Immunonutrition: gut microbiota,glutamine and omega 3 polyunsatturated fatty acids

Domina Petric

Department of Clinical pharmacology and toxicology,University Hospital Center Split,Split,Croatia.

Background

Immunonutrition is an interdisciplinary field of research that unites knowledge and skills related to clinical nutrition,clinical immunology,infections and inflammation,injury and tissue damage[1].Immunonutrients are glutamine,arginine,taurine,leucine,cysteine,nucleotides,omega 3-polyunsatturated fatty acids (PUFA),vitamins and trace elements.Glutamine and omega 3 PUFA can modulate immune function towards a more balanced immune response,whilst vitamins and trace elements form an antioxidant defense system that protects the body and tissues from deleterious effects of free radicals in oxidative stress [2].Immunonutritionists also study the importance of gut microbiota,because of its bilateral connections to both the nervous and immune system [1].The importance and clinical relevance of immunonutrition is being studied widely in medicine,including in oncology,endocrinology,rheumatology,clinical immunology and allergology.Here,author summarizes available scientific literature on the importance of immunonutrition and its clinical relevance.

Gut microbiota

Factors that influence gut microbiota are motility of gastrointestinal tract,intake of pharmaceutical compounds (antacids,antibiotics,nonsteroidal anti-inflammatory drugs),smoking,alcohol abuse,gastrointestinal tract transit time,mucosal blood flow and renal clearance.Disproportionate uptake of luminal antigens,coupled with suppression of immune responsiveness or the failure in immunological tolerance,may cause the imbalance of immune response with consequent development of various antigen-related autoimmune diseases: gliadin →celiac disease;casein,β-lactoglobulin →allergic gastroenteropathies[3-8].

Celiac disease (CD) is frequently associated with type 1 diabetes mellitus (DMT1) and autoimmune thyroiditis,suggesting a common pathogenic mechanism in these three distinct autoimmune disorders.Mucosal barrier dysfunction has been studied and confirmed to be present in CD,DMT1 and multiple sclerosis.Alteration of gut microbiota composition,such as reducedBacteroidesandBifidobacteriumand overgrowth ofCampylobacter,Streptococcus,LeuconostocandCandida albicans,is associated with aberrations of T-cell immune responses,especially with abnormal mobilization and accumulation of Th17 cells in the lamina propria.Th17 cells are considered to be essential mediators in autoimmunity and autoimmune diseases,as these have potent inflammatory effects.Th17 cells secrete proinflammatory cytokines IL-17,IL-17F and IL-22.The increased production of Th17 cell effector cytokines and the consequent increase in antimicrobial peptide production from epithelial cells augments the ability of the host to fight of intestinal infections.Still,it may also be a key pathogenic mechanism in the development of autoimmune processes because excessive and prolonged secretion of proinflammatory cytokines can increase the likelihood of chronic autoimmune inflammation [9-19].

Results of a study showed that gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals (P<0.01).It has been found that COVID-19 patients had lower levels of gut commensals with immunomodulatory potential,such asFaecalibacterium prausnitzii,Eubacterium rectale,and bifidobacterial,and these levels remained low in samples collected up to 30 days after disease resolution.Alterations of gut microbiome composition was associated with disease severity and concordant with elevated concentrations of inflammatory cytokines,C-reactive protein (CRP),lactate dehydrogenase (LDH),aspartate aminotransferase (AST),and gamma-glutamyl transferase(GGT).Authors concluded that gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses [20].Perturbations of gut microbiome might also be associated with long COVID-19 syndrome.Nutrition plays an important factor in the maintenance of a healthy immune response against infection.Sufficient protein intake is important for optimal antibody production.Vitamin A and zinc deficiency has been associated with increased susceptibility to infection.Poor nutrient status is associated with inflammation and oxidative stress,which impairs the ability of immune system to fight back infection,especially COVID-19 which is associated with cytokine storm,severity of which is proportionate to the severity of COVID-19.Optimal levels of vitamins and trace elements,especially vitamins A,C,E,D,and zinc;addition of carotenoids,polyphenols and dietary fiber(anti-inflammatory) in diet,may be relevant factors for the reduction of inflammation and oxidative stress associated with COVID-19 [21].

Glutamine

Glutamine is a non-essential amino acid.It has been found that glutamine can stimulate enterocyte proliferation,reduce gastrointestinal bacterial translocation and protect the intestinal mucosa from the uptake of antigens.Intraluminal glutamine induces protective gut mechanisms (antioxidant enzymes glutathione and haem-oxygenase-1,anti-inflammatory transcription factor,peroxisome proliferator activator receptor γ) [2].Results of a study showed the annual declines of glutamate and glutamine levels in patients suffering from secondary progressive multiple sclerosis.Authors concluded that glutamate and glutamine levels could be promising new biomarkers of disease progression [22].This study showed the correlation of glutamine levels decline with disease progression,but it is also plausible to hypothesize that glutamine supplementation could be beneficial for the patients who have multiple sclerosis.This could be investigated in a randomized placebo-controlled clinical trial,in which one group of patients would receive glutamine supplementation,whilst control group would receive placebo,along with standard MS pharmacotherapy in both groups.

Evidence supports the benefit of oral (enteral) glutamine in reducing symptoms and improving quality of life in oncology patients because glutamine supplementation provides nutritional support and it mitigates mucosal damage associated with chemo-and radiotherapy[23].However,it has been shown that many types of cancers are characterized by elevated glutamine consumption.Dysregulation of glutaminase and glutamine synthetase are key events that allow the anabolic adaptation of tumors [24].Glutamine contributes to both of the energy-forming pathways in cancer cells: oxidative phosphorylation and glycolysis,and it can reinforce the activity of proliferative signaling pathways,which are important for malignant cell proliferation.Excess glutamine can be exported in some cancer cells in exchange for leucine and other essential amino acids.Cells with enhanced expression of Myc oncoproteins are sensitive to glutamine deprivation,which induces depletion of TCA cycle intermediates,depression of ATP levels,delayed growth,diminished glutathione pools,and apoptosis [25].Although glutamine supplementation can on the one hand be beneficial as a nutritional support for oncology patients,there is evidence on the other hand that the excess glutamine may enhance neoplastic cell proliferation.Therefore,it is difficult to make a solid clinical recommendation regarding glutamine supplementation in oncology.

Supplementation of immunonutrients,especially glutamine,which is depleted from muscle stores during severe metabolic stress (sepsis,major surgery,burns),is beneficial in patients with surgical and critical illness,and for patients suffering immunodeficiency [26].

Available evidence does not support the use of glutamine in Crohn′s disease,but these investigations are based on small numbers of patients [27],meaning that larger clinical trials should be designed in order to investigate the potential clinical relevance of glutamine supplementation in Crohn′s disease and other inflammatory bowel diseases.

Omega 3 PUFA

Omega-3 fatty acids are polyunsaturated fatty acids with a terminal double bond on carbon number 3.Fish oil contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),both of which have favorable immunomodulatory and anti-inflammatory properties.The administration of EPA and DHA balances the immune response which may result in a faster resolution of inflammation and recovery.Animal experiments and clinical intervention studies indicate that omega 3 PUFA might be useful in the management of inflammatory and autoimmune diseases that are associated with an increased production of proinflammatory cytokines.Results of several clinical trials showed the potential benefit (decreased disease activity) of EPA and DHA supplementation in rheumatoid arthritis,Crohn′s disease,ulcerative colitis,psoriasis,lupus erythematosus,multiple sclerosis and migraine headaches [2,28].Results of a systematic review confirmed the results of previous meta-analyses on beneficial properties of omega 3 PUFA supplementation in rheumatoid arthritis: decrease of disease activity,reduction of leukotriene B4 and positive effect on blood lipid profile were recorded in available scientific literature [29].

Resolvins are a member of specialized pro-resolving mediators,which are produced from omega-3 PUFA as a response to an acute inflammatory process,in the way of termination and resolution of inflammation.Any dysregulation of the resolution phase defect results in prolonged,persistent inflammation and eventually fibrosis.Dysregulation of resolvins pathway may have implications in the pathogenesis of systemic sclerosis [30] and therefore,the investigation of omega-3 PUFA supplementation in systemic sclerosis might be relevant as well.

Results of a clinical trial showed that vitamin D supplementation for five years,with or without omega 3 PUFA,reduced autoimmune disease by 22%,whilst omega 3 PUFA with or without vitamin D reduced the autoimmune disease rate by 15% [31].

A study on NZBWF1 mouse,which spontaneously develops lupus,found that exposure to crystalline silica significantly decreases latency and promotes rapid progression of the disease.Researchers also found that dietary supplementation with human-relevant doses of DHA impedes crystalline silica-induced gene expression,ectopic lymphoid structures neogenesis,autoantibody elevation,and glomerulonephritis in the lupus-prone mouse model.Authors concluded that these findings point to the feasibility of enhancing tissue omega-3 highly unsaturated fatty acids as a personalized nutritional intervention to impede onset and progression of environment-triggered autoimmune disease[32].

