Modulation of host defence against bacterial and viral infections by omega-3 polyunsaturated fatty acids

Accepted Manuscript Modulation of host defence against bacterial and viral infections by omega-3 polyunsaturated fatty acids Marie-Odile Husson, Delphine Ley, Céline Portal, Madeleine Gottrand, Thomas Hueso, Jean-Luc Desseyn, Frédéric Gottrand PII:

S0163-4453(16)30252-3

DOI:

10.1016/j.jinf.2016.10.001

Reference:

YJINF 3825

To appear in:

Journal of Infection

Received Date: 18 April 2016 Revised Date:

7 October 2016

Accepted Date: 7 October 2016

Please cite this article as: Husson M-O, Ley D, Portal C, Gottrand M, Hueso T, Desseyn J-L, Gottrand F, Modulation of host defence against bacterial and viral infections by omega-3 polyunsaturated fatty acids, Journal of Infection (2016), doi: 10.1016/j.jinf.2016.10.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Modulation of host defence against bacterial and viral infections by omega3 polyunsaturated fatty acids Running title: Impact of n-3 PUFA in infections

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Marie-Odile Husson, Delphine Ley, Céline Portal, Madeleine Gottrand, Thomas Hueso, Jean-

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Luc Desseyn, Frédéric Gottrand

Corresponding author: Marie-Odile Husson

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LIRIC UMR 995 Inserm; Univ. Lille; CHU Lille, F-59000 Lille, France

LIRIC UMR 995 Inserm, Université de Lille, CHRU de Lille, Faculté de Médecine, Place de Verdun,

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F-59045 Lille cedex, France.

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tel: 0033 686 767 584. Email: [email protected]

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Summary Objectives Although n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) are used widely in the treatment of chronic inflammatory diseases, their effect in infectious disease requires a particular attention.

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Methods The present article discusses their anti-inflammatory and immune properties involved in the host defence and presents a systematic review of the effects of their oral administration on the prevention and outcome of experimental and clinical infections.

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Results

At a dose corresponding to an human dose of 500 mg/day, n-3 LC-PUFAs intake is beneficial against experimental infections caused by extracellular pathogens including Streptococcus

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pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus by reducing inflammation, and reduces the incidence of pneumococcal infections in the elderly, but at 2 to 4-fold higher doses as occurs in some human intervention and /or during long-term it becomes detrimental in intestinal infections with Citrobacter rodentium or Helicobacter hepaticus by exacerbating anti-inflammatory response. They are also harmful against

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infections caused by intracellular pathogens as Mycobacterium tuberculosis, Salmonella, Influenza virus and Herpes simplex virus by affecting the immune cell response. Conclusion

The effects of n-3-LC-PUFAs on infections depend on the pathogen and the n-3 LC-PUFA

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dose and timing. Caution should be recommended for high-dose and long-term

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supplementation in humans.

Key words:

n-3 LC-PUFA, anti-inflammatory, immunomodulatory, outcome, prevention, infection

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ACCEPTED MANUSCRIPT Highlights -

The impact of oral n-3 PUFAs intake on the risk and outcome of infections is still a matter of debate

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In experimental studies oral n-3 PUFAs intake is either beneficial or harmful

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Caution is recommended for high-dose and long-term supplementation of n-3 PUFAs

Search strategy and selection criteria

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in humans

This review article includes 2 parts. The first is an overview of the different mechanisms

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involved in the anti-inflammatory response and immunomodulatory properties of n-3 LCPUFAs which can affect the course of infection. The second part summarizes the effect of an oral supplementation of n-3 LC-PUFAs in experimental and clinical infectious diseases. This

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section is a systematic review, in which we analyzed the role of n-3 LC-PUFAs in the treatment and prevention of infectious diseases both in experimental models and clinical trials. These data were extracted from PUBMED by including data combining n-3 LC-PUFA or EPA and DHA or fish oil intake with bacteria and virus and excluding those obtained with

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parasites.

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Introduction Consumption of fish oil (FO) as a source of omega-3 or n-3 long-chain polyunsaturated fatty acids (LC-PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is widely recommended to reduce inflammation in immune/inflammatory chronic diseases such as diabetes1,2, atherosclerosis3, cardiovascular diseases4⁠ , neurodegenerative diseases such as

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Alzheimer disease5, and arthritis6. Extensive data suggest that the anti-inflammatory and immunomodulatory properties of n-3 LC-PUFAs may also be beneficial in treating infectious diseases.

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The innate immune system by detecting rapidly microorganisms is the first line of defence against pathogens, and its aim is to rapidly destroy and clear microorganisms. To do so, the innate immune system triggers an immediate inflammatory response that induces

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migration and activation of phagocytic cells and T cells into infected sites and initiation of the adaptive immune response with recognition of antigen by B lymphocytes. However, an excessive inflammatory response may induce greater tissue damage than that caused by microorganisms. Moreover, macrophage and T-cell activation varies according to the type of microorganism and may exert adverse effects. Some microorganisms such as viruses and

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intracellular pathogens induce a cellular immune response and a pro-inflammatory-dominant response, which are designated Th1 and M1, whereas extracellular microorganisms induce a humoral response and an anti-inflammatory-dominant response, called Th2 and M27.

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n-3 LC-PUFAs may play a key role in host defence against infections by limiting excessive inflammation and by improving the immune response. However, in some

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circumstances, an excessive anti-inflammatory response or immunomodulation may adversely affect the course of infection. Whether n-3 LC-PUFAs are beneficial or harmful in the prognosis of infectious disease remains a challenging question. This question was previously addressed by Anderson and Fritsche in 20028 and we update here this topic by a systematic review including the latest experimental and clinical data and analysing how n-3 LC-PUFAs by their anti-inflammatory and immunomodulatory properties may prevent and/or improve, or either worsen the outcome of bacterial and viral infections.

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Anti-inflammatory and immune properties of n-3 LC-PUFAs during infection The

different

mechanisms

involved

in

the

anti-inflammatory

response

and

immunomodulatory properties of n-3 LC-PUFAs during infection are presented in Figure 1. A large part of the anti-inflammatory and immunomodulatory properties of n-3 LC-PUFAs

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results from their incorporation into phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids of membrane cells. This incorporation occurs inside lipid microdomains, called rafts, for EPA and DHA, and outside rafts for DHA9, and decreases the fluidity of the cell membrane9 (Figure 1A). The first consequence of the change in fluidity is

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alteration in activity of cell’s actin skeleton, which is accompanied by a reduction in phagocytosis of microorganisms by macrophages and antigen-presenting cells (APCs),

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phagolysosome formation, and killing activity of macrophages10. These alterations occur especially in macrophages collected from FO-fed animals when cultured in presence of intracellular pathogens such as Mycobacterium tuberculosis11 or Salmonella12. The second consequence is inhibition of the clustering of surface proteins during cell interactions, which is involved in numerous signalling pathways such as the maturation and migration of dendritic cells13, T-cell proliferation14, and Th1 and Th17 activation through decreased binding between

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the antigen and major histocompatibility complex (MHC) class II on APCs and the T-cell receptor on T cells15. n-3 LC-PUFAs also reduce cell-mediated cytotoxicity and natural killer (NK) cell activity16, but do not affect Th2 and regulatory T-cell (Treg) differentiation17. n-3 LC-PUFAs also affect B cell activation18. Taken together, these data suggest that n-3 PUFAs

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interfere directly in the immune response against microorganisms.

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Incorporation of n-3 LC-PUFAs into the cell membrane induces a pivotal change in the production of eicosanoids and resolvins (Figure 1B), which compete with arachidonic acid (AA) for phospholipase A2 activity. Liberated inside the cytosol, the fatty acid (FA) are degraded into prostaglandins (PGs), leukotrienes (LTs), and thromboxane (TX) through cyclooxygenase-2

(COX2),

5-lipoxygenase,

and

thromboxane

synthetase

activity,

respectively, and into resolvins through 15- and 5-lipoxygenases, COX2, or other reactions. Thus, n-3 LC-PUFAs decrease the synthesis of eicosanoids derived from AA such as PGE2, PGI2, PGF2a, LTB4 which are involved in pro-inflammatory responses such as increased endothelial permeability and chemotaxis of leukocytes, and promote the synthesis of PGE3 and LT5 from EPA, which exhibit weaker effects on inflammation19,20.

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ACCEPTED MANUSCRIPT Lipoxins are derived from AA, and the resolvins D and E are derived from DHA and EPA, respectively. These molecules are involved in the resolution of inflammation by reducing chemotaxis and activation of neutrophils, increasing neutrophil apoptosis, and promoting alternative activation of macrophages that are less inflammatory than classically

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activated macrophages21–24. The role of lipoxins in infection has been studied in transgenic mice deficient in lipoxygenase. Compared with wild-type mice, these transgenic mice are more resistant to aerosol infection with M. tuberculosis25 and exhibit less lung inflammation and increased production of interleukin-12 (IL-12), interferon-gamma (IFN-γ), and nitric

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oxide (NO) needed to control the pathogen. The longer survival of the transgenic animals suggests that lipoxins play a deleterious role in M. tuberculosis infection.

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By contrast, resolvins D and E have marked therapeutic benefit against some bacterial and viral infections. The intraperitoneal administration of resolvin E1 6 hours after intratracheal instillation of Escherichia coli reduces pulmonary neutrophil infiltration, increases neutrophil apoptosis by macrophages, and decreases bronchoalveolar IL-6 level and lung inflammation26. This reduction in inflammation coincides with increased bacterial

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clearance and survival of experimentally infected mice. In experimental peritonitis, intraperitoneal administration of resolvin D5 or D1 reduces the number of viable bacteria in the blood and peritoneal exudate. Resolvin D1 also increases survival of infected mice27. In a murine sepsis model initiated by caecal ligation and puncture, intravenous administration of

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resolvin D2 sharply decreases the local and systemic bacterial burden, excessive cytokine production, and neutrophil recruitment, increases peritoneal mononuclear cell and

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macrophage phagocytosis, and eventually increases survival28. The topical application of resolvins also reduces the severity of experimental Staphylococcus aureus skin acute infection29, Porphyromonas gingivalis periodontitis24, and Herpes simplex virus ocular infection by limiting inflammation and restoring connective tissue30,31. The resolvin protectin D1 reduces the replication of influenza virus by inhibiting the nuclear export of viral transcripts in lung cells32. Intravenous injection of protection D1 12 hours before and immediately after infection with Influenza A virus subtype H5N1 increases antibody production and improves the survival of virus-infected mice32,33 and restores the level of protectin D1, which decreases during severe influenza infection in infected cells32. Protectin D1 is also used as a vaccine adjuvant to improve the antibody-mediated immune response34,35.

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ACCEPTED MANUSCRIPT Free EPA, DHA, and AA, can inhibit nuclear factor κB (NF-κB) activation in cells by acting as ligands for peroxisome proliferator-activated receptors (PPARs)36,37 (Figure 1C). When bound to these ligands, PPARs block the IκB-α component of NF-κB and inhibits IκB kinase activity and NF-κB translocation into the nucleus38. This mechanism has been demonstrated in vitro by adding EPA and DHA in cultures of endothelial cells stimulated with

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lipopolysaccharides (LPS) or other inflammatory mediators39. These data are supported in vivo by the overexpression of PPAR in the lungs of mice chronically infected with Pseudomonas aeruginosa and fed EPA and DHA, which suggests that PPARs participate in

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the reduction of inflammation40.

EPA and DHA can interfere in microorganism–cell interactions by two main mechanisms. Once incorporated into cell membranes, EPA and DHA inhibit the clustering of

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Toll Like receptors (TLRs) bound to their microbial components and inhibit the consequent signalling pathways leading to the activation of NF-κB (Figure 1A). Once released into the blood from the liver and adipocytes during sepsis through lipase and phospholipase activation41,42, EPA and DHA inhibit downstream inflammatory cascades. This effect can vary according to the interactions between TLRs and microorganisms so that EPA and DHA

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may act as agonists of TLR4 instead of lipid A of LPS of Gram-negative bacteria and of TLR2, TLR1, and TLR6 instead of the lipoproteins of Gram-positive bacteria (Figure 1D). This last mechanism has been demonstrated in vitro by adding DHA or FO to LPS-stimulated macrophage culture43,44 and is supported by observations of patients with sepsis who

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exhibited an increase in free n-3 PUFA concentration in the blood and decreased production of pro-inflammatory cytokines by mononuclear leukocytes after 2 days of FO infusion45.

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The anti-inflammatory properties of EPA and DHA induced by inhibition of NF-κB

activation may be completed by their action on the inflammasome, which is a central regulator of innate immunity and inflammation46 (Figure 1E). Its activation depends of several intracellular microbial sensors including NOD-like receptors (NLRs) that form large cytoplasmic complexes with other molecules and link the sensing of microbial products to the proteolytic activation of the pro-inflammatory cytokines IL-1β and IL-1846. Stimulation of macrophages with n-3 LC-PUFAs reduced NLR3 inflammasome activation, abolished caspase-1 activation and in consequence IL-1β and IL-18 secretion47. This suppression results from stimulation of G protein-coupled receptors 120 and 40 by n-3 LC-PUFAs47.

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ACCEPTED MANUSCRIPT Through direct antibacterial activity, orally ingested n-3 LC-PUFAs can alter the intestinal microbiota, which is known to modulate the innate48 and adaptive immunity49 (Figure 1F). This antibacterial activity results from peroxidation of FAs by bacterial catalase and superoxide dismutase enzymes, which leads to the production of toxic antibacterial compounds, disruption of the electron transport chain and oxidative phosphorylation, and

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detergent activity, which disrupts phospholipids and creates transient or permanent pores in the cell membrane of microorganisms50. The minimum concentrations of EPA or DHA able to inhibit the growth of bacteria vary from 32 to 1024 mg/L depending on the bacterial species and strains50–52 and are compatible with the intestinal concentrations caused by daily dietary

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supplementation with n-3 LC-PUFAs.

The antibacterial properties of EPA and DHA on intestinal microbiota have been

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demonstrated in mice fed an FO-enriched diet for 253 or 6 weeks54. Compared with mice fed a control diet, the FO diet decreased the number of Firmicutes and Clostridium species, which are involved in T-cell activation and immune cell maturation55. Recent studies show that offspring from mice fed a diet enriched in n-3 LC-PUFAs have altered intestinal microbiota, as shown by loss of Bacteroidetes, increased number of Firmicutes including Blautia, Clostridium, Lactococcus, and Eubacterium species, and reduction in the number of other

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Firmicutes such as Roseburia and Lachnospiraceae species56. These alterations are associated reductions in neutrophil infiltration and activation, which worsen S. aureus skin infection and

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tend to increase the mortality rate of E. coli peritonitis57.

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n-3 LC-PUFAs in experimental and clinical infectious diseases Methodology

Literature search was conducted following a systematic approach. A search in the Pubmed database was carried out using the search terms ‘n-3 LC-PUFA, EPA, DHA or fish oil combined with bacterial and viral infections’. Data obtained with parasites were excluded. The electronic literature search included English studies published between January 1980 and January 2016. There were no restriction on the type of study design. Following the initial screening, the references of all eligible studies were examined to identify any other potentially relevant articles. Collectively, the effects of n-3 LC-PUFAs have been studied in pulmonary,

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ACCEPTED MANUSCRIPT gut, systemic, and local infections caused by major bacterial and virus pathogens. Fifty two articles were included in the present review.

Results Experimental studies of the effects of dietary n-3 LC-PUFAs on the outcome of respiratory,

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gut, systemic, and local infectious diseases are presented in Table 1.

Pseudomonas aeruginosa and Burkholderia cenocepacia are two main pathogens observed in cystic fibrosis (CF). This genetic disease is caused by mutations in the CF

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transmembrane conductor regulator (CFTR) gene, which codes for a chloride channel expressed in epithelial cells of various organs such as the intestine, pancreas, and lungs. Because abnormalities in FA metabolism58 and bronchopulmonary inflammation caused by

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bacterial infection are very common in CF patients, several studies have evaluated the antiinflammatory properties of n-3 PUFA supplementation consisted of 1.2% w/w of EPA+DHA (ratio: 2/1) during P. aeruginosa infection using wild-type mice and CFTR-deficient (Cftr–/–) mice infected chronically or acutely with P. aeruginosa. This dose, providing 1.6 mg/kg body weight/ day of EPA+DHA, corresponds to the recommended daily dose in human of 500 mg,

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i.e. 8 mg/kg body weight /day for an human of 60 kg for whom the recommended proportion of fat in the diet is 5-fold higher than in mice. Its five weeks administration in chronically infected C57BL/6 mice decreased mortality and gel-forming mucin 5B overexpression, and increased distal alveolar fluid clearance59,60. These clinical observations coincided with

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changes in the inflammatory response, which was characterised by an increase in neutrophil flux and TNF-α release on day 1 of infection and a more constant IL-6 secretion during the

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next 4 days60. A study of the kinetics of the inflammatory response during the first 24 hours in a model of acute P. aeruginosa infection showed that EPA/DHA delayed the proinflammatory response and caused slower but sustained neutrophil recruitment, keratinocyte chemoattractant (KC) release, and NF-κB activation during the first 2 hours, and overexpression of the anti-inflammatory response H. as shown by increased IL-10 and PPAR activation. This sequential activation coincided with a reduction in bacterial load and mortality40. Administration of a diet with a similar content in EPA+DHA but at a different ratio (ratio EPA/DHA: 2/1) in C57BL/6 mice for 5 weeks significantly improved lung injury and survival, accelerated bacterial clearance, and decreased inflammation61. Daily supplementation with a Peptamen solution (Nestlé Clinical Nutrition) enriched in 40 mg of DHA for 1 week was sufficient to reduce neutrophil number and eicosanoid level (6-keto-

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ACCEPTED MANUSCRIPT PGF1α, PGF2α, PGE2, and thromboxane B2) in Cftr–/– mice challenged by aerosolised Pseudomonas LPS62 but had no effect on their survival when mice were chronically infected by the bacteria63. However, supplementation with EPA/DHA at a lower but dose relevant to that administered to humans for 6 weeks (EPA+DHA, 1.2% w/w. ratio EPA/DHA: 2/1) improved the outcome of acute P. aeruginosa infection64. This beneficial effect was more

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pronounced in female Cftr–/– mice, which are more susceptible to P. aeruginosa infection than are males. The EPA/DHA diet reduced mortality and lung injury in females but reduced only the inflammatory response (neutrophil counts and KC and IL-6 levels) in males64. Although the results of these experimental studies are encouraging, there are not enough human data to recommend n-3 LC-PUFA supplementation to reduce the incidence and severity of P.

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aeruginosa infections in CF patients. Systematic reviews65,66 have concluded that short-term supplementation with 2.7 g/day of EPA may improve forced expiratory volume, forced vital

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capacity, and Shwachman score67, and that short (50 mg/body weight/ day) - or long-term supplementation (16 mg/body weight/day) influences the serum phospholipid FA pattern and inflammatory markers in CF patients68–70. Minor adverse effects and steatorrhea have also been reported.

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No studies have examined the effects of n-3 LC-PUFA supplementation on experimental B. cepacia infection. However, 50 mM of DHA inhibited the growth of B. cepacia bacteria in vitro and limit their pathogenicity in a Galleria mellonella caterpillar model of infection. Treatment of infected larvae with a single dose of DHA (50 mM)

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increased their survival rate and reduced the bacterial load71. Additionally, treatment with DHA increased the immune response of the larvae, which suggests an intrinsic ability of DHA

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to modulate the response of G. mellonella to B. cepacia infection.

Streptococcus pneumoniae causes severe pneumonia in children and older people. Its

pathogenicity depends on the capsule that protects the bacteria from phagocytosis and induces an exaggerated host inflammatory response that causes tissue injury. The ability of n-3 LCPUFAs to decrease excessive pulmonary inflammation during S. pneumoniae infection was investigated by feeding BALB/c mice with 0.5 ml flaxseed oil (2% of acid α-linoleic, which is converted in EPA/DHA in the body) administered orally with a feeding catheter72, or with sea-cod oil containing a similar amount of n-3 LC-PUFAs73. Short-term supplementation (4–5 weeks) of both oils showed no beneficial effects. However, long-term administration (9 weeks of flaxseed oil or 60 days of sea-cod oil) provided protection against pneumococcal

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ACCEPTED MANUSCRIPT pneumonia by reducing histopathological lesions of lung tissue and inflammatory markers, and by increasing IL-10 production during the course of infection. Moreover, sea-cod oil reduced mortality and pulmonary bacterial load. Greater phagocytic activity of alveolar macrophages and decreased apoptosis of neutrophils have also been reported74. To complement these data, the beneficial effects of n-3 LC-PUFAs on the incidence of

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pneumococcal pneumoniae was assessed in Humans through a prospective study including 38,378 male US health professionals aged 44 to 79 years, followed for ten years by questionnaires on lifestyles and n-6 and n-3 FA and fish intake. Pneumonia risk was reduced 4% for every 1 g/day increase in n-6 linoleic acid intake and 31% for every 1 g/day increase significantly related to pneumonia risk75.

