Diet composition drives tissue-specific intensity of murine enteric infections.

Diet composition plays a large role in regulating gut health and enteric infection. In particular, synthetic "Western-style" diets may predispose to disease, while whole-grain diets containing high levels of crude fiber are thought to promote gut health. Here, we show that, in contrast to this paradigm, mice fed with unrefined chow are significantly more susceptible to infection with Trichuris muris, a caecum-dwelling nematode, than mice fed with refined, semi-synthetic diets (SSDs). Moreover, mice fed with SSD supplemented with inulin, a fermentable fiber, developed chronic T. muris burdens, whereas mice fed with SSD efficiently cleared the infection. Diet composition significantly impacted infection-induced changes in the host gut microbiome. Mice infected with the bacterium Citrobacter rodentium were also more susceptible to pathogen colonization when fed with either chow or inulin-enriched SSD. However, transcriptomic analysis of tissues from mice fed with either SSD or inulin-enriched SSD revealed that, in contrast to T. muris, increased C. rodentium infection appeared to be independent of the host immune response. Accordingly, exogenous treatment with interleukin (IL)-25 reduced T. muris burdens in inulin-fed mice, whereas IL-22 treatment was unable to restore resistance to C. rodentium colonization. Diet-mediated effects on pathogen burden were more pronounced for large intestine-dwelling pathogens, as effects on small the intestinal helminth (Heligmosomoides polygyrus) were less evident, and protozoan (Giardia muris) infection burdens were equivalent in mice fed with chow, inulin-enriched SSD, or SSD, despite higher cyst excretion in chow-fed mice. Collectively, our results point to a tissue- and pathogen-restricted effect of dietary fiber levels on enteric infection intensity.IMPORTANCEEnteric infections induce dysbiosis and inflammation and are a major public health burden. As the gut environment is strongly shaped by diet, the role of different dietary components in promoting resistance to infection is of interest. While diets rich in fiber or whole grain are normally associated with improved gut health, we show here that these components predispose the host to higher levels of pathogen infection. Thus, our results have significance for interpreting how different dietary interventions may impact on gastrointestinal infections. Moreover, our results may shed light on our understanding of how gut flora and mucosal immune function is influenced by the food that we eat.

Profiling of hepatic transcriptomes reveals modulatory effects of parasitic infection on the metabolic response to dietary polyphenols in pigs.

Polyphenols are a class of bioactive plant compounds with health-promoting properties, however, the interactions between polyphenols and pathogen infection and their cumulative impact on inflammation and metabolic health are not well understood. Here, we investigated if a subclinical parasitic infection modulates the hepatic response to dietary polyphenol supplementation in a porcine model. Pigs were fed a diet with or without 1% grape proanthocyanidins (PAC) for 28 days. During the final 14 days of the experiment, half the pigs in each dietary group were inoculated with the parasitic nematode Ascaris suum. Serum biochemistry was measured and hepatic transcriptional responses were determined by RNA-sequencing coupled with gene-set enrichment analysis. A. suum infection resulted in reduced serum phosphate, potassium, sodium, and calcium, and increased serum iron concentrations. In uninfected pigs, PAC supplementation markedly changed the liver transcriptome including genes related to carbohydrate and lipid metabolism, insulin signaling, and bile acid synthesis. However, during A. suum infection, a separate set of genes were modulated by dietary PAC, indicating that the polyphenol-mediated effects were dependent on infection status. A. suum infection strongly influenced the expression of genes related to cellular metabolism, and, in contrast to the effects of PAC, these changes were mostly identical in both control-fed and PAC-fed pigs. Thus, the hepatic response to infection was mostly unaffected by concurrent polyphenol intake. We conclude that the presence of a commonly occurring parasite substantially influences the outcome of dietary polyphenol supplementation, which may have important relevance for nutritional interventions in populations where intestinal parasitism is widespread.

Garlic-Derived Metabolites Exert Antioxidant Activity, Modulate Gut Microbiota Composition and Limit Citrobacter rodentium Infection in Mice.

The garlic-derived compounds propyl propane thiosulfinate (PTS) and propyl propane thiosulfonate (PTSO) are metabolites with putative health benefits against intestinal inflammation that may be related to their antioxidant activity. However, the underlying mechanisms remain unclear, and whether PTS-PTSO can promote gut health by altering the microbiota and exert protection against enteric pathogens needs further investigation. Here, we explored the antioxidant activity of PTS-PTSO in murine macrophages in vitro, and in an in vivo model of bacterial infection with the bacterial pathogen Citrobacter rodentium. PTS-PTSO attenuated reactive oxygen species in lipopolysaccharide-stimulated macrophages in a nuclear factor erythroid factor 2-related factor 2 (Nrf2)-dependent manner, decreased nitric oxide levels both in macrophages in vitro and in the sera of mice fed PTS-PTSO, and had putatively beneficial effects on the commensal gut microbiota. Importantly, PTS-PTSO decreased faecal C. rodentium counts, concomitant with upregulation of Nrf2-related genes in colon tissue. Thus, PTS-PTSO mediates Nrf2-mediated antioxidant activity and modulates gut microbiota, which may protect the host against C. rodentium colonization. Our results provide further insight into how PTS-PTSO and related bioactive dietary compounds may reduce enteric infections.

Garlic-Derived Organosulfur Compounds Regulate Metabolic and Immune Pathways in Macrophages and Attenuate Intestinal Inflammation in Mice.