Results of a systematic review showed that omega-3 PUFA and fish oils supplementations have beneficial effects on reducing the relapsing rate,inflammatory markers,and improving the quality of life for patients who have multiple sclerosis [33].

Results of a clinical trial showed that H3-L6 diet (EPA+DHA 1.5 g/day,linoleic acid ≤1.8% of energy) and H3 diet (EPA+DHA 1.5 g/day,linoleic acid circa 7% of energy) altered bioactive mediators implicated in headache pathogenesis and decreased frequency and severity of headaches,but did not significantly improve quality of life[34].

Conclusion

Immunonutrition as an interdisciplinary field of research integrates knowledge and skills related to clinical nutrition,clinical immunology,infections and inflammation,injury and tissue damage.Immunonutrients are glutamine,arginine,taurine,leucine,cysteine,nucleotides,omega 3 PUFA,vitamins and trace elements.Glutamine and omega 3 PUFA are immunomodulators.Vitamins and trace elements together form an intrinsic antioxidant defense system.The subject of research in the field of immunonutrition is also gut microbiota and its bilateral influence on immune system.Many factors influence gut microbiota (antibiotics,antacids,nonsteroidal anti-rheumatics (NSAR),smoking,alcohol abuse,motility and transit time of gastrointestinal tract,mucosal blood flow,renal clearance)with consequent disproportionate uptake of luminal antigens,which can in the context of suppressed immune responsiveness or failure of immune-tolerance cause the development of various antigen-related autoimmune diseases,such as celiac disease or allergic gastroenteropathies.Mucosal barrier dysfunction has been found in CD,DMT1 and multiple sclerosis,representing the common pathophysiological factor in these three distinct autoimmune diseases.Alteration of gut microbiota composition is associated with aberrant T-cell immune response,namely abnormal mobilization and accumulation of Th17 cells in the lamina propria.As Th17 cells are considered to be essential mediators in autoimmune disorders,alteration of gut microbiota can be considered as an important pathophysiological factor in the development of autoimmune process.Excessive and prolonged Th17-related proinflammatory cytokines,such as interleukin-17 (IL-17),interleukin-17F (IL-17F) and interleukin-22 (IL-22),can create conditions for the development of chronic autoimmune inflammation.Although it has been known that glutamine can stimulate enterocyte proliferation,reduce gastrointestinal bacterial translocation,protect the intestinal mucosa from the uptake of antigens,and induce protective mechanisms in the gut,the use of glutamine supplementation was not widely studied in autoimmune diseases and therefore no firm clinical recommendation can be made at this point.Although glutamine supplementation can on the one hand be beneficial as a nutritional support for oncology patients because it has been found that it can reduce symptoms,mitigate mucosal damage associated with chemo-and radiotherapy and improve quality of life,there is evidence on the other hand that the excess glutamine may enhance neoplastic cell proliferation.Therefore,it is difficult to make a solid clinical recommendation regarding glutamine supplementation in oncology as well.However,there is sufficient evidence to support the use of glutamine supplementation during severe metabolic stress,such as in sepsis,major surgery,and burns or in immunocompromised patients.

Nutritional supplementation based on omega 3 PUFA (EPA,DHA)with or without vitamin D has been studied in autoimmune diseases showing some promising results in both prevention and complementary treatment (nutritional support) in various autoimmune diseases and neurological disorders associated with gut dysbiosis,namely rheumatoid arthritis,Crohn′s disease,ulcerative colitis,psoriasis,lupus erythematosus,multiple sclerosis and migraine headaches.Products of omega 3 PUFA,resolvins are involved in termination and resolution of inflammation,and therefore,might be an important factor for the prevention and/or mitigation of prolonged and persistent inflammation,that is seen in autoimmune disorders,and eventually fibrosis,which is altogether relevant in the pathogenesis of systemic sclerosis.Although omega 3 PUFA supplementation has not yet been studied in systemic sclerosis,it might be relevant to investigate the potential clinical relevance of such supplementation.Further research on the clinical relevance of omega 3 PUFA supplementation with or without vitamin D in the prevention and treatment of autoimmune diseases is necessary in order to expand our knowledge about immunonutrition and its clinical implications.