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Journal Reference : Mart M. Breugem, Raimond B. Ravelli, J. Paul van Schayck, Anna Z. Mykytyn, Hans Q. Kuijpers, Debby Schippers, Willine J. Peters, Bart L. Haagmans, Hans Clevers. Science , ; eabc DOI: ScienceDaily, 4 May Hubrecht Institute.
Retrieved January 13, from www. D The severity of the diarrhea was scored after PR8 infection 0, normal stool or absent; 1, slightly wet and soft stool; 2, wet and unformed stool with moderate perianal staining of the coat; and 3, watery stool with severe perianal staining of the coat. E The pathology of liver and kidney was assayed after PR8 infection. To rule out the possibility that the influenza virus entered the gastrointestinal tract and directly caused immune injury at this site, we tested for the presence of virus within the small intestine after i.
To test this possibility in a more rigorous way, we i. However, pathological injury was not found in any of the examined tissues Fig. These results collectively suggest that influenza infection does not directly cause immune injury in the small intestine. Thus, we unexpectedly observed that influenza infection induced severe immune injury within the intestine only when the virus infected the respiratory tract and immune injury occurred in the lung.
Influenza virus does not infect the small intestine directly. The levels of the influenza virus—derived matrix protein gene in lung and small intestine were detected by PCR. The levels of the influenza virus—derived matrix protein gene in small intestine were detected by PCR after PR8 infection C. The length of colon was recorded after PR8 infection E. NS: not significant. Changes in intestinal microbiota are often involved in the occurrence of intestinal inflammation in many mouse models Lupp et al.
To determine whether intestinal microbiota was involved in influenza—induced intestinal immune injury, we first assayed whether viral infection affected the relative composition of several major bacterial groups within the intestinal microbiota. Although the number of total bacteria remained the same after infection as quantified by both real-time PCR and selective culture Fig. We next administered combinatorial antibiotics to the mice via their drinking water to deplete intestinal microbiota Ichinohe et al.
In antibiotic-treated mice, the lungs still sustained severe immune-mediated injury after PR8 infection, but the small intestine and colon were protected Fig. In another way, transferring intestinal microbiota from PR8-infected mice into healthy WT mice increased the number of Enterobacteriaceae and caused intestinal immune injury in recipient mice even in the absence of viral infection as compared with the intestinal microbiota from saline-treated mice Fig.
Thus, these data suggest that respiratory influenza infection induces intestinal immune injury by altering the composition of intestinal microbiota. Antibiotic treatment reduces influenza-induced intestinal immune injury. A Bacteria in the small intestine were assayed by real-time PCR and selective culture in blood plate 7 d after PR8 infection. The pathology of lung and small intestine was assayed 7 d after PR8 infection C.
The length of colon was recorded 7 d after PR8 infection D. Major bacterial groups in the intestinal microbiota E and the pathology of small intestine were assayed 6 d later F.
G The number of E. The pathology of lung and small intestine H and major bacterial groups in intestinal microbiota I were assayed 6 d after PR8 infection. Escherichia coli is an important component of Enterobacteriaceae , and pathogenic E. The number of E. Treating mice with streptomycin——an antibiotic to which E. Furthermore, directly infecting mice i.
Thus, these data suggest that the increase of E. To explore the mechanism by which intestinal bacteria caused intestinal immune injury during influenza infection, many different types of proinflammatory cells involved in intestinal inflammation Zhou et al.
Depletion of NK1. ILA deficiency reduces influenza-induced immune injury in small intestine but not in lung. A The pathology of lung and small intestine from control and PKtreated mice was assayed 6 d after PR8 infection. The percentage and number of Th17 cells increased in the small intestine and colon after PR8 infection Fig.
Furthermore, treating mice i. Together, these data suggest that influenza infection—induced intestinal immune injury is dependent on Th17 cells.
Increased Th17 cells occur in the small intestine during influenza virus infection. D The number of Th17 cells in liver and kidney was detected 7 d after PR8 infection.
G Transfer of intestinal microbiota from saline-treated or PR8-infected mice into healthy WT mice by the i. Because we observed that influenza—induced intestinal immune injury is dependent on both intestinal microbiota and Th17 cells, we wondered whether there was an association between intestinal bacteria and Th17 cells.
The results showed that the percentage and number of Th17 cells in the small intestine were unchanged in antibiotic-treated mice after PR8 infection as compared with uninfected control mice Fig. Collectively, these data suggest that changes in intestinal microbiota induced by influenza infection promote Th17 cell production, which subsequently causes intestinal immune injury.
