Current insights on gut microbiome and chronic urticaria: progress in the pathogenesis and opportunities for novel therapeutic approaches

Figures & data

Figure 1. The manifestations and pathophysiology of chronic urticaria.

Both IgE-mediated type I and IgG-mediated type II allergies are the main pathophysiological mechanisms of CU, through which the MCs are activated and then release various inflammatory factors. Eosinophils, T cells and basophils can be recruited from the blood to the skin in response to these factors. Lower PH, higher permeability, elevated level of inflammation and the barrier disruption can be discovered in the intestine of CU patients, whose skins show wheals and angioedema.

CU, chronic urticaria; MCs, mast cells; PDG2, prostaglandin D2; TNF-ɑ, tumor necrosis factor-ɑ; IL, interleukin; FcεRI, high-affinity IgE receptor (By Figdraw).

Table 1. A summary of current evidence on the association between gut microbiome composition and chronic urticaria (mainly CSU).

Authors	Observation group (sample size)	Control group (sample size)	Detection technology	Increased gut microbiota in patients	Decreased gut microbiota in patients	Increased metabolites in vivo	Decreased metabolites in vivo	References	alpha diversity compared with control group
Zhu et.al (2023)	CSU (Stool:26; Blood:29)	HC (Stool:26; Blood:38)	metagenomics sequencing and short-chain fatty acids metabolomics	Family Enterobacteriaceae, Peptostreptococcaceae Genus Klebsiella Species Klebsiella pneumoniae, Bacteroides stercoris, Escherichia coli	Family Rikenellaceae Genus Alistipes Species Roseburia hominis, Clostridium leptum, Bacteroides, Ruminococcus obeum	LPS	SCFAs	Gut microbiota facilitate chronic spontaneous urticaria	Low
Wang et.al (2020)	CSU (10)	HC (10)	16S rRNA gene sequencing and untargeted metabolomic analyses	Family Enterobacteriacea	Phylum Firmicutes; Genus Bacteroides, Faecalibacterium, Bifidobacterium, Lactobacillus, Ruminococcaceae		docosahexaenoic acid, arachidonic acid, glutamate succinic acid	Gut Microbiome and Serum Metabolome Analyses Identify Unsaturated Fatty Acids and Butanoate Metabolism Induced by Gut Microbiota in Patients with Chronic Spontaneous Urticaria	Low
Wang et.al (2021）	CSU (39)	HC (40)	16S rRNA gene sequencing	Phylum Firmicutes, Genus Faecalibacterium, Roseburia, Lachnospira, Gemmiger, Prevotella, Bifidobacterium	Phylum Proteobacteria Genus Blautia, Ruminococcus, Oscillospira, Megamonas, Dialister, Bacteroides, Parabacteroides, Alistipes, Sutterella	a-mangostin, glycyrrhizic acid	3-indolepropionic acid, xanthine, isobutyric acid	Abnormalities in Gut Microbiota and Metabolism in Patients With Chronic Spontaneous Urticaria	low
Lu et.al (2019)	CU (10)	HC (10)	16S rRNA sequencing	Phylum Proteobacteria, Actinobacteria Order Enterobacteriales, Lactobacillales, Pseudomonadales Genus Veillonella, Sutterella, Streptococcus, Clostridium, Escherichia Species E. coli	Phylum Bacteroidetes Genus Faecalibacterium, Prevotella, Lachnobacterium Species Faecalibacterium prausnitzii, Prevotella copri, Bacteroides fragilis, Bacteroides plebeius			Altered Gut Microbiota Diversity and Composition in Chronic Urticaria	low
Nabizadeh et.al (2017)	CU (20)	HC (20)	Real-time PCR	Family Enterobacteriaceae	Genus: Akkermansia, muciniphila, Clostridium leptum, Faecalibacterium prausnitzii			Association of altered gut microbiota composition with chronic urticaria	low
Liu et.al (2021)	CSD (25)	HC (25)	16S ribosomal DNA sequencing, QPCR	Phylum Fusobacteria Class Gammaproteobacteria, Fusobacteria Order Enterobacteria, Fusobacteria Family Enterobacteriaceae, Fusobacteraceae, Peptostreptococcaceae, Streptococcaceae Genus Klebsiella	Phylum Firmicutes Class Clostridia, Alphaproteobacterial, Deltaproteobacteria Order Clostridiales, Rhodospirillales, Caulobacterales, Desulfovibrionales Family Ruminococceae, Rikenellaceae, Muribaculaceae, Christensenellaceae, Caulobacteraceae Genus/species Subdoligranulum, Ruminococcus bromii			Biomarkers of Gut Microbiota in Chronic Spontaneous Urticaria and Symptomatic Dermographism	low
Rezazadeh et.al (2018)	CU (20)	HC (20)	PCR, Real-time PCR		Genus Lactobacillus, Bifidobacterium			The protective effect of Lactobacillus and Bifidobacterium as the gut microbiota members against chronic urticaria
Luo et.al (2023)	CSU (15)	HC (15)	16S rRNA gene sequencing	Phylum Firmicutes Genus Faecalibacterium, Roseburia, Prevotella, Dialister, Coprococcus, Gemmiger, Oscillospira, Lachnospira	Phylum Bacteroidetes, Proteobacteria Genus Bacteroides, unidentified- Ruminococcus, Pseudomonas, Megamonas, Lactobacillus	purine and other nucleotide metabolites	Unsaturated fatty acids	Combined microbiome and metabolome analysis of gut microbiota and metabolite interactions in chronic spontaneous urticaria	high
Zhang et.al (2021)	CSU (20)	HC (20)	16s rRNA massive sequencing	Phylum Firmicutes, Bacteroidetes, Proteobacteria, Verrucomicrobia, Class Bacilli Order Enterobacterales Family Enterobacteriaceae	Genus Megamonas, Megasphaera, Dialister			Gut Microbiome Alterations and Functional Prediction in Chronic Spontaneous Urticaria Patients	No significant difference
Yüksekal et.al (2022)	CSU (20)	HC (20)	16S RNA sequencing, bioinformatic analysis	Phylum Bacteroidetes Family Lachnospiraceae, Ruminococcaceae, Clostridiaceae Genus Intestinibacter, Megasphaera, Sutterella	Order Clostridiales Family Bifidobacteriaceae, Lachnospiraceae, Ruminococcaceae, Veillonellaceae, Prevotellaceae, Coriobacteriaceae Genus Succinivibrio			Investigation of intestinal microbiome in chronic spontaneous urticaria patients	high
Ćesić et.al (2023)	CSU (22)	HC (23)	16S rRNA sequencing	Genus Bacteroides, Streptococcus, Agathobacter, Bifidobacterium, Lactobacillus	Class Clostridia Family Lachnospiraceae Genus Roseburia, Faecalibacterium, Ruminococcus, Lachnospira, Prevotella, Blautia, Coprococcus, Subdoligranulum, Eubacterium eligens			Association of Gut Lachnospiraceae and Chronic Spontaneous Urticaria	Low

