The Complex Interactions Between Rotavirus and the Gut Microbiota

Abstract

Human rotavirus (HRV) is the leading worldwide cause of acute diarrhea-related death in children under the age of five. RV infects the small intestine, an important site of colonization by the microbiota, and studies over the past decade have begun to reveal a complex set of interactions between RV and the gut microbiota. RV infection can temporarily alter the composition of the gut microbiota and probiotic administration alleviates some symptoms of infection in vivo, suggesting reciprocal effects between the virus and the gut microbiota. While development of effective RV vaccines has offered significant protection against RV-associated mortality, vaccine effectiveness in low-income countries has been limited, potentially due to regional differences in the gut microbiota. In this mini review, we briefly detail research findings to date related to HRV vaccine cohorts, studies of natural infection, explorations of RV-microbiota interactions in gnotobiotic pig models, and highlight various in vivo and in vitro models that could be used in future studies to better define how the microbiota may regulate RV infection and host antiviral immune responses.

Keywords: animal models; immunity; in vitro models; microbiota; rotavirus (human and animal); rotavirus vaccine.

Figure 1

Effects of the gut microbiota on rotavirus vaccines (RVV) and rotavirus (RV) infection. (A) Promotion of RVV Responses: Gnotobiotic pig studies have suggested that overall, the gut microbiota and specific probiotics promote RVV efficacy and the development of protective IgA responses, which in turn limit future RV infection. (B) Prevention of RV infection: Clinical trials as well as studies in gnotobiotic pigs and neonatal rats have shown that the commensal microbiota and probiotics may also reduce symptoms of RV infection, partially through development of increased IL-10 levels and anti-RV IgA (1). Murine and gnotobiotic neonatal rat models have shown probiotics may reduce RV infection by inducing mucin secretion (2). Alternately, some studies in mice have shown that bacteria may facilitate RV infection by limiting anti-RV IgA responses and degrading mucins which potentially prevent RV-cell attachment (1, 2). Cytokines type I (IFN-α/β) and III IFNs (IFN-λ) are also antiviral (3), and virome element murine astrovirus (MuAstV) can protect against RV by inducing IFN-λ, thereby upregulating interferon stimulated genes (ISG) (4). Gnotobiotic pig studies have indicated that probiotics can inhibit RV infection and reduce disturbance of the intestinal barrier as observed through increased Villin, Muc2, CgA, and Pcna and decreased Sox9 expression, indicating restoration of differentiated enterocyte, goblet, enteroendocrine and transient amplifying progenitor cell function and decreased proliferation of stem cells, respectively (4). Bacteria can also directly interact with RV particles, which may reduce infection (5). Studies in mice have shown that elements of the gut microbiota including bacterial flagellin can activate IL-18 and IL-22 signaling to protect against RV (6). Segmented filamentous bacteria (SFB) can also prevent RV infection through immune cell-independent mechanisms (7).