Because respiratory influenza infection influences the composition of intestinal microbiota, which subsequently promotes Th17 cell production and causes intestinal immune injury, we wanted to know how respiratory influenza infection destroyed the microecological homeostasis of the intestinal microbiota. The CCL25 chemokine is expressed by intestinal epithelial cells IECs and functions to specifically guide CCR9-expressing effector lymphocytes into the small intestine as a homing mechanism Campbell and Butcher, Consistent with previous observations, CCL25 expression in the small intestine tissue was much higher than any other tissues, including liver, kidney, and lung Fig.
Treating mice i. These results suggest that the CCL25—CCR9 axis contributes to altering the composition of the intestinal microbiota after influenza infection and the subsequent development of intestinal inflammation via recruiting effector lymphocytes into the intestinal mucosa. Anti-CCL25 antibody treatment reduces influenza—induced intestinal immune injury. The number of positive spots was counted 20 h later. K Parabiotic pairs of WT mice were established first, and the left partner was i.
The pathology of small intestine was assayed 6 d after PR8 infection. Next, we explored which lymphocyte subsets were recruited by CCL25 in our influenza model. For the second question, Th17 cells were not found to be increased in lung after PR8 infection Fig.
More convincing evidences showed that E. Thus, these data suggest that Th17 cell polarization, but not recruitment, occurs in the small intestine in situ during influenza infection. Because Th17 cell polarization occurs in the small intestine in situ during influenza infection, we next explore what kind of factors mediated this process. However, treating mice i. Thus, the increase of IL-6 is not the main reason for Th17 cell polarization in our study. IL has been reported to contribute to intestinal inflammation in various mouse models Zhou et al.
In our study, IL expression in the small intestine, but not in serum, was up-regulated after PR8 infection Fig. Transferring intestinal microbiota from PR8-infected mice also increased IL expression in the small intestine of recipient mice Fig.
Next, treating mice with a neutralizing anti—IL antibody during PR8 infection effectively reduced intestinal immune injury Fig. Thus, IL, which was induced by intestinal bacteria, contributes to intestinal immune injury during influenza infection.
However, IL neutralization did not influence the changes of the intestinal microbiota Fig. Intestinal microbiota induces Th17 cell polarization in situ via triggering IL production.
B The pathology of lung and small intestine from control and anti—IL-6—treated mice was assayed 6 d after PR8 infection. C IL expression in the small intestine and serum was detected 6 d after PR8 infection.
D Transfer of intestinal microbiota from saline-treated or PR8-infected mice into healthy WT mice by the i. IL expression in the small intestine was detected 6 d later. Mucosal tissues, including the gastrointestinal, respiratory, and urogenital tracts, etc. Although much has been learned from studying each of these components individually, the mucosal immune system has not yet been examined from a holistic point of view as a system-wide organ Gill et al.
Unexpectedly, we observed that respiratory influenza infection in mice caused immune injury not only in the lung but also specifically in the intestine, as it had no influence on the pathology in nonmucosal organs such as the liver or kidney. Because this resembles the symptoms exhibited by humans after influenza infection, these influenza virus—infected mice provide a good model in which to study the mechanisms underlying how respiratory influenza infection causes intestinal immune injury; furthermore, these observations provide further evidence to support the existence of a common mucosal immune system.
Pathogens extensively disseminate beyond the limits of the primary infection site in almost all cases of infectious diseases, particularly at the early stage of infection. Although some studies suggest that influenza virus disseminates into extrapulmonary tissues or organs during infection Korteweg and Gu, , others contradict this finding Mauad et al. It therefore remains a mystery how influenza infection can be associated with immune injury to extrapulmonary tissues or organs if these injuries are not induced by direct virus infection of these tissues or organs Polakos et al.
In our mouse model of respiratory influenza infection, no influenza virus was detected in the small intestine, and i. Thus, the intestinal immune injury observed in our study was not directly caused by influenza infection of the intestine. An explosive increase in neutrophils is responsible for influenza-induced acute lung injury and death. IL is a potent regulator for the neutrophils recruitment. In our mouse model of respiratory influenza infection, ILA and ILF expressions in lung also increased after infection, but ILA deficiency could not reduce influenza-induced lung injury.
Recruitment and infiltration of inflammatory cells into the gastrointestinal mucosa critically regulates the development as well as progression of IBD Wurbel et al. You may be able to reduce your risk by following these tips:.
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Share on: Facebook Twitter. Show references Alexandraki, I. Acute viral gastroenteritis in adults. Accessed Aug.
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