Correction: New insights into intestinal phages.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

New insights into intestinal phages.

The intestinal microbiota plays important roles in human health. This last decade, the viral fraction of the intestinal microbiota, composed essentially of phages that infect bacteria, received increasing attention. Numerous novel phage families have been discovered in parallel with the development of viral metagenomics. However, since the discovery of intestinal phages by d'Hérelle in 1917, our understanding of the impact of phages on gut microbiota structure remains scarce. Changes in viral community composition have been observed in several diseases. However, whether these changes reflect a direct involvement of phages in diseases etiology or simply result from modifications in bacterial composition is currently unknown. Here we present an overview of the current knowledge in intestinal phages, their identity, lifestyles, and their possible effects on the gut microbiota. We also gather the main data on phage interactions with the immune system, with a particular emphasis on recent findings.

IL-17A-mediated neutrophil recruitment limits expansion of segmented filamentous bacteria.

Specific components of the intestinal microbiota are capable of influencing immune responses such that a mutualistic relationship is established. In mice, colonization with segmented filamentous bacteria (SFB) induces T-helper-17 (Th17) cell differentiation in the intestine, yet the effector functions of interleukin (IL)-17A in response to SFB remain incompletely understood. Here we report that colonization of mice with SFB-containing microbiota induced IL-17A- and CXCR2-dependent recruitment of neutrophils to the ileum. This response required adaptive immunity, as Rag-deficient mice colonized with SFB-containing microbiota failed to induce IL-17A, CXCL1 and CXCL2, and displayed defective neutrophil recruitment to the ileum. Interestingly, neutrophil depletion in wild-type mice resulted in significantly augmented Th17 responses and SFB expansion, which correlated with impaired expression of IL-22 and antimicrobial peptides. These data provide novel insight into a dynamic IL-17A-CXCR2-neutrophil axis during acute SFB colonization and demonstrate a central role for neutrophils in limiting SFB expansion.

Oral tolerance to ovalbumin in mice: induction and long-term persistence unaffected by Staphylococcus aureus enterotoxin B and Clostridium perfringens type A enterotoxin.

Oral administration of dietary antigen (Ag) results in the systemic Ag-specific immunologic unresponsiveness termed oral tolerance. Its induction is of importance in the young where numerous symptoms are associated with IgE-mediated food-hypersensitivity reactions. Two related enterotoxins, cholera toxin and Escherichia coli heat-labile enterotoxin, have been shown to abrogate oral tolerance (i.e. IgG and IgE antibody (Ab) unresponsiveness) to an unrelated and simultaneously fed Ag. However, a critical role has been suggested for the gut flora in recovery of a hyporesponsive state. The purpose of the present study was to investigate whether the Staphylococcus aureus enterotoxin B (SEB) and Clostridium perfringens type A enterotoxin (CPE), involved in many diarrheas, could affect the induction and long-term persistence of oral tolerance to ovalbumin (OVA). Using conventional and germ-free mice fed once or twice with enterotoxin plus OVA, we investigated the possible role of the indigenous gut flora. In addition, we tested the influence of CPE synthesized in vivo in the digestive tract of gnotobiotic mice on the induction of OVA-specific oral tolerance. Mice were immunized intraperitoneally with OVA twice, and IgG and IgE Ab levels were measured by ELISA. Neither SEB nor CPE, orally given or synthesized in vivo (CPE), prevented the induction of oral tolerance to OVA. Moreover, the IgG Ab unresponsiveness persisted over 2 mo in the conventional mice fed with toxin plus OVA as also observed in the OVA controls. The results indicate that, independent of the gut flora's influence, SEB and CPE did not affect the induction nad long-term persistence of oral tolerance to co-ingested Ag.

Gut flora allows recovery of oral tolerance to ovalbumin in mice after transient breakdown mediated by cholera toxin or Escherichia coli heat-labile enterotoxin.

Oral tolerance, the antigen-specific immunologic unresponsiveness after antigen (Ag) feeding, is of physiologic importance in preventing antibody (Ab) responses to dietary proteins. This is important in the young, especially at weaning when numerous dietary Ag are encountered for the first time. Two related enterotoxins responsible for much diarrhea in the infant, cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT), have been shown to abrogate oral tolerance to an unrelated Ag fed simultaneously. The main objective of this study was to determine whether the gut flora can play a role in the CT- or LT-mediated abrogation of oral tolerance to the dietary protein ovalbumin (OVA), on a short-term and long-term basis. Conventional and germ-free mice were fed once or twice with toxin plus OVA. After two intraperitoneal immunizations with OVA, anti-OVA IgG and IgE Ab levels were measured. Because IgG and IgE Ab responses were detected, both CT and LT abrogated oral tolerance to OVA in conventional and germ-free mice. As time progressed (observations over 3 mo), whereas the specific IgG Ab response in the germ-free mice remained similar to that of the bicarbonate-fed controls, a hyporesponsive state was observed in conventional mice. The results showed that, although the gut flora did not prevent the CT- and LT-mediated abrogation of oral tolerance, it did shorten the effect and allow oral tolerance to be recovered.

The absence of gut flora, the doses of antigen ingested and aging affect the long-term peripheral tolerance induced by ovalbumin feeding in mice.

Several factors have been shown to affect the induction of peripheral tolerance induced by the oral route, also called oral tolerance. In the present study, we explored factors that shorten the duration of the IgG and IgE antibody unresponsiveness induced after ingestion of ovalbumin (OVA). Accordingly, we explored the effects of aging, the absence of gut flora, and ingestion of either one dose of 20 mg OVA or 5 doses of 1 mg OVA in young adult conventional (CV) mice and germ-free (GF) mice, and older CV mice. In young CV mice fed 20 mg OVA, IgG and IgE antibody unresponsiveness were still observed 2 to 3 months after feeding. In CV mice, neither aging nor 5 low doses of OVA prevented the induction of IgG and IgE antibody unresponsiveness but they reduced its duration. In young GF mice given 20 mg OVA, IgG antibody unresponsiveness only lasted between 7 and 21 days after feeding, but IgE antibody unresponsiveness lasted much longer. We believe these findings should be taken into account in the treatment of autoimmune and allergic diseases, for cases requiring conditions of antigen ingestion suitable for lasting suppression of peripheral antibody responses. The animal models used here might be of interest for better understanding of the mechanisms involved in the long-term persistence of oral tolerance.