Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation

Abstract

Summary Host factors in the intestine help select for bacteria that promote health. Certain commensals can utilize mucins as an energy source, thus promoting their colonization. However, health conditions such as inflammatory bowel disease (IBD) are associated with a reduced mucus layer, potentially leading to dysbiosis associated with this disease. We characterize the capability of commensal species to cleave and transport mucin-associated monosaccharides and identify several Clostridiales members that utilize intestinal mucins. One such mucin utilizer, Peptostreptococcus russellii, reduces susceptibility to epithelial injury in mice. Several Peptostreptococcus species contain a gene cluster enabling production of the tryptophan metabolite indoleacrylic acid (IA) that promotes intestinal epithelial barrier function and mitigates inflammatory responses. Furthermore, metagenomic analysis of human stool samples reveals that the genetic capability of microbes to utilize mucins and metabolize tryptophan is diminished in IBD patients. Our data suggest that stimulating IA production could promote anti-inflammatory responses and have therapeutic benefits.

Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes

“…Conversely, commensals produce electrophilic metabolites that engage the host antioxidant response. Peptostreptococcus rusellii reduce susceptibility to epithelial injury in mice and contain a unique biosynthetic gene cluster enabling production of the tryptophan metabolite, indoleacrylic acid (Wlodarska et al, 2017). This electrophilic compound directly engages the Keap1/Nrf2-dependent antioxidant response to limit inflammatory cytokine production in macrophages (Wlodarska et al, 2017).…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…For example, tryptophan catabolites, detected by pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AhR), drive a multitude of anti‐inflammatory and protective barrier functions. IEC AhR sensing of dietary components and tryptophan catabolites contributes to the maintenance of intestinal barrier integrity by inducing IEC differentiation from crypt stem cells and mitigating inflammatory responses . PXR was recently shown to respond to indole 3‐propionic acid, a tryptophan metabolite produced by commensal Clostridium sporogenