Dietary Polyunsaturated Fatty Acids Modulate Immunity to Influenza Virus Infection

Dietary fish oils, rich in n-3 polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are known to have anti-inflammatory properties. While the immunosuppressive effects of n-3 PUFA may be beneficial for some chronic inflammatory disorders, these same anti-inflammatory properties may be detrimental for a response to an infection when a functional immune system is needed to eradicate an invading pathogen. Despite the availability of vaccines and antiviral agents, influenza virus continues to be a major cause of morbidity and mortality worldwide. Given that n-3 PUFA-rich fish oil supplementation by human populations is on the rise, and with the increasing threat of an influenza pandemic, we tested the impact of fish oil feeding on the immune response to influenza virus infection. Using in vivo and in vitro models, we found n-3 PUFA, supplied at physiologically relevant levels, suppressed immune responses following influenza infection. Although the anti-inflammatory properties of fish oil resulted in decreased lung inflammation in influenza infected mice, it also led to increased mortality and increased viral titers in surviving mice post infection. Impairment of host resistance was likely due to reduced inflammatory cell trafficking into the lungs in conjunction with lower cytokine production during infection. Influenza virus infection also resulted in a significant increase in EPA content in the infected lung, while infection had little effect on DHA in fish oil fed mice. Although changes in fatty acid membrane profiles can result in functional changes, dendritic cells and T cells from infected fish oil fed mice were able to respond to viral antigen equivalent to control fed mice. In response to viral infection, airway epithelial cells induce pro-inflammatory and antiviral mediators. We found that specific DHA to EPA ratios suppressed these mediators of infected human primary bronchial epithelial cells. Together, data from our studies indicate that n-3 PUFA treatment can have a profound effect in the host response to influenza virus infection. Given that fish oil supplementation is used by both adults and children, there is a significant public health benefit in further investigating how PUFAs alter immune function

High-Fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates with Obesity and Insulin Resistance in Mouse

Obesity induced by high fat (HF) diet is associated with inflammation which contributes to development of insulin resistance. Most prior studies have focused on adipose tissue as the source of obesity-associated inflammation. Increasing evidence links intestinal bacteria to development of diet-induced obesity (DIO). This study tested the hypothesis that HF western diet and gut bacteria interact to promote intestinal inflammation, which contributes to the progression of obesity and insulin resistance.Conventionally raised specific-pathogen free (CONV) and germ-free (GF) mice were given HF or low fat (LF) diet for 2-16 weeks. Body weight and adiposity were measured. Intestinal inflammation was assessed by evaluation of TNF-alpha mRNA and activation of a NF-kappaB(EGFP) reporter gene. In CONV but not GF mice, HF diet induced increases in body weight and adiposity. HF diet induced ileal TNF-alpha mRNA in CONV but not GF mice and this increase preceded obesity and strongly and significantly correlated with diet induced weight gain, adiposity, plasma insulin and glucose. In CONV mice HF diet also resulted in activation of NF-kappaB(EGFP) in epithelial cells, immune cells and endothelial cells of small intestine. Further experiments demonstrated that fecal slurries from CONV mice fed HF diet are sufficient to activate NF-kappaB(EGFP) in GF NF-kappaB(EGFP) mice.Bacteria and HF diet interact to promote proinflammatory changes in the small intestine, which precede weight gain and obesity and show strong and significant associations with progression of obesity and development of insulin resistance. To our knowledge, this is the first evidence that intestinal inflammation is an early consequence of HF diet which may contribute to obesity and associated insulin resistance. Interventions which limit intestinal inflammation induced by HF diet and bacteria may protect against obesity and insulin resistance

NF-κB^EGFP in intestinal tissue of GF mice treated with HF or LF fecal slurry.

<p>Fecal slurry from mice fed HF diet induces NF-κB^EGFP expression to a greater extent than fecal slurries from mice fed LF diet (Image representative of observation in 3 pairs of mice) in intestine tissues of GF NF-κB^EGFP mice. Abbreviations: Duo: duodenum; Jej:Jejunum; Ile: ileum; Col:colon.</p

Secondary antibodies used in immunofluorescence.

<p>Secondary antibodies used in immunofluorescence.</p

Correlation coefficients between ileal TNF-α mRNA and body weight, adiposity in all CONV and GF mice on both diets and in CONV mice on HF diet only.

<p>a: <i>P</i><0.05.</p

Primary antibodies used in immunofluorescence.

<p>Primary antibodies used in immunofluorescence.</p

Immunostaining for antigenic markers (red) compared with NF-κB (green) and overlay showing colocalization (white arrows).

<p>Immunostaining for antigenic markers (red) compared with NF-κB (green) and overlay showing colocalization (white arrows).</p