to infection involves a defect in interleukin (IL)-22, which plays a pivotal role in mucosal defense mechanism. Administration of flagellin, a Toll-like receptor 5 (TLR-5) agonist, can protect mice and primates against respiratory infections in a non-pathological background. We hypothesized that TLR-5-mediated stimulation of innate immunity might improve the development of bacteria-induced exacerbations in a COPD context. Mice chronically exposed to cigarette smoke (CS), mimicking COPD symptoms, are infected with S. pneumoniae, and treated in a preventive and a delayed manner with flagellin. Both treatments induced a lower bacterial load in the lungs and blood, and strongly reduced the inflammation and lung lesions associated with the infection. This protection implicated an enhanced production of IL-22 and involved the recirculation of soluble factors secreted by spleen cells. This is also associated with higher levels of the S100A8 anti-microbial peptide in the lung. Furthermore, human mononuclear cells from non-smokers were able to respond to recombinant flagellin by increasing IL-22 production while active smoker cells do not, a defect associated with an altered IL-23 production. This study shows that stimulation of innate immunity by a TLR-5 ligand reduces CS-induced susceptibility to bacterial infection in mice, and should be considered in therapeutic strategies against COPD exacerbations.

Interleukin-22 protects against non-typeable Haemophilus influenzae infection: alteration during chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease is a major health problem becoming a leading cause of morbidity and mortality worldwide. A large part of these disorders is associated with acute exacerbations resulting from infection by bacteria, such as non-typeable Haemophilus influenzae (NTHi). Our understanding of the pathogenesis of these exacerbations is still elusive. We demonstrate herein that NTHi infection of mice chronically exposed to cigarette smoke (CS), an experimental model of chronic obstructive pulmonary disease (COPD), not only causes acute pulmonary inflammation but also impairs the production of interleukin (IL)-22, a cytokine with potential anti-bacterial activities. We also report that mice lacking IL-22, as well as mice exposed to CS, have a delayed clearance of NTHi bacteria and display enhanced alveolar wall thickening and airway remodeling compared with controls. Supplementation with IL-22 not only boosted bacterial clearance and the production of anti-microbial peptides but also limited lung damages induced by infection both in IL-22-/- and CS-exposed mice. In vitro exposure to CS extract altered the NTHi-induced IL-22 production by spleen cells. This study shows for the first time that a defect in IL-22 is involved in the acute exacerbation induced by NTHi infection during experimental COPD and opens the way to innovative therapeutic strategies.

Oxidative stress-mediated iNKT-cell activation is involved in COPD pathogenesis.

Chronic obstructive pulmonary disease (COPD) is a major clinical challenge mostly due to cigarette smoke (CS) exposure. Invariant natural killer T (iNKT) cells are potent immunoregulatory cells that have a crucial role in inflammation. In the current study, we investigate the role of iNKT cells in COPD pathogenesis. The frequency of activated NKT cells was found to be increased in peripheral blood of COPD patients relative to controls. In mice chronically exposed to CS, activated iNKT cells accumulated in the lungs and strongly contributed to the pathogenesis. The detrimental role of iNKT cells was confirmed in an acute model of oxidative stress, an effect that depended on interleukin (IL)-17. CS extracts directly activated mouse and human dendritic cells (DC) and airway epithelial cells (AECs) to trigger interferonγ and/or IL-17 production by iNKT cells, an effect ablated by the anti-oxidant N-acetylcystein. In mice, this treatment abrogates iNKT-cell accumulation in the lung and abolished the development of COPD. Together, activation of iNKT cells by oxidative stress in DC and AECs participates in the development of experimental COPD, a finding that might be exploited at a therapeutic level.

Natural killer T cells and the regulation of asthma.

A crucial role has been suggested for invariant natural killer T cells (iNKT) in regulating the development of asthma, a complex and heterogeneous disease characterized by airway inflammation and airway hyperreactivity (AHR). iNKT cells constitute a unique subset of T cells responding to endogenous and exogenous lipid antigens, rapidly secreting a large amount of cytokines, which amplify both innate and adaptive immunity. Herein, we review recent studies showing a requirement for iNKT cells in various models of asthma in mice and monkeys as well as studies in human patients. Surprisingly, in several different murine models of asthma, distinct subsets of iNKT cells were required, suggesting that iNKT cells serve as a common critical pathogenic element for many different forms of asthma. The importance of iNKT cells in both allergic and non-allergic forms of asthma, which are independent of adaptive immunity and associated with airway neutrophils, may explain situations previously found to be incompatible with the Th2 paradigm of asthma.

Upward migration of Vesuvius magma chamber over the past 20,000 years.

Forecasting future eruptions of Vesuvius is an important challenge for volcanologists, as its reawakening could threaten the lives of 700,000 people living near the volcano. Critical to the evaluation of hazards associated with the next eruption is the estimation of the depth of the magma reservoir, one of the main parameters controlling magma properties and eruptive style. Petrological studies have indicated that during past activity, magma chambers were at depths between 3 and 16 km (refs 3-7). Geophysical surveys have imaged some levels of seismic attenuation, the shallowest of which lies at 8-9 km depth, and these have been tentatively interpreted as levels of preferential magma accumulation. By using experimental phase equilibria, carried out on material from four main explosive events at Vesuvius, we show here that the reservoirs that fed the eruptive activity migrated from 7-8 km to 3-4 km depth between the ad 79 (Pompeii) and ad 472 (Pollena) events. If data from the Pomici di Base event 18.5 kyr ago and the 1944 Vesuvius eruption are included, the total upward migration of the reservoir amounts to 9-11 km. The change of preferential magma ponding levels in the upper crust can be attributed to differences in the volatile content and buoyancy of ascending magmas, as well as to changes in local stress field following either caldera formation or volcano spreading. Reservoir migration, and the possible influence on feeding rates, should be integrated into the parameters used for defining expected eruptive scenarios at Vesuvius.

Evidence for mantle metasomatism by hydrous silicic melts derived from subducted oceanic crust.

The low concentrations of niobium, tantalum and titanium observed in island-arc basalts are thought to result from modification of the sub-arc mantle by a metasomatic agent, deficient in these elements, that originates from within the subducted oceanic crust. Whether this agent is an hydrous fluid or a silica-rich melt has been discussed using mainly a trace-element approach and related to variable thermal regimes of subduction zones. Melting of basalt in the absence of fluid both requires high temperatures and yields melt compositions unlike those found in most modern or Mesozoic island arcs. Thus, metasomatism by fluids has been thought to be the most common situation. Here, however, we show that the melting of basalt under both H2O-added and low-temperature conditions can yield extremely alkali-rich silicic liquids, the alkali content of which increases with pressure. These liquids are deficient in titanium and in the elements niobium and tantalum and are virtually identical to glasses preserved in mantle xenoliths found in subduction zones and to veins found in exhumed metamorphic terranes of fossil convergent zones. We also found that the interaction between such liquids and mantle olivine produces modal mineralogies that are identical to those observed in metasomatized Alpine-type peridotites. We therefore suggest that mantle metasomatism by slab-derived melt is a more common process than previously thought.