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in n-3 alpha-linolenic acid intake. However, the intakes of EPA and DHA were not

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Mycobacterium tuberculosis is an intracellular pathogen. In the lung, the bacteria are internalised into alveolar macrophages, which are unable to digest and eradicate them. Experimental infection in guinea pigs infected with virulent M. tuberculosis by the aerosol route showed that dietary n-3 LC-PUFA (13.5 % w/w) consumption during 3 or 6 weeks reduced lymphoproliferative responses and was associated with a greater bacterial load in the lungs compared with an n-6 FA-enriched diet at 3 and 6 weeks after infection76. Fat-1-

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transgenic mice, which endogenously produce n-3 PUFAs77, are more susceptible to M. tuberculosis infection than wild-type mice. Transgenic mice exhibit reduced pulmonary inflammation, failure of macrophages to control infection, and more bacteria in the spleen and

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lungs11,78. By contrast, incorporation of AA in macrophages stimulates TNF-α secretion in M. tuberculosis-infected macrophages and increases their bacterial activity79. In contrast to the in

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vitro results, n-6 LC-PUFA (7.4% w/w) tends to increase the survival of M. tuberculosis in mice in proportion to the balance between control of the pathogen and an excessive immune response79. These experimental data are consistent with the epidemiological observation that the high consumption of fish is correlated to the high incidence of tuberculosis in selected populations such as the Inuit80.

The host protection against Influenza A virus requires neutrophils, NK cells, T lymphocytes, and secretion of both inflammatory and antiviral cytokines. The effect of n-3 LC-PUFAs during Influenza A virus infection was assessed in experimental infections using intranasal instillation of virus train H3N2 in BALB/c mice fed a diet comprising 5% w/w of n-3 LC-PUFA81 or the mouse-adapted strain of influenza A virus/Puerto Rico/8/34 in

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ACCEPTED MANUSCRIPT C57BL/6 mice fed diet comprising 4% FO (% of EPA+DHA not defined)82. Both mouse strains fed an FO-enriched diet for 2 weeks were significantly more susceptible to virus infection and had a higher mortality rate and higher viral load on days 5 and 7 of infection compared with mice fed a diet enriched with beef tallow. A FO diet affects the immune response by reducing IFN-γ, TNF-α, and IL-6 levels, virus cytotoxicity, IgG titre in serum,

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and IgA titre in bronchoalveolar lavage82. These data contradict previous studies using IV administration of protectin D1, which improved the survival of Influenza-infected mice33. These conflicting results suggest that n-3 LC-PUFA intake does not provide sufficient protectin D1 concentration to be beneficial. The effects of n-3 LC-PUFA and protectin D1 to

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prevent or treat influenza A virus infection have not been studied in humans and require further studies.

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The effects of n-3 LC-PUFAs on Helicobacter pylori, which causes gastritis, depend on direct antibacterial activity and anti-inflammatory properties. In one study, 50 µM DHA inhibited H. pylori growth in vitro by altering the lipid outer membrane83. In another study, 100 µM DHA decreased the production of IL-8, COX2, and NO by H. pylori-infected cultured cells84. These properties were confirmed in mice that consumed 50 µM DHA n-3

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LC-PUFAs in drinking water for 2 weeks and showed a preventive effect by reducing H. pylori colonisation83,85. The DHA concentration used was determined according to the notion that a daily dose of 1 g for total n-3 PUFA in humans leads to a concentration of 50 to 100 µM in the gastric milieu. However, n-3 LC-PUFAs cannot be used as drug to treat H. pylori.

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In a clinical trial in which metronidazole was replaced by 1.5 g of eicosapen in combination with clarithromycin and a proton pump inhibitor, their intake was less effective than

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metronidazole in eradicating H. pylori in patients with non-ulcer dyspepsia (34% vs 78%)86.

Helicobacter hepaticus promotes inflammatory colitis in mice that are deficient in

IL-10 or in transcriptional factors such as SMAD3 or Rag factors87. In both genetically deficient mouse strains, H. hepaticus colonic infection is characterised by lymphocytic infiltration of the lamina propria and increased expression of Th1 cytokine genes88. In SMAD3-deficient mice, a diet enriched with 0·85% (w/w) EPA+DHA consumed before and during active colitis did not affect colitis severity, whereas a diet enriched in a higher concentration of EPA+DHA (1.35, 2.2, 3.5 %, w/w) worsened colitis, and increased adenocarcinoma formation and mortality in a dose-dependent manner89. The harmful effects

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ACCEPTED MANUSCRIPT observed with the higher concentration of n-3 LC-PUFAs are associated with increases in CD8+ cell and Treg cell populations, which suggests that EPA/DHA has immunosuppressive properties during colonic infection89.

EPA/DHA intake affects colitis induced by Citrobacter rodentium infection in

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C57BL/6 mice. A diet enriched with 6·3% (w/w) of EPA+DHA administered for 3 weeks90 or 5 weeks91 before and during the course of infection changed the membrane phospholipid composition of intestinal cells, reduced local inflammation, decreased production of proinflammatory cytokines and chemokines, and attenuated colonic injury compared with C. rodentium infection in mice fed a diet high in n-6 LC-PUFAs. In a model of murine colitis,

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5 weeks of a diet enriched in 1% w/w of EPA+DHA influenced the intestinal microbiota91 by reducing the content of Clostridium coccoides bacteria, which are associated with

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inflammatory bowel disease92, and by increasing the content of Lactobacillus spp. and Bifidobacteria spp., which have known anti-inflammatory properties93. However, this regimen increased mortality and was associated with decreased expression of intestinal alkaline phosphatase and inability to neutralise circulating LPS during infection91.

