ZIP8-Mediated Intestinal Dysbiosis Impairs Pulmonary Host Defense against Bacterial Pneumonia.

Derrick R Samuelson,Sannette C Hall,Todd A Wyatt,Daryl J Murry,Yashpal S Chhonker,Kelly C Cunningham,Deandra R Smith,Daren L Knoell

doi:10.3390/ijms23031022

Abstract

Pneumococcal pneumonia is a leading cause of morbidity and mortality worldwide. An increased susceptibility is due, in part, to compromised immune function. Zinc is required for proper immune function, and an insufficient dietary intake increases the risk of pneumonia. Our group was the first to reveal that the Zn transporter, ZIP8, is required for host defense. Furthermore, the gut microbiota that is essential for lung immunity is adversely impacted by a commonly occurring defective ZIP8 allele in humans. Taken together, we hypothesized that loss of the ZIP8 function would lead to intestinal dysbiosis and impaired host defense against pneumonia. To test this, we utilized a novel myeloid-specific Zip8KO mouse model in our studies. The comparison of the cecal microbial composition of wild-type and Zip8KO mice revealed significant differences in microbial community structure. Most strikingly, upon a S. pneumoniae lung infection, mice recolonized with Zip8KO-derived microbiota exhibited an increase in weight loss, bacterial dissemination, and lung inflammation compared to mice recolonized with WT microbiota. For the first time, we reveal the critical role of myeloid-specific ZIP8 on the maintenance of the gut microbiome structure, and that loss of ZIP8 leads to intestinal dysbiosis and impaired host defense in the lung. Given the high incidence of dietary Zn deficiency and the ZIP8 variant allele in the human population, additional investigation is warranted to improve surveillance and treatment strategies.

Highlights

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide
The beta (β)-diversity between WT and ZIP8 knockout (Zip8KO) mice was affected by the loss of ZIP8 expression, as determined by a distance-based redundancy analysis on the sample-wise Bray–Curtis dissimilarity distances using phyloseq and vegan
We found that bacteria from the genuses Desulfovibrio (ASV16) and Intestinimonas (ASV65), as well as the families Clostridiales Family_XIII (AVS140) and Lachnospiraceae (ASV30), were enriched in WT mice compared to Zip8KO mice (Figure 1B)

Summary

Introduction

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Streptococcus pneumoniae (pneumococcus) remains the most commonly identified cause of CAP in the US [1–4]. The incidence of CAP continues to rise, contributing to increased hospitalizations and mortality [5,6]. A major cause of CAP is compromised immune function [7]. Zinc (Zn) is required for proper immune function [8–10], and an insufficient dietary intake is highly prevalent within vulnerable populations [11,12]. Zndeficient subjects are more susceptible to bacterial and viral pathogens [13] and have a higher incidence of pneumonia [14–16] while Zn supplementation can reduce the incidence of pneumonia [17–19]

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Discussion

Conclusion