Microbiota Depletion Promotes Human Rotavirus Replication in an Adult Mouse Model

Abstract

Intestinal microbiota-virus-host interaction has emerged as a key factor in mediating enteric virus pathogenicity. With the aim of analyzing whether human gut bacteria improve the inefficient replication of human rotavirus in mice, we performed fecal microbiota transplant (FMT) with healthy infants as donors in antibiotic-treated mice. We showed that a simple antibiotic treatment, irrespective of FMT, resulted in viral shedding for 6 days after challenge with the human rotavirus G1P[8] genotype Wa strain (RVwa). Rotavirus titers in feces were also significantly higher in antibiotic-treated animals with or without FMT but they were decreased in animals subject to self-FMT, where a partial re-establishment of specific bacterial taxons was evidenced. Microbial composition analysis revealed profound changes in the intestinal microbiota of antibiotic-treated animals, whereas some bacterial groups, including members of Lactobacillus, Bilophila, Mucispirillum, and Oscillospira, recovered after self-FMT. In antibiotic-treated and FMT animals where the virus replicated more efficiently, differences were observed in gene expression of immune mediators, such as IL1β and CXCL15, as well as in the fucosyltransferase FUT2, responsible for H-type antigen synthesis in the small intestine. Collectively, our results suggest that antibiotic-induced microbiota depletion eradicates the microbial taxa that restrict human rotavirus infectivity in mice.

The Role of Host Glycobiology and Gut Microbiota in Rotavirus and Norovirus Infection, an Update

“…Thus, bacteria belonging to lactobacilli, Mucispirillum, Oscillospira, and Bilophila genera were negatively linked to RV infection in mice. Faecal material transplantation with infants as donors did not restrict infectivity in this model, suggesting that the microbiota from the donors was not able to control RV infection in this model and that mice autochthonous bacteria were needed for the process [96]. Although differences depending on the host and viral strains cannot be excluded, all these data point to the microbiota as a major factor limiting RV replication.…”

“…Recently, it has been shown that microbiota ablation with antibiotics in mice allows for infection with the human RV strain Wa (G1P [8]), which replicates very inefficiently in animals with normal microbiota [96]. These results are in conflict with earlier experiments which demonstrated that microbiota eradication by antibiotics results in reduced infection of murine RV (EC strain), as shown by lower viral shedding in adult mice and diminished diarrhea incidence in mice pups [84].…”

“…Furthermore, recent experiments with the murine EDIM strain confirmed that antibiotic treatment and the consequent decrease in intestinal bacterial loads or the use of germ-free mice results in increased RV infection [97], which argues against a positive effect of the microbiota in RV infection. In the experiments with the Wa strain, animals with ablated microbiota and subsequent subjection to self-transplantation of intestinal microbiota partially recovered the resistance to infection, which allowed the identification of bacterial taxa that likely participate indirectly or directly in the restriction of Wa infection in mice [96]. Thus, bacteria belonging to lactobacilli, Mucispirillum, Oscillospira, and Bilophila genera were negatively linked to RV infection in mice.…”

“…In this case, IL-22-mediated protection did not involve IFN, because it was also found in mice lacking the transcriptional factor STAT1, which increases the expression of interferon-stimulated genes [97]. Mice treated with antibiotics in which the human RV Wa strain was able to replicate also presented alterations in the expression of genes related to the immune and inflammatory response, such as IL-1β and CXCL15, and the FUT2 enzyme [96], but the relevance of these facts in RV infection has to be evaluated.…”

Therapeutic Approach Targeting Gut Microbiome in Gastrointestinal Infectious Diseases

“…Mechanistically, the interaction between gut microbiota and viruses seems to stabilize enteric viruses, enhance their adhesion to host cells, inhibit antibody production, and create a conducive environment for viral replication and immune evasion [125]. Conversely, several studies found that antibiotic-treated or germ-free animal models have higher rotavirus replication and more severe symptoms, which can be mitigated by FMT [124,126,127]. An elevated abundance of Akkermansia and a reduced abundance of Faecalibacterium were correlated with higher levels of viral antibodies [128].…”