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Unhealthy Diet Triggers Epigenetic Changes in Innate Immune System

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Exposure to a Western diet high in refined sugars, salt and saturated fat can have a permanent impact on the body’s immune system even if the diet is later changed.

An international team of researchers has found that the immune system reacts to typically high-calorie, Western-style diets in much the same way that it does to bacterial infections, setting in motion inflammatory responses and long-term innate immune system stimulation that could play a role in the development of diet-related diseases, such as diabetes and cardiovascular diseases (CVD).

The studies, led by a team at the University of Bonn, found that feeding mice a Western Diet (WD) that was high in fat and sugar and low in fiber triggered epigenetic changes in immune system progenitor cells in the bone marrow, which led to heightened, aggressive-type innate immune stimulation that persisted long after the mice were put back on their normal diets.

The findings could have “important social relevance,” states lead researcher Eicke Latz, M.D., Ph.D., director of the Institute for Innate Immunity at the University of Bonn. “The foundations of a healthy diet need to become a much more prominent part of education than they are at present.”

The investigtors, from Germany, The Netherlands, the U.S., and Norway, report their studies in Cell, in a paper entitled “Western Diet Triggers NLRP3-Dependent Innate Immune Reprograming.”

Over 80% of deaths in Western societies are now caused by chronic, noncommunicable diseases, including those such type 2 diabetes, obesity, and cardiovascular diseases, which are linked to aging and eating Western-type high-calorie diets, the researchers write. Low-density lipoprotein cholesterol (LDL-C) has been identified as a key player in the development of atherosclerosis, for example, but the immune system may also play a role in disease development. “…it is also well appreciated that disease progression is strongly associated with inflammatory processes involving cells of the innate immune system, mainly monocyte-derived macrophages.”

The innate immune system is one of two arms of the natural vertebrate defense mechanism against infections. The adaptive immune system induces antigen-specific memory when it encounters a pathogen, while the innate immune system mounts nonantigen-specific protective responses, triggered by innate immune signaling receptors. But the innate immune system doesn’t just react to invading pathogens, the researchers note. “…these receptors can further recognize ‘sterile’ danger signals, which are thought to trigger inflammation in noncommunicable diseases.”

There is also increasing evidence to suggest that the innate immune system can mount a long-lasting “innate immune memory” or “trained immunity.” While such innate immume memory has probably evolved to provide nonspecific protection from secondary infections, “it is also conceivable that ‘sterile’ inflammatory triggers, such as Western diet (WD), can induce trained immunity,” the team suggests. “It has only recently been discovered that the innate immune system has a form of memory,” explains Prof. Dr. Latz, who is also a scientist at the German Center for Neurodegenerative Diseases (DZNE). “After an infection, the body’s defenses remain in a kind of alarm state, so that they can respond more quickly to a new attack.”

To investigate the potential effects of diet on trained immunity, the researchers turned to a mouse model of atherosclerosis. Animals were fed a Western diet for four weeks, after which they were switched back to a diet of their normal chow. The results showed that when animals were fed the Western diet they demonstrated transient hypercholesterolemia and systemic inflammatory responses, but these responses returned to normal when the animals were put back on their regular chow. Notably, “the unhealthy diet led to an unexpected increase in the number of certain immune cells in the blood of the mice, especially granulocytes and monocytes,” comments co-author Anette Christ, Ph.D., a postdoctoral fellow at the Institute of Innate Immunity at the University of Bonn. “This was an indication for an involvement of immune cell progenitors in the bone marrow.”

Further tests by the researchers indicated that the Western diet triggered transcriptional changes in the animals’ bone marrow progenitor cells that persisted, even after the mice were put back on their regular chow. Despite this dietary switchback the genetic reprogramming of the immune cells and their precursors persisted. “…WD feeding induced a complex myeloid cell reprograming leading to longlasting and qualitatively altered hyper-responsiveness even after resting mice from WD feeding, ” the authors write. Further analysis showed that these changes primed immune system cells to trigger enhanced innate immune responses.”

“Genomic studies did, in fact, show that the Western diet had activated a large number of genes in the progenitor cells,” notes co-author Prof. Dr. Joachim Schultze, from the Life & Medical Sciences Institute (LIMES) at the University of Bonn and the German Center for Neurodegenerative Diseases (DZNE). “The genes affected included those responsible for proliferation and maturation.”

Examination of blood cells from animals that had shown a particularly strong innate immune system training effect found genetic evidence for involvement of the NLRP3 inflammasome signaling complex as the Western diet “sensor.” Inflammasomes recognize pathogens and other harmful substances and trigger inflammatory responses. The researchers don’t yet know how the NLRP3 inflammasome recognizes a Western-style diet, but what is apparent is that unhealthy eating triggers the epigenetic changes that underpin the maintenance of long-term heightened innate immune memory. “The inflammasome triggers such epigenetic changes,” Dr. Latz comments. “The immune system consequently reacts even to small stimuli with stronger inflammatory responses such as hematopoiesis and maintenance of a hyperresponsive state with the generation of myeloid cells that are programmed to respond to secondary inflammatory triggers more potently.”

The authors acknowledge that more studies will be needed to “clarify the important question as to which cell-type activation of the inflammasome is required to induce the observed epigenetic reprogramming effects we have demonstrated.” Nevertheless, they write, “Mechanistically, we identified the NLRP3 inflammasome as the central receptor, which mediates WD-induced systemic inflammation and myeloid precursor reprogramming, opening therapeutic opportunities to interfere with WD-associated pathologies….Hence, this may pave the road for new therapeutic CVD interventions, such as the use of small molecule inhibitors that block the NLRP3 signaling pathway.”

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