NatureOct 30, 2026

Diet at the start of disease affects how tissues remember inflammation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Nov 1, 2026

Abstract

Transient exposure to a high-fat diet (HFD) for just 4 days significantly exacerbates skin inflammation in lean mice.

High-fat diet exposure at the onset of acute type 17 skin inflammation leads to disease severity comparable to chronic obesity.
Dietary changes outside the critical 4-day peri-initiation window do not affect the inflammatory response.
Switching obese mice to a low-fat diet during the same 4-day window completely prevents disease exacerbation.
Neutrophils are rapidly recruited to the skin during HFD exposure, displaying elevated levels of specific inflammatory markers.
Inhibition or depletion of neutrophils or the NLRP3 pathway reduces the inflammatory amplification caused by HFD.
Mice that experienced HFD at disease onset maintain an altered immune memory, leading to increased inflammation upon subsequent challenges.

Simplified

Obesity, which is often associated with prolonged exposure to an obesogenic diet, substantially alters immunity^1-7, but whether brief dietary changes shape acute inflammatory responses and long-term tissue memory remains unclear. Here we show that transient high-fat diet (HFD) exposure at the onset of acute type 17 skin inflammation exacerbates disease in lean mice to levels comparable to those associated with chronic obesity. This effect is restricted to a discrete 4-day peri-initiation window; HFD outside this window has no impact, whereas switching obese mice to a low-fat diet (LFD) during a similar window fully blunts disease amplification. Mechanistically, HFD rapidly recruits neutrophils into the skin, and neutrophils in challenged skin express high levels of Nlrp3 (ref. ⁸) and Il1b. Neutrophil depletion, genetic Nlrp3 deficiency and pharmacological NLRP3 inhibition each blunt the HFD-induced inflammatory amplification. These findings nominate a neutrophil-NLRP3-IL-1β axis that licences pathogenic IL-1R1⁺CD4⁺ T helper type 17 (T_H17) cells^9,10. After recovery, a chromatin-poised tissue-resident memory T cell population persists. Consequently, mice exposed to HFD at disease onset develop exaggerated inflammation upon recurrence, despite recovery and maintenance on LFD. Transient HFD similarly amplifies lung T_H17 inflammation through neutrophil- and IL-1R1-dependent mechanisms. 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 memory¹¹ when they coincide with tissue inflammation.

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Funding

Competing interests

Competing interests: J.B.C. and R.J.C. received grants from BMS, Janssen, Regeneron, Sanofi and Sun Pharma outside the submitted work. K.J.S. is a co-founder and equity holder of Merrifield Therapeutics and has equity in American Bioenhancement. K.J.S. has received research funds from Merck, Eli Lilly and Pfizer, and consulting fees from AbbVie, Novo Nordisk and American Bioenhancement. The Combes laboratory receives research support from Eli Lilly and Genentech for work unrelated to this Article. A.J.C. is a member of the scientific advisory board of Foundery Innovations and has received consulting fees from Survey Genomics. S.P.B. has received an honorarium from Amgen for a scientific seminar.

PubMed

Diet at the start of disease affects how tissues remember inflammation

Abstract

Full Text

Funding

Competing interests

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