Nutritional immunotherapy: An overview

In previous posts (1,2), I have briefly reviewed the importance of adipocytes and molecules secreted by the adipose tissue in immunity. Overall, increases in adiposity alterate the inflammatory balance, shifting towards a pro-inflammatory state, which contributes to the development of obesity-associated diseases. 

Given that metabolic and immune pathways are interconnected, and that metabolism controls function in immune cells, it is possible to modulate the immune system through nutrition. This is what I call "Nutritional Immunotherapy", which simply means targeting the immune system with nutritional tools for treating inflammatory and autoimmune diseases. 

Nutrition acts both directly and indirectly on the immune system, as shown in the following diagram:

Relationship between nutrition and the immune system. See text for details.

1. Nutrition influences the composition and function of adipose tissue (AT): Energy intake regulates fat mass, affecting the function and differentiation of pre- and mature adipocytes (direct effect). The concentration of specific fatty acids in AT is proportional to their abundance in the diet (indirect effect). The dietary fatty acid profile also affects membrane lipid composition on other cell types, which regulates cell functioning.  
2. Adipose tissue is an immune organ: There are several immune cells present in AT from different body sites, differing each one in the proportion of cell types. Lymph nodes present in AT are sorrounded by perinodal adipocytes, which have a higher proportion of polyunsaturated fatty acids (PUFA) than adipocytes far from the nodes.  Lymphoid clusters within AT include milky spots (MS) and fat-associated lymphoid clusters (FALCs), which have an active role determining whole-body immune responses. Adipocytes are also able to secrete adipocytokines (leptin, resistin, adiponectin, etc.) and classical cytokines (IL-6, TNF-a, etc.). 
3. Adipose tissue regulates energy intake: Cytokines secreted by AT regulate appetite and energy balance, acting through neural pathways involved in energy homeostasis.
4. Nutrition affects the gut flora: Microbial composition of the human gut flora is very responsive to diet. Small changes in either macronutrient distribution or food choices affect differently not only the relative proportion of certain species, but also their metabolism and gene expression patterns.
5. Gut flora regulates fat mass and metabolism: Digestion of plant cell walls, oligosaccharides and other food components by gut bacteria increases the energy yield of food, contributing to energy intake. Acetate and propionate, produced by the fermentation of soluble fiber, are metabolized (predominantly) in skeletal muscle and the liver, respectively. Gut microbiota also supress FIAF activity and promotes hepatic triglyceride synthesis. Metabolism of drugs and xenobiotics is dependent on the composition of the gut flora. 
6. Gut flora regulates immunity: The presence of specific bacteria shapes the immune system and regulates mucosal and peripheral immune responses. The gut flora also competes with enteropathogens directly and by the action of antimicrobial peptides. Evolutionary co-adaptation has given gut bacteria and other microorganisms essential roles for mammalian health. 
7. Nutrition regulates immunity: Energy availability and macronutrients regulate the function, maturation and differentiation of immune cells. 

Nutrition has the potential to act on all levels mentioned above. This is why a good diet is very important not only for prevention, but also for treatment of diseases of civilization.

Important components

The nutritional immunotherapy protocol integrates concepts from immunology, molecular and evolutionary biology. The first two help us answer the "how" question, while the latter helps us understand the "why". 

What differences this protocol from other diets is that it takes into account the fact that people who already have developed an inflammatory and/or autoimmune disorder respond differently to any diet. This means that the response to a diet is individual, and more importantly, in this case, the starting point is not a natural one. This point is important for understanding the recommendations given hereafter.  

The history of the patient, specially those aspects that would compromise the response to certain macronutrients and the normal development of a tolerant immune system, needs to be addressed before trying to make any nutritional adjustment. Nowadays, with genetic tools (like 23andMe), tailoring the diet according to the genotype is possible and helpful. 

Important factors for the success and application of the protocol are shown below.

Relevant factors for the protocol

Mode of birth

Hygiene practices during childhood

Family diet, diet history and maternal environment

Medical history

Genotype

Social/lifestyle experiences

Symptoms

Self-assessment

Bloodwork

 Mode of birth

This important but commonly overlooked factor is determinant for immune development and future health. Vaginal birth is the natural mode of birth because it stimulates not only hormonal responses in the mother and the child, but because it promotes an adequate colonization of the neonate, one that we have been adapted for. At birth, the newborn is sterile*, so it can be colonized virtually by any species. Babies born by cesarean section have an abnormal microbiota, as they harbor bacteria from the hospital's environment, medical practitioners and the mother's skin. Normally, during the passage through the birth canal, the infant is exposed to vaginal and cervical flora. Because of its proximity, newborns are also rapidly colonized by maternal gut microbiota, which seems to be the predominant source of bacteria. Pre-term infants also display a different pattern of microbial colonization.

Hygiene practices during childhood 

Gut development is a continuous process that has its last phase during late infancy/early childhood, as the child transitions from breastmilk to complementary foods. Exclusive breastfeeding (and ingestion of colostrum) is very important for preventing inadequate colonization, as it has bacteria, immune and growth factors which promote immune development. Breastmilk also has a perfect nutritional composition, with oligosaccharides (and other components) that promote the growth and establishment of commensal bacteria (predominately Bifidobacteria). Formula-fed infants display an aberrant gut microbiota and normal colonization is severly delayed (if not completely disrupted).

Microbial exposure favors diversification and exposure to pathogens, which is necessary for stimulation of immune memory and tolerance. Contact with animals, eating raw food and playing in the dirt are a necessary part of a healthy lifestyle in infancy. Excessive hygiene and antibiotic use promote dysbiosis. 

Family diet, diet history and maternal environment 

The diet eaten by your father, mother and grandparents influences the expression of genes involved in energy metabolism. These effects are transmitted intergenerationally and lasting during adulthood. Inadequate dietary patterns followed during childhood and adulthood worsen immune and metabolic function. Additionally, maternal status during pregnancy (stress, nutrition, etc.) has profound effects on many genes. 

Medical history 

Previous diseases, antibiotic abuse and utilization of other substances can influence both the normal functioning of the immune system as well as metabolism.

Genotype 

The presence of certain alleles are important for tolerance of specific food components (ie. lactose) and variability in immune responses (ie. MHC alleles, cytokine gene polymorphism).

Social/lifestyle experiences 

Having bad social relationships, lack of optimism, stress and other common lifestyle experiences affect the inflammatory status of the body. For example, losing a game in very competitive persons increases the levels of inflammatory cytokines higher than in non-competitive subjects. Mental stress also seem to affect the composition of the gut microbiota and gut permeability. 

Symptoms, self-assessment and bloodwork

Any symptom (either bad or good) is valuable for trying to identify potential problems. Self-assessment, including anthropometric measures, emotional status or the characteristics of feces can also help narrowing the spectrum of possible disorders. Bloodwork and biomarkers are helpful for confirming assumptions and health status.

Summary

Before beginning any nutritional therapy, it is important to check for past events and factors that affect the metabolic and immune status. This will aid in finding the right dietary composition that helps the most with a given problem and reducing the time of experimentation needed for finding the adequate nutrition and supplementation for an individual.  

*Although recent evidence suggests that bacteria colonize the gut in uterus.