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No clear and consistent effects of n-3 LC-PUFA supplementation on infectious colitis initiation or progression have been reported in humans. The effects of supplementation have been assessed in patients with acute myeloid leukaemia, for whom enterocolitis is a serious and potentially fatal complication. The results provided little evidence to support adding n-3

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LC-PUFAs (% not defined) to parenteral nutrition to reduce the incidence and severity of neutropenic colitis, and the number of patients analysed was too small to justify routine treatment94. A role of pathogenic bacteria in Crohn’s disease has not been demonstrated

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clearly. The incidence of the disease may relate to the dietary intake of n-6 PUFAs95, and one epidemiological study shows that dietary intake of 4 g/day for 58 weeks of n-3 PUFAs has a protective role96. However, the effects of n-3-PUFA on Crohn’s disease remain controversial and may depend on the dose and the location within the inflamed intestine97.

EPA/DHA supplementation has been studied in models of peritonitis and sepsis induced by caecal ligation and puncture in Sprague Dawley rats. Sepsis can be caused by the enteric capsulated bacteria such as E. coli and Bacteroides fragilis, which are resistant to phagocytosis and contribute to abscess formation and inflammation. Two studies have shown that parenteral administration of lipid emulsions containing FO (percentage and composition

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ACCEPTED MANUSCRIPT not defined) for 4 days98 or 2 weeks99 before caecal ligation and puncture reduces the mortality rate. However, as described previously here, the intake of 4 % (w/w) of n-3 LCPUFAs for a longer time, such as during gestation until the age of 6 weeks, did not reduce E. coli peritonitis and tends to increase mortality57. This harmful effect correlated with a change in intestinal microbiota. An increased content Lactobacillus is involved in the anti-

induced by n-3 PUFA intake may be deleterious.

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inflammatory response100, which suggests that an excessive anti-inflammatory response

Four weeks of administration of an FO-enriched diet (percentage of FO and

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composition not defined) is ineffective in reducing reduce the severity of Salmonella typhimurium infection in Swiss Webster mice. This regimen increases mortality when bacteria are administered orally and the number of bacteria in the spleen when they are instilled

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intraperitoneally101. Host immunity and inflammatory markers are not assessed, but S. typhimurium is a facultative intracellular pathogen, and these results may be attributed to decreased bacterial phagocytosis and impairment of the inflammatory response. n-3 LC-PUFAs inhibit Hepatitis C virus (HCV) RNA replication102, but, because

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hepatitis is characterised by strong metabolic abnormalities, studies have investigated whether PUFA supplementation can correct these abnormalities. Interestingly, n-3 LC-PUFAs (8.8% w/w) inhibit the expression of HCV induced-lipogenesis genes102, and improve the outcome of infection. Epidemiological studies have shown that high consumption of n-3

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PUFA-rich fish reduces the risk of developing hepatocellular carcinoma103 and parental nutrition with n-3 LC-PUFA during 7 days may reduce the infection rate and improve liver

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function recovery after hepatectomy of humans104.

As described above, EPA and DHA have antimicrobial activity and can inhibit the

growth of S. aureus, including strains resistant to methicillin, at a mean concentration of 128 mg/L and can lyse these bacteria within 15–30 min52,105. EPA and DHA have been applied successfully as topical agents in the treatment of skin lesions infected by S. aureus106. Because they also have antimicrobial activity against Propionibacterium acnes, they may represent a new strategy for acne treatment, especially in synergistic combination with antimicrobial agents already used clinically105. However, it is unlikely that antimicrobial activity will be effective in improving the outcome of more severe skin infections such as abscesses and systemic infection after oral administration. The main interest in n-3 PUFA

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ACCEPTED MANUSCRIPT supplementation to prevent or treat S. aureus infection remains the anti-inflammatory properties. Gavage with FO (percentage of EPA+DHA not defined) via gastrostomy of Sprague Dawley rats for 5 days decreased the mortality rate from intra-abdominal abscess107. This decrease was associated with decreases in inflammation and PGE2 release. However, longer-term administration of a high content of n-3 LC-PUFAs (4% w/w) by animals to the

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age of 6 weeks worsened the outcome after intradermal infection of adults rats with a virulent strain of S. aureus that was resistant to methicillin57. The size of the dermal lesions was larger, the inflammatory response was reduced, and the number of bacteria was similar compared

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with animals fed the control diet.

Infection of the cornea with Herpes simplex virus 1 (HSV-1) is one of the most common causes of blindness. In a model of herpes stromal keratitis in BALB/c mice,

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supplementation with a diet containing 20% FO (composition not defined) for 2 weeks before and during infection induced earlier and more severe lesions than in the control group. The exacerbation of the disease was attributed to a reduction in NO production by macrophages and hypersensitivity of T cells to HSV-1 antigens108.

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Streptococcus B causes neonatal sepsis, pneumonia, and meningitis. The effects of n-3 LC-PUFA supplementation, started on day 2 of gestation and continued throughout lactation in Sprague Dawley rats, was investigated in a model of intraperitoneal injection of Streptococcus B in neonatal rat pups on day 7 of life. Suckling pup rats fed FO had

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significantly higher survival rates than did rats fed corn oil. This increase was attributed to a decreased in PGE2 release in lung homogenates109.

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Listeria monocytogenes is an intracellular pathogen that causes severe infection in

immunocompromised patients such as newborns and elderly people. FO intake significantly impairs host resistance of weaning C3H/Hen mice after intraperitoneal injection of L. monocytogenes. Mice fed FO had a lower survival rate and decreased bacterial clearance in the spleen compared with mice fed a diet rich in n-6 PUFAs or monounsaturated or saturated FAs110. This impairment may reflect alter T-cell activation and decreased production of cytokines such as IFN-γ and IL-12111.

