The reduced SCFA-producing gut microbes are involved in the inflammatory activation in Kawasaki disease

Abstract

Kawasaki disease (KD), an acute febrile systemic vasculitis in children, has become the leading cause of acquired heart disease in developed countries. Recently, the altered gut microbiota was found in KD patients during the acute phase. However, little is known about its characteristics and role in the pathogenesis of KD. In our study, an altered gut microbiota composition featured by the reduction in SCFAs-producing bacteria was demonstrated in the KD mouse model. Next, probiotic Clostridium butyricum (C. butyricum) and antibiotic cocktails were respectively employed to modulate gut microbiota. The use of C. butyricum significantly increased the abundance of SCFAs-producing bacteria and attenuated the coronary lesions with reduced inflammatory markers IL-1β and IL-6, but antibiotics depleting gut bacteria oppositely deteriorated the inflammation response. The gut leakage induced by dysbiosis to deteriorate the host’s inflammation was confirmed by the decreased intestinal barrier proteins Claudin-1, Jam-1, Occludin, and ZO-1, and increased plasma D-lactate level in KD mice. Mechanistically, SCFAs, the major beneficial metabolites of gut microbes to maintain the intestinal barrier integrity and inhibit inflammation, was also found decreased, especially butyrate, acetate and propionate, in KD mice by gas chromatography-mass spectrometry (GC-MS). Moreover, the reduced expression of SCFAs transporters, monocarboxylate transporter 1 (MCT-1) and sodium-dependent monocarboxylate transporter 1 (SMCT-1), was also shown in KD mice by western blot and RT-qPCR analyses. As expected, the decrease of fecal SCFAs production and barrier dysfunction were improved by oral C. butyricum treatment but was deteriorated by antibiotics. In vitro, butyrate, not acetate or propionate, increased the expression of phosphatase MKP-1 to dephosphorylate activated JNK, ERK1/2 and p38 MAPK against excessive inflammation in RAW264.7 macrophages. It suggests a new insight into probiotics and their metabolites supplements to treat KD.

Advancing lifelong precision medicine for cardiovascular diseases through gut microbiota modulation

“…established a mouse model of KD using a water-soluble component of Candida albicans and observed a reduction in SCFA-producing bacteria in the gut of KD model mice, accompanied by compromised intestinal barrier function and exacerbated inflammatory responses in KD. 60 However, when supplemented with butyrate-producing bacteria, the mice demonstrated alleviated intestinal barrier damage. Subsequent experiments involving butyrate supplementation in KD mice revealed decreased circulating levels of IL-6 and TNF-α and reduced inflammatory cell infiltration in the coronary arteries, implying a beneficial role of the gut microbiota-derived metabolite, butyrate, in KD.…”

“…Kawasaki disease (KD), an acute febrile systemic vasculitis primarily occurring in children, is a major cause of acquired heart disease in this population, often resulting in coronary artery lesions. 60 The majority of KD patients (approximately 80%) are under the age of 5. While the precise etiology of KD remains elusive, abnormal immune responses, such as aberrant neutrophil activation, excessive expansion of Th17 cells, depletion of Treg cells, and overproduction of inflammatory factors (e.g., IL-1, IL-2, IL-6, IL-8, and TNF-α), have been implicated in this condition.…”

Gut Microbiota and Vascular Diseases: An Update

“…Kawasaki disease (KD), an acute febrile disease characterized by destruction of small and mid-sized arteries, is the leading cause of acquired heart disease in children [65,67]. The interplay between the gut microbiota and KD has gradually been revealed [65,68]. Microbial diversity has consistently been found to be diminished in patients with KD in various studies, although the alterations in the gut microbiota have varied, partially because of differences in study populations and methods [67,69,70].…”

“…Notably, Enterococcus and Helicobacter were positively associated with IL-6 levels in patients with KD, and Fusobacteria, Shigella, and Streptococcus were positively with KD activity [67,71]. Recently, Wang's data have revealed that gut microbiota producing SCFAs are significantly diminished in KD model mice [68]. Intriguingly, administration of Clostridium butyricum enriches SCFA-producing bacteria and abolishes the progression of KD, and is accompanied by decreases in IL-1β and IL-6, and maintenance of intestinal barrier integrity [68].…”

“…Recently, Wang's data have revealed that gut microbiota producing SCFAs are significantly diminished in KD model mice [68]. Intriguingly, administration of Clostridium butyricum enriches SCFA-producing bacteria and abolishes the progression of KD, and is accompanied by decreases in IL-1β and IL-6, and maintenance of intestinal barrier integrity [68]. Mechanistic explorations have further demonstrated that butyrate, but not other SCFAs, contribute to the protective effects through elevated phosphatase MKP-1 and downregulated MAPK pathways [68].…”