SCOPE: Garlic is a source of bioactive phytonutrients that may have anti-inflammatory or immunomodulatory properties. The mechanism(s) underlying the bioactivity of these compounds and their ability to regulate responses to enteric infections remains unclear. METHODS AND RESULTS: This study investigates if a garlic-derived preparation (PTSO-PTS) containing two organosulfur metabolites, propyl-propane thiosulfonate (PTSO), and propyl-propane thiosulfinate (PTS), regulate inflammatory responses in murine macrophages and intestinal epithelial cells (IEC) in vitro, as well as in a model of enteric parasite-induced inflammation. PTSO-PTS decreases lipopolysaccharide-induced secretion of TNFα, IL-6, and IL-27 in macrophages. RNA-sequencing demonstrates that PTSO-PTS strongly suppresses pathways related to immune and inflammatory signaling. PTSO-PTS induces the expression of a number of genes involved in antioxidant responses in IEC during exposure to antigens from the parasite Trichuris muris. In vivo, PTSO-PTS does not affect T. muris establishment or intestinal T-cell responses but significantly alters cecal transcriptomic responses. Notably, a reduction in T. muris-induced expression of Tnf, Saa2, and Nos2 is observed. CONCLUSION: Garlic-derived organosulfur compounds exert anti-inflammatory effects in macrophages and IEC, and regulate gene expression during intestinal infection. These compounds and related organic molecules may thus hold potential as functional food components to improve gut health in humans and animals.

The phytonutrient cinnamaldehyde limits intestinal inflammation and enteric parasite infection.

Phytonutrients such as cinnamaldehyde (CA) have been studied for their effects on metabolic diseases, but their influence on mucosal inflammation and immunity to enteric infection are not well documented. Here, we show that consumption of CA in mice significantly down-regulates transcriptional pathways connected to inflammation in the small intestine, and alters T-cell populations in mesenteric lymph nodes. During infection with the enteric helminth Heligomosomoides polygyrus, CA treatment attenuated infection-induced changes in biological pathways connected to cell cycle and mitotic activity, and tended to reduce worm burdens. Mechanistically, CA did not appear to exert activity through a prebiotic effect, as CA treatment did not significantly change the composition of the gut microbiota. Instead, in vitro experiments showed that CA directly induced xenobiotic metabolizing pathways in intestinal epithelial cells and suppressed endotoxin-induced inflammatory responses in macrophages. Collectively, our results show that CA down-regulates inflammatory pathways in the intestinal mucosa and can limit the pathological response to enteric infection. These properties appear to be largely independent of the gut microbiota, and instead connected to the ability of CA to induce antioxidant pathways in intestinal cells. Our results encourage further investigation into the use of CA and related phytonutrients as functional food components to promote intestinal health in humans and animals.

Regulation of Enteric Infection and Immunity by Dietary Proanthocyanidins.

The role of dietary components in immune function has acquired considerable attention in recent years. An important focus area is to unravel the role of bioactive dietary compounds in relation to enteric disease and their impact on gut mucosal immunity. Proanthocyanidins (PAC) are among the most common and most consumed dietary polyphenols, and are characterised by their variable molecular structures and diverse bioactivities. In particular, their anti-oxidative effects and ability to modulate gut microbiota have been widely described. However, there is limited evidence on the mechanism of action of PAC on the immune system, nor is it clearly established how PAC may influence susceptibility to enteric infections. Establishing the sites of action of PAC and their metabolites within the gut environment is fundamental to determine the applicability of PAC against enteric pathogens. Some mechanistic studies have shown that PAC have direct modulatory effects on immune cell signalling, isolated pathogens, and gut mucosal barrier integrity. Boosting the recruitment of immune cells and suppressing the amount of pro-inflammatory cytokines are modulating factors regulated by PAC, and can either be beneficial or detrimental in the course of re-establishing gut homeostasis. Herein, we review how PAC may alter distinct immune responses towards enteric bacterial, viral and parasitic infections, and how the modulation of gut microbiota may act as a mediating factor. Furthermore, we discuss how future studies could help unravel the role of PAC in preventing and/or alleviating intestinal inflammation and dysbiosis caused by enteric disease.

Dietary phytonutrients and animal health: regulation of immune function during gastrointestinal infections.

The composition of dietary macronutrients (proteins, carbohydrates, and fibers) and micronutrients (vitamins, phytochemicals) can markedly influence the development of immune responses to enteric infection. This has important implications for livestock production, where a significant challenge exists to ensure healthy and productive animals in an era of increasing drug resistance and concerns about the sector's environmental footprint. Nutritional intervention may ultimately be a sustainable method to prevent disease and improve efficiency of livestock enterprises, and it is now well established that certain phytonutrients can significantly improve animal performance during challenge with infectious pathogens. However, many questions remain unanswered concerning the complex interplay between diet, immunity, and infection. In this review, we examine the role of phytonutrients in regulating immune and inflammatory responses during enteric bacterial and parasitic infections in livestock, with a specific focus on some increasingly well-studied phytochemical classes-polyphenols (especially proanthocyanidins), essential oil components (cinnamaldehyde, eugenol, and carvacrol), and curcumin. Despite the contrasting chemical structures of these molecules, they appear to induce a number of similar immunological responses. These include promotion of mucosal antibody and antimicrobial peptide production, coupled with a strong suppression of inflammatory cytokines and reactive oxygen species. Although there have been some recent advances in our understanding of the mechanisms underlying their bioactivity, how these phytonutrients modulate immune responses in the intestine remains mostly unknown. We discuss the complex inter-relationships between metabolism of dietary phytonutrients, the gut microbiota, and the mucosal immune system, and propose that an increased understanding of the basic immunological mechanisms involved will allow the rational development of novel dietary additives to promote intestinal health in farmed animals.