Conclusion

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ACCEPTED MANUSCRIPT This review shows that n-3 LC-PUFA intake may be both beneficial and deleterious in the prevention and control of infectious diseases. A dose of EPA+DHA corresponding to a daily dose of 0.5 g/day for healthy humans improves the outcome of experimental infections caused by opportunistic extracellular pathogens, which induce a strong inflammatory response either by releasing toxins that lyse cells and tissue (P. aeruginosa, S. aureus, H. pylori) or by the

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presence of a capsule (S. pneumonia, E. coli, Streptococcus B), which protects the pathogen against phagocytosis early in the innate immune response. Thus, the beneficial effects of n-3 LC-PUFAs may result from their anti-inflammatory properties, which limit tissue damage associated with the pathogen and the inflammatory response. The mechanisms involved in the

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anti-inflammatory properties of n-3 LC-PUFAs include switching of pro-inflammatory PG2 and LTx4 towards less inflammatory products such as PGE3 and LTx5, and inhibition of NFκB through inhibition of signalling pathways and PPAR activation. The most efficient

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mechanism probably involves the production of resolvins that regulate inflammation. Besides, their sole administration may improve the outcome of some infections.

By contrast, experimental studies show that n-3 LC-PUFA supplementation at a 2 to 4 fold higher dose is detrimental in the outcome of C. rodentium or H. hepaticus colitis, and that

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for a long time, such as throughout gestation, lactation, and after weaning of animals, worsened S. aureus infections as skin abscesses. This longer supplementation induces changes in the gut microbiota composition by increasing anti-inflammatory bacterial species, which reduce local and systemic inflammation and impair immune host defences. Thus, n-3 PUFA

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supplementation during infection may prove detrimental because of the anti-inflammatory properties when the host inflammatory response is critical for survival. The dose and timing

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of their intake appear essential for achieving this balance. In addition, n-3 LC-PUFA supplementation is detrimental in respiratory, systemic, ocular infections with intracellular pathogens such as M. tuberculosis, Influenza A virus, Salmonella spp, L. monocytogenes, and Herpes simplex virus, which need an immune cell response to eradicate infected cells. In these infections, n-3 LC-PUFAs are deleterious because of their immunosuppressive properties.

Except in some cases, where n-3 LC-PUFA was used successfully in the treatment of skin infection as topic and unsuccessfully in the treatment of H. pylori gastritis instead of an antibiotic, the study of the impact of n-3 LC-PUFA in humans has focused on the prevention of

infection

and

was

measured

through

epidemiological

studies

in

elderly,

immunocompromised people as patients with acute myeloid leukaemia, or those with chronic

16

ACCEPTED MANUSCRIPT pathology as hepatitis or with a high risk of infection as CF and Crohn’s disease. These clinical studies show that n-3 LC-PUFA intake reduces the incidence of pneumococcal infection in elderly. But we lack of clinical data to confirm this preventive effect in the incidence of infections by P. aeruginosa in CF patients who are deficient in n-3 LC-PUFA intestinal absorption, even if a few clinical studies performed are promising. The impact of n-

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3 LC-PUFA on Crohn’s disease requires additional studies to define the right balance between the inflammatory and immune responses, which must be sufficient to eradicate potential pathogens but weak enough not to induce tissue damage and suppress immunity. The studies reviewed here also highlight the importance of clinical trials to define the optimum n-3 LC-

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PUFA doses, timing of intake, and clinical status of patients who might be prescribed n-3 supplementation. Given the above mentioned concerns about potential aggravation of infectious diseases by n-3 PUFAs, although no cases of infection have been reported in

supplementation in humans.

Acknowledgments

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pharmacovigilance database, caution is recommended for high-dose and prolonged

We thank the French Foundation in Digestive Tract Diseases and Nutrition 'DigestScience' for its

Funding statement

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support.

This research did not receive any specific grant from funding agencies in the public,

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commercial, or not-for-profit sectors.

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Conflict of interest

No potential conflict of interest disclosures issues for any of the authors.

Figure 1

Mechanisms underlying the actions of EPA and DHA. A, In membrane cells, inhibition of raft properties affects Th1, Th7, and cytotoxic T cells, B activation, and TLR clustering; B, in cells, synthesis of leukotrienes, prostaglandins, and thromboxanes have weak inflammatory effects, and resolvins are involved in the resolution of inflammation; C, in cells, binding to PPAR inhibits NF-κB activation; D, in serum, competition in LPS–TLR4 binding; E, in serum, inhibition of inflammasome activation; F, in the gut, inhibition of the growth of

17

ACCEPTED MANUSCRIPT intestinal bacterial species indirectly affects local inflammation and immune system

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development.

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ACCEPTED MANUSCRIPT

Table 1. Experimental studies of the effects of dietary n-3 LC-PUFAs on the outcome of respiratory, gut, systemic, and local infectious diseases Animals, pathogen, infection

Diet (% w/w), timing

Observed effects

Ref.

