5.1. Omega-3 and Omega-6
Responses to immune stimuli require both the initiation and resolution of an immune response [63
]. Central to this coordinated response are polyunsaturated fatty acids (PUFAs) of the omega-6 and omega-3 series that serve as substrates for the synthesis of signaling molecules, including eicosanoids and docosanoids (Figure 1
]. Diet serves as a source of a variety of key PUFAs, including the essential fatty acids, linoleic acid (18, 2n
-6) and alpha-linolenic acid (18, 3n
-3), as well as their longer chain and more highly unsaturated products arachidonic acid (arachidonic acids (AA); 20, 4n
-6), eicosapentaenoic acid (eicosapentanoic acid (EPA; 20, 5n
-3)) and docosahexaenoic acid (docosapentanoic acid (DHA) 22, 6n
-3). Nutritional manipulation of the membrane content of PUFAs, particularly of the longer chain omega-3 series (LCn3PUFA), has generated great interest due to their enrichment in various immune cell types, as well as their ability to both reduce AA contents of the membrane and antagonize AA metabolism. Several eicosanoid derivates of AA, including prostaglandin E2 and 4-series leukotrienes, have been implicated in promoting sensitization to allergens and increased disease severity, and thus, adequate LCn3PUFA status during both early immunological development and at the time of established immune–antigen interfacing may modify disease risk.
The EAACI position paper suggests that, in patients with the lowest preexisting levels of long-chain polyunsaturated fatty acids (LC-PUFAs), supplementation may be beneficial in allergy prevention, particularly in those with low levels of omega-3 fatty acids [65
]. Such protective effects are most commonly seen in pregnant and lactating women, whereby increasing maternal and breast milk LCn3PUFA levels are associated with reduced risk of AD and development of food allergies, although significant heterogeneity in the evidence base exists [65
]. Sources of this heterogeneity need further consideration, but likely relate to the dose of LCn3PUFA used in clinical trials, baseline and achieved LCn3PUFA status, the timing of supplementation, common genetic variants throughout fatty acid metabolism and immunity, and microbiome composition [65
]. Current recommendations emphasize an individualized approach to nutrition and further, well-designed human studies with challenge-proven food allergy are necessary [66
LCn3PUFA have received substantial interest for not only their role in prevention of immune-mediated disease, but also their impact on reducing the severity of established disease. In addition to the role of EPA and DHA in antagonizing AA metabolism, they serve as substrates for the production of less potent eicosanoids (from EPA) and specialized pro-resolving mediators (SPMs) [64
]. SPMs include resolvins (D- and E-series produced from DHA and EPA, respectively), protectins, and maresins (derived from DHA), and appear to act primarily by inhibiting the recruitment and activation of multiple immune cell types, conferring pro-resolving and analgesic properties [68
]. These novel compounds provide further enthusiasm for omega-3 fatty acids in managing immune-mediated diseases and underlie the enthusiasm for EPA/DHA supplementation in autoimmunity.
Of the available literature base in autoimmune diseases, a substantial body of randomized controlled trials testing the impact of LCn3PUFA, primarily EPA and DHA mixtures, exist for both inflammatory bowel diseases and rheumatoid arthritis. To date, the literature in inflammatory bowel disease has been disappointing. Available systematic reviews and meta-analyses of controlled trials [70
] consistently show that LCn3PUFA supplementation does not prolong states of disease remission in Ulcerative Colitis or Crohn’s Disease, and there is high uncertainty due to low quality about the effect of LCn3PUFA in active disease. Notably, supplementation is not without side effects, with patients exhibiting an increased risk of diarrhea and upper gastrointestinal side effects. The complexity of the immunopathology of Ulcerative Colitis and Crohn’s Disease, involving impaired mucosal barrier function, varied cell types of the innate and adaptive immune system and their secreted mediators, gut microbial composition and the response to other various luminal factors make it difficult to explain why LCn3PUFAs have likely failed to influence clinical disease. Recent studies in animal models employing the dextran sulphate sodium model of colitis additionally suggest that high-dose LCn3PUFA worsen disease phenotypes when started just prior to dextran-sulphate-sodium provision [75
], conflicting with existing evidence from transgenic Fat1 mice [76
], capable of synthesizing their own omega-3 fatty acids, that have demonstrated significant protection from colitis. Such data suggest that the degree of tissue omega-3 status saturation, the relative impact on other fatty acid species, and timing of increased omega-3 status require further investigation to determine any potential efficacy of omega-3 fatty acids in humans with inflammatory bowel disease.
