Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis

Abstract

Atopic dermatitis (AD), also known as eczema, is one of the most common chronic skin conditions worldwide, affecting up to 16% of children and 10% of adults. It is incurable and has significant psychosocial and economic impacts on the affected individuals. AD etiology has been linked to deficiencies in the skin barrier protein, filaggrin. In mammalian skin, l-histidine is rapidly incorporated into filaggrin. Subsequent filaggrin proteolysis releases l-histidine as an important natural moisturizing factor (NMF). In vitro studies were conducted to investigate the influence of l-histidine on filaggrin processing and barrier function in human skin-equivalent models. Our further aim was to examine the effects of daily oral l-histidine supplementation on disease severity in adult AD patients. We conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study to explore the effects of oral l-histidine in adult AD patients (n=24). In vitro studies demonstrated that l-histidine significantly increased both filaggrin formation and skin barrier function (P<0.01, respectively). Data from the clinical study indicated that once daily oral l-histidine significantly reduced (P<0.003) AD disease severity by 34% (physician assessment using the SCORingAD tool) and 39% (patient self-assessment using the Patient Oriented Eczema Measure tool) after 4 weeks of treatment. No improvement was noted with the placebo (P>0.32). The clinical effect of oral l-histidine in AD was similar to that of mid-potency topical corticosteroids and combined with its safety profile suggests that it may be a safe, nonsteroidal approach suitable for long-term use in skin conditions that are associated with filaggrin deficits such as AD.

Keywords: amino acid; atopic dermatitis; eczema; filaggrin; l-histidine; nutritional supplement; skin barrier.

Figure 1

L-histidine increases filaggrin protein formation in confluent human (HaCaT) keratinocyte monolayers. (A) Representative Western blots showing a decrease in 120 kDa filaggrin and an increase in 37 kDa filaggrin formation after treatment with L-histidine. (B) L-lysine and D-histidine had no significant effect on filaggrin protein expression while L-histidine increased the 37 kDa to 120 kDa filaggrin ratio (P<0.01), as compared to controls. (C) L-histidine increased the 37 kDa:120 kDa filaggrin ratio in a dose-dependent manner (R²=0.54, P<0.01). Error bars represent mean ± SD, where n=6. All bands were standardized to housekeeping protein keratin 10 loading control. ^**p<0.01. Abbreviations: OD, optical density; WB, Western blot.

Figure 2

L-histidine enhances the barrier function of organotypic skin model as indicated by penetration of Lucifer Yellow fluorescent dye. (A) A representative image of organotypic skin model with Lucifer Yellow dye seen under fluorescence and H&E staining. (B) Skin models grown in 5 mM L-histidine had reduced dye penetration (N=5; P<0.01), whereas L-lysine and L-serine had no effect on barrier function. Note: ^**p<0.01, n=5. Abbreviation: H&E, hematoxylin and eosin.

Figure 3

Clinical study protocol and patient details. (A) Schema showing the study protocol, (B) patients completed POEM questionnaires weekly, and (C) disposition of patients. There was a good correlation between SCORAD and POEM scores (R²=0.62) in study patients in Group A (■) (n=11) and Group B (□) (n=10) at week 0. There was no difference in mean SCORAD or POEM scores between the two groups (P=0.86). Abbreviations: POEM, Patient Oriented Eczema Measure; SCORAD, SCORing Atopic Dermatitis; WO, washout period.

Figure 4

Effects of L-histidine nutritional supplementation on AD disease severity. (A) SCORAD and (B) POEM scores (mean ± SEM) were significantly reduced in Group A (■) patients at weeks 4 and 8 (SCORAD, P=0.0029 and P=0.0029; POEM, P=0.0020 and P=0.0010, respectively) in period 1, whilst the placebo had no effect in Group B (□) patients in period 1 (SCORAD, P=0.3223 and P=0.5391; POEM, P=0.8438 and P=0.2695, respectively). There is a clear “carry-over”effect of L-histidine in Group A between weeks 8 and 12, which precludes meaningful statistical analysis within the study period 2. Abbreviations: AD, atopic dermatitis; POEM, Patient Oriented Eczema Measure; SCORAD, SCORing Atopic Dermatitis; SEM, standard error of the mean; WO, washout period.