1

60

EPA+DHA1 (1.2% w/w), ↓ mortality ↓ pulmonary bacterial load 5 weeks ↓ lung injury, pro-inflammatory markers expression delayed during the first 2 h overexpression of anti-inflammatory markers at 8 h at 8 h

40

C57BL/6 mice, P. aeruginosa PaO1, acute infection

EPA+DHA2 (1.2% w/w), ↓ mortality 5 weeks ↓ pulmonary bacterial load ↓ lung injury

61

Cftr–/– mice, aerosol of P. aeruginosa LPS

DHA, 40 mg/day, 1 week ↓ neutrophil number and eicosanoid level

62

Cftr–/– mice, P. aeruginosa M57-15, chronic infection

DHA, 40 mg/day, 1 week no decrease in survival or in neutrophil and macrophage numbers

63

Cftr–/– mice, P. aeruginosa PaO1, acute infection

EPA+DHA1 (1.2% w/w), ↓ the pulmonary bacterial load and ↓ inflammatory markers in males 6 weeks ↓ mortality and ↓ lung injury in females

64

Galleria mellonella caterpillar, Burkholderia cepacia K56-2

50 mM DHA, 1 day

↓ morality, bacterial load and expression of virulence factors

71

BALB/c mice, Streptococcus pneumoniae D39/2

0.5 ml Flaxseed oil (2% ac α linoleic), 9 weeks

↓ histopathological involvement ↓ inflammatory markers (MPI, NO) ↑ IL-10

72

BALB/c mice, S. pneumoniae D39/2

Sea-cod oil, 60 days

↓ mortality, ↓ pulmonary bacterial load ↓ MDA, NO, LTB4, ↑ IL-10

73

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C57BL/6 mice, P. aeruginosa PaO1, acute infection

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C57BL/6 mice, Pseudomonas aeruginosa EPA+DHA (1.2% w/w), ↓ mortality PaO1, chronic infection 5 weeks ↓ distal alveolar fluid clearance ↑ neutrophil recruitment (day 1), TNF-α (day 1), and IL-6 (days 1–4)

Guinea pig, Mycobacterium tuberculosis EPA+DHA (13.5% w/w), ↑ bacterial load in the lungs H37Rv 3 and 6 weeks ↓ tuberculin skin test

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↓ lymphocyte proliferation Endogenous synthesis of n-3 PUFAs

↑ number of bacteria in spleen and lungs ↓ pulmonary inflammation and macrophage functions

78

BALB/c mice, Influenza A virus, H3N2

EPA+DHA (5% w/w), 2 weeks

↑ pulmonary viral load on days 5 and 7 ↓ INF-γ level, IgG titre in serum, and IgA titre in lung lavage

81

C57BL/6 mice, Influenza A virus Puerto Rico/8/34

FO (4%), (% EPA+DHA not defined), 2 weeks

↑ mortality ↑ pulmonary viral load on days 5 and 7 ↓ INF-γ; TNF-α, and IL-6 levels at day 5 and 7

82

C57BL/6 mice, Helicobacter pylori SS1

50 µM DHA, 2 weeks

↓ colonization and gastritis ↓ local inflammation

Smad3–/– mice, H. hepaticus 3B1

EPA+DHA (0.85% w/w), No change in colitis 8 weeks

Smad3–/– mice, H. hepaticus 3B1

EPA+DHA (1.35, 2.2, 3.5% w/w), 8 weeks

C57BL/6 mice, Citrobacter rodentium DBS100

EPA+DHA (6.5% w/w), 3 weeks

C57BL/6 mice, C. rodentium DBS100

EPA+DHA (1% w/w), 5 weeks

Sprague Dawley rats, peritonitis by caecal ligation and puncture

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Fat-1 transgenic mice , M. tuberculosis H37Rv

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4

83

89

89

↓ colitis ↓ inflammatory markers (MPO, KC, MIP-2, INF-γ, IL-17A), ↑ IL-10

90

↓ colitis ↓ IFN-γ, TNF-α, IL-17A, IL-22, IL-23, Relm-β Modulation of gut microbiota composition ↑ mortality by sepsis ↓ expression of intestinal alkaline phosphatase

91

FO (nd4), 4 days

↓ mortality Correction of immunosuppressive effects caused by sepsis

98

Sprague Dawley rats, peritonitis by caecal ligation and puncture

FO (nd4), 2 weeks

↓ mortality

99

BALB/c mice, Escherichia coli 01 K18

EPA+DHA (4% w/w), gestation, lactation, and 2–3 weeks

Trend towards worsened responses Modulation of gut microbiota composition

57

Swiss Webster mice, Salmonella

FO (nd4), 4 weeks

↑ mortality after oral administration

101

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↑ colitis, adenocarcinoma formation, mortality, ↓ CD8+ cells, ↑Treg cells

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↑ bacteria number in spleen after intra peritoneal instillation

typhimurium 4

↓ mortality ↓ inflammatory markers (PGE2)

107

FO (nd ), 5 days

BALB/c mice, S. aureus methicillin resistant USA300 LAC

EPA+DHA (4% w/w), ↑ skin lesions gestation, lactation and 2- ↓ inflammatory markers (Th1 and Th17) 3 weeks

57

Sprague Dawley rats, Group B Streptococcus

FO (nd4), pups of females ↓ mortality fed during gestation and ↓ inflammatory marker (PGE2) breeding

109

↑ mortality ↑ bacterial load in spleen

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C3H/HeN mice, Listeria monocytogenes FO (17%; % EPA+DHA not defined), 4 weeks

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Sprague Dawley rats, Staphylococcus aureus pellet

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BALB/c mice, herpes virus simplex FO (20%; % EPA+DHA ↑ severity of ocular lesions strain F not defined), 2 weeks 1 2 EPA/DHA ratio 2:1 ; EPA/DHA ratio 1:2 ; 3 produces n-3 PUFAs endogenously; 4 nd: percentage of FO and n-3 LC-PUFAs not defined

110

108

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Highlights -

The impact of oral n-3 PUFAs intake on the risk and outcome of infections is still a matter of debate

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In experimental studies oral n-3 PUFAs intake is either beneficial or harmful

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Caution is recommended for high-dose and long-term supplementation of n-3 PUFAs in

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humans