The Impact of Nutrition on Autoimmune Disease – Part 3
Written by: Matt Baran-Mickle
Metabolism and Immunity
The obesity epidemic is widely recognized, and while the precise causes are not entirely clear, the presence of excessive nutrient intake and subsequent systemic metabolic dysfunction is not controversial. Obesity is frequently accompanied by a variety of conditions that are collectively referred to as the metabolic syndrome, including high plasma glucose, high plasma fatty acids/triglycerides, hypertension, and insulin resistance; immunological alterations in obesity are increasingly recognized as well, and the presence of chronic inflammation is a hallmark of the condition.
These immunological alterations are quite pronounced, and include the accumulation of activated lymphocytes and innate cells in obese fat tissue, and a depletion of Treg cells, as well as mucosal barrier disruption and dysbiosis. Recent work has begun to unravel the interrelation of immunity and metabolism, and provides some intriguing evidence for our developing understanding of autoimmune disease.
Like every other cell, leukocytes require energy and metabolic substrate to maintain normal cellular function, and to divide and proliferate. The metabolic requirements of dividing lymphocytes are particularly pronounced, and their activation is accompanied by a switch to almost exclusively glycolytic metabolism, which allows for the production of metabolic intermediates that are required to generate amino acids, lipids and nucleic acids for the generation of new cells during an immune response. On the other hand, non-activated lymphocytes and Treg cells rely primarily on oxidation, and are non-proliferative.
Lymphocytes rely on intracellular and extracellular energy-sensing pathways in order to determine the proper response to a given stimulus, and fat cells provide signals to this effect via the hormones leptin and adiponectin, which signal energy sufficiency/excess and insufficiency/deficit, respectively. Leptin secretion increases in proportion to fat mass, while adiponectin is secreted in inverse proportion, and both act strongly on lymphocytes to elicit specific responses.
In lean fat tissue, adiponectin secretion far outweighs leptin output, and in response, leukocytes in fat tissue are primarily tolerogenic Treg cells and non-activated leukocytes that rely on oxidative metabolism. In obese fat tissue, on the other hand, leptin production predominates, and the presence of glycolytic, activated, inflammatory lymphocytes is dramatically increased.
The presence of activated lymphocytes in fat tissue is surprising, given that activation is dependent on recognition of an antigen and subsequent stimulation. In recent years, the hypothesis that these cells recognize self-proteins in obese fat tissue has gained credibility, and the very recent discovery that fat cells can participate in immunity as members of the innate immune system by activating T cells makes a strong case that obesity is, in fact, an autoimmune disease.
In the presence of excess energy (i.e. the high circulating levels of macronutrients found in obesity) and permissive signaling through energy-sensing pathways (i.e. leptin), inactive, self-reactive T cells can make the switch to glycolytic metabolism and proliferation, allowing the generation of an autoimmune response; the depletion of Treg cells and a loss of adiponectin secretion compounds and permits this aberrant activation, and could potentially be a key mechanism in the generation of autoimmune disease in the rest of the body. In this way, there is a clear line of evidence connecting chronic over-nutrition and the development of autoimmune disease.
Conclusion and Perspectives
We have seen how multiple pathways may contribute to the development of autoimmune disease, and that these act, potentially, through the disruption of energy homeostasis and mucosal immune function. A lingering issue in the discussion of dietary influences on autoimmunity is the order of events; inflammation can drive metabolic dysfunction, alterations in intestinal permeability, and dysbiosis, so causality could lie in any of these directions, or originate from some other source entirely.
The unifying factor in the discussion is a loss of tolerance to self tissues via the generation of inflammation, and multiple roles of diet in driving the development of an inflammatory environment. Evidence for the metabolic effects of immunity on the loss of tolerance suggest that over-nutrition may be a crucial component of this process, and could effect the mucosal barrier, as evidenced by the presence of dysbiosis and intestinal permeability in obese patients. Bioactive compounds in cereal grains, like gliadin, provide a source for the initiation of intestinal inflammation, while a lack of fiber and other potentially disruptive nutritional behaviors can drive dysbiosis. Taken together, this evidence suggests that the modern nutritional environment can promote inflammation and the initiation of autoimmune disease, and increasing research interest in the direct impacts of nutrition on autoimmunity may soon provide dearly-needed evidence to support a true mechanistic understanding of the causal relationships at play.
Kanneganti, T.-D., & Dixit, V. D. (2012). Immunological complications of obesity. Nature immunology, 13(8), 707–12. doi:10.1038/ni.2343
Matarese, G., Procaccini, C., & De Rosa, V. (2012). At the crossroad of T cells, adipose tissue, and diabetes. Immunological reviews, 249(1), 116–34. doi:10.1111/j.1600-065X.2012.01154.x
Matt Baran-Mickle graduated from Hampshire College in 2013 with a BA in Human Physiology and Immunology, completing a senior thesis investigating the connections between nutrition and autoimmune disease from an immunological perspective. He completed pre-med requirements during his undergraduate work, and hopes to pursue a degree in Naturopathic medicine beginning in 2015. In the meantime, he eats, trains, and works in Boulder, CO.