CU: chronic urticaria; CSU: chronic spontaneous urticaria; HC: healthy control; SCFAs: short-chain fatty acids; LPS: lipopolysaccharide.

Figure 2. The alteration and influence of gut microbiome in chronic urticaria.

(a) Gut dysbiosis: decreased levels of SCFAs-producing pathogens, increased levels of opportunistic pathogens and relevant intestinal infections, including HP and parasite. (b) Changes of metabolites: the levels of SCFAs and unsaturated fatty acids are reduced in the intestine of CU patients, while those of LPS and purine metabolites are elevated. (c) Intensified inflammation in intestine: The upregulation of LPS and downregulation of SCFAs appear as a result of gut dysbiosis, contributing to the abnormal differentiation of naïve T cells. The levels of IL-4 and IL-17 are elevated due to more Th2 and Th17, and less Treg and Th1. MCs are activated to release some inflammatory mediators like IL-3, TNF-ɑ and histamine. (d) Roles of parasite infection: enhancing the sensitivity of MCs; breaking the mucosal barrier and amplify the intestinal permeability; producing metabolites and interact with DCs to influence the differentiation of naïve T cell; forming CIC (IgG and parasite antigen) and activate the complement system to promote the release of inflammatory mediators.

SCFAs, short chain fatty acids; HP, helicobacter pylori; CU, chronic urticaria; LPS, lipopolysaccharides; IL, interleukin; TNF-ɑ, tumor necrosis factor-ɑ; Th, T helper cells; Treg, regulatory T cells; MCs, mast cells; C3a, complement 3a; C5a, complement 5a; DCs, dendrite cells; CIC, immune complexes (By Figdraw).

Figure 3. Summary of relevant therapies of chronic urticaria targeted at gut microbiome.

Therapeutic approaches targeting gut microbiome in chronic urticaria. Gut microbiome-based therapeutics for CU including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), and others (helminth therapy and Mediterranean Diet). Treg, regulatory T cells (By Figdraw).