The impact of LCn3PUFA in rheumatoid arthritis is more promising. Supplementation has been shown to reduce leukotriene B4 [77
], a chemotactic factor released from neutrophils that is a key driver of inflammatory arthritis [78
]. Consistent with this reduction in causal pathophysiological mediators of disease, systematic reviews and meta-analyses of small clinical trials in rheumatoid arthritis consistently identify reduced non-steroidal anti-inflammatory use, improved pain, joint tenderness and improved physical functioning [79
]. Effective doses of LCn3PUFA in shorter term supplementation trials have tended to be in the pharmacological range (>2.5 g/d EPA + DHA), though self-reported intakes of food sources of omega-3 fatty acids are associated with improved self-reported disease scores [78
]. Large, confirmatory trials in patients with rheumatoid arthritis are needed for LCn3PUFA status monitoring and supplementation to become standard of care; indeed, the available evidence leaves many questions about the optimal dose, duration, and composition of omega-3 fatty acids, their effectiveness alongside modern medications (e.g., TNF-alpha inhibitors), and their role in sero-positive vs sero-negative disease states.
In line with the role of nutrition on the immune system, we have more a glimpse than a profound understanding of how the microbiome can be beneficially influenced by dietary compounds. However, it is well appreciated that fibers as non-digestible parts of fruits, vegetables and cereals are an important energy source for bacteria that, by fermentation, lead to the production of short-chain fatty acids (SCFA) as essential nutrients for humans. In numerous studies using different fiber interventions, fibers have been attributed to maintain intestinal homeostasis by enhancing epithelial barrier function, inhibiting pathogen-induced cytotoxicity and preventing colonization with pathogenic bacteria.
Despite most studies having been performed in in vivo animal models, there is early proof that fiber intake can also ameliorate pathology in humans in various organs. A high-fiber diet favors microbial diversity and production of SCFA and prevents the fermentation of less favorable substrates such as proteins and amino acids, leading to a reduced risk for colorectal cancer and Crohn’s disease [82
]. In addition, SCFA are absorbed and distributed systemically via blood circulation and thereby, may also prevent pathologies outside the gut. Patients suffering from asthma or cystic fibrosis present with a reduced microbial diversity in the gut leading to a shift from SCFA production to lipid, amino acid and carbohydrate metabolism [84
]. A long-term fiber-rich diet has been shown to improve lung function and to lower the risk for COPD [86
]. In addition to this microbial gut–lung axis, evidence exists that the gut–brain axis can also be influenced by fibers beneficially. Studies using dietary supplementation with Glucose-oligosaccharides or human milk oligosaccharides indicated a reduction of anxiety scores in irritative bowel syndrome patients and acetate influenced appetite by enhancing the production of regulatory neuropeptides [88
]. Furthermore, people following a Mediterranean diet (30 g fiber/day) have a lower risk for type-2 diabetes and patients at risk for cardiovascular disease show lower incidence of events, highlighting the beneficial effects of fibers on metabolic syndrome [90
]. Mechanistically, high-fiber diets may influence immune-mediated diseases, e.g., by the impact of SCFAs on signaling through G-protein coupled receptors (GPR), namely GRP41, GPR43 and GPR109A [93
], that are highly expressed on a variety of tissues including myeloid-derived immune cells. Additionally, acetate and butyrate, two common SCFAs, exhibit the capacity to inhibit histone deacetylase activity [95
], broadly influencing chromatin structure and the epigenetic state of the cell. Further in vivo animal work and human studies are needed to assess the contribution of epigenetic modifications to immune cell function, though a significant body of work suggests that HDAC inhibition in epithelial cells is critical for barrier function and influencing the immune response [97
This highlights the potential of fibers as an important tool for disease prevention [98
]. The challenge in the future will be to integrate fibers into our diets and efforts should be undertaken to educate children (and adults) to at least reach the recommended intake of 25–31 g fiber/day or even higher amounts (Table 2
). However, personalized approaches also need to be implemented as one-size does not fit all and, under certain underlying diseases (e.g., inflammatory bowel disease) and prompt increase of dietary fiber content, unwanted side effects of a high-fiber diet such as flatulence, stomachaches, constipation and diarrhea might occur.