Switching briefly to a low-fat diet at the onset of an inflammatory disease such as psoriasis could have major repercussions on its trajectory in both the short and long term, preclinical research suggests.
The study showed how mice that changed diet for just a few days experienced systemic remodeling that affected both acute inflammatory responses and also imprinted on long-term tissue memory.
A low-fat diet for just four days blunted the amplification of psoriasis-like skin inflammation instigated in obese mice. Conversely, lean mice eating a high-fat diet temporarily experienced disease amplification to a level associated with chronic obesity.
Changes in local immune responsiveness could be seen months later after inflammation was triggered again, noted lead researcher Zewen Jiang, PhD, from the University of California at San Francisco, and co-workers.
“Together, these findings show that dietary state during a narrow temporal window can durably reprogram disease trajectory, suggesting that short-lived physiological states may become embedded in local immune memory when they coincide with tissue inflammation,” they reported in Nature.
Obesity substantially alters immunity in multiple contexts, including infection, autoimmunity, and cancer. Its impact is particularly pronounced on skin, exacerbating inflammation and complicating therapeutic responses.
Psoriasis—a type 17 inflammatory disease—is tightly linked with obesity.
The researchers examined whether comparatively brief dietary changes lasting only days—before remodeling across multiple organ systems is established—could acutely modify triggered inflammatory responses and durably imprint long-term tissue inflammatory memory.
Specifically, they tested whether a high-fat diet in the short or long term amplified inflammation after topical challenge to approximate psoriasis in lean mice and whether a low-fat diet restrained inflammation in obese mice.
In this way, the findings could reveal the consequences of the diet itself rather than merely the consequences of established obesity.
Just a week on the high-fat diet was enough to markedly exacerbate inflammation induced by the immune response modifier imiquimod, reshaping tissue immunity even when the animals were not obese. The impact was comparable to that seen in mice with chronic obesity, with the high-fat diet having an impact after four days.
There was a lasting change in local immune responsiveness that was evident months later after rechallenge, even after the animals were returned to a low-fat diet.
Feeding them glucose within the same time frame did not enhance the triggered inflammation, suggesting that simply increasing exposure to sugar did not have the same impact as a fat-enriched obesogenic diet.
Further investigation revealed that CD4+ T cells mediated the exacerbation seen with the high-fat diet, with pathogenic IL-1R1+ CD4+ T helper type 17 cells driving its effects. NLRP3 drives diet-amplified disease.
The high-fat diet at the onset of inflammatory disease amplified its recurrence weeks later after rechallenge and the animals had returned to a low-fat diet, indicating that diet shaped disease trajectory beyond the initial flare. CD4+ tissue-resident memory mediated dietary memory.
The GLP-1 receptor agonist semaglutide improved glucose handling, reduced body weight and adiposity, and lowered circulating insulin and leptin, but did not attenuate inflammatory responses amplified by the high-fat diet.
“Although longer-term treatment with GLP-1 receptor agonists and related incretin-based therapies may improve established psoriasis in patients with obesity or type 2 diabetes, our experiment addressed the distinct question of whether short-term semaglutide treatment blocks the additional amplification imposed by coincident HFD [high-fat diet] exposure,” the researchers pointed out.
“It did not, indicating that systemic metabolic improvement and diet-primed inflammatory susceptibility are separable.”
