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

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.

The Microbiome as Part of the Contemporary View of Tuberculosis Disease

“…Influenza, a primary respiratory infection, may cause digestive tract manifestations through hematogenous dissemination of infected lymphocytes from the respiratory tract [ 88 ]; and a decreased Bacteroides/Firmicutes ratio in the GI tract has been observed during RSV respiratory tract infection [ 89 ]. On the other hand, gut dysbiosis has been associated with both decreased levels of butyrate and exacerbated bacterial pneumonia, which supports the critical role of SCFAs in pulmonary host defense [ 90 ] and increases susceptibility to infections [ 91 , 92 ].…”

Piglet cardiopulmonary bypass induces intestinal dysbiosis and barrier dysfunction associated with systemic inflammation

“…For SCFAs, a validated UPLC-MS/MS was also used to evaluate samples ( Samuelson et al, 2022 ). In total, eight SCFAs were quantitated.…”

Divalent Metal Uptake and the Role of ZIP8 in Host Defense Against Pathogens

“…These changes were likewise associated with distinct patterns of mucin production (upregulated in male and down-regulated in female mice), which may explain the observed differential effects on the composition of the intestinal microbiota ( Kable et al, 2020 ). Finally, our group has recently demonstrated that myeloid-specific Zip8KO mice exhibit marked differences in the cecal microbial communities when compared to WT mice ( Samuelson et al, 2022 ). Specifically, we found that the loss of ZIP8 expression in myeloid lineage cells resulted in significant differences in beta-diversity and specific bacterial taxa.…”

“…Precisely, we found that bacteria from the genuses Desulfovibrio and Intestinimonas , as well as the families Clostridiales Family_XIII and Lachnospiraceae, were enriched in WT mice compared to Zip8KO mice. Conversely, bacteria from the genuses Muribaculum , Erysipelatoclostridium , Mucispirillum , Parasutterella , and Prevotellaceae _UCG-001 , as well as from the family Ruminococcaceae were enriched in Zip8KO mice compared to WT mice ( Samuelson et al, 2022 ). 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 ( Samuelson et al, 2022 ), which suggest that impaired Zn uptake not only influences the gastrointestinal microbiota, but that these changes also significantly influence host immune regulation.…”

“…Conversely, bacteria from the genuses Muribaculum , Erysipelatoclostridium , Mucispirillum , Parasutterella , and Prevotellaceae _UCG-001 , as well as from the family Ruminococcaceae were enriched in Zip8KO mice compared to WT mice ( Samuelson et al, 2022 ). 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 ( Samuelson et al, 2022 ), which suggest that impaired Zn uptake not only influences the gastrointestinal microbiota, but that these changes also significantly influence host immune regulation. While most of the literature support the hypothesis that Zn deficiency or impaired Zn uptake alters the microbiome, one study did not observe any substantial alterations to the gut microbiota in mice with dietary Zn deficiency ( Mayneris-Perxachs et al, 2016 ).…”