# Postbiotics and Nicotinamide Utilize Distinct Mechanisms to Improve Skin Barrier Integrity, Inflammation, and Keratinocyte Differentiation

## TL;DR

This study shows how postbiotics and nicotinamide improve skin health through different mechanisms, including boosting skin barrier function and reducing inflammation.

## Contribution

The study reveals strain-specific and distinct mechanisms of postbiotics and nicotinamide in regulating skin barrier and inflammation using integrated multiomics and machine learning.

## Key findings

- B. breve promotes keratinocyte differentiation and suppresses inflammation.
- NAM reduces inflammation but downregulates keratinocyte differentiation.
- Postbiotics and NAM mitigate skin damage from cleansers, supporting their therapeutic potential.

## Abstract

The modulation of immune responses and tissue regeneration by postbiotics is a rapidly advancing area in skin care. Here, we show that whole‐cell postbiotics derived from
Bifidobacterium breve
, Limosilactobacillus reuteri, and Ligilactobacillus salivarius, along with nicotinamide (NAM), enhance keratinocyte growth, differentiation, and skin epithelial barrier integrity in ex vivo human skin, as determined by electrical impedance spectroscopy (EIS), multiomics, and machine learning.
B. breve
promoted keratinocyte differentiation and suppressed inflammatory pathways, while
L. reuteri
and
L. salivarius
primarily reduced inflammatory pathways. Although NAM downregulated keratinocyte differentiation, it exerted anti‐inflammatory effects. Machine learning analyses linked EIS changes to certain genes, highlighting strain‐specific mechanisms. In addition,
B. breve
,
L. reuteri
, and NAM mitigated a common skin cleanser‐induced skin epithelial damage, further supporting their therapeutic potential. In conclusion, integrating skin barrier measurements with omics and machine learning enabled the dissection of essential anti‐inflammatory and keratinocyte differentiation mechanisms and genes of a strengthened skin barrier.

Integrating skin barrier measurements with omics and machine learning, we found that postbiotics and NAM regulate skin homeostasis through distinct, strain‐ and dose‐dependent mechanisms. Postbiotics primarily modulate skin barrier function by promoting keratinocyte differentiation and suppressing inflammation. Together, integrated functional, molecular, and machine learning analyses identify key pathways underlying skin barrier regulation. EIS, electrical impedance spectroscopy; ETV4, ETS translocation variant 4; KRT81, keratin 81; LATS2, large tumor suppressor kinase 2; LC–MS, liquid chromatography‐mass spectrometry; mM, millimolar; NAM, nicotinamide; NOTCH1, neurogenic locus notch homolog protein 1; OVOL2, ovo‐like zinc finger 2; RNA‐seq, RNA sequencing; w/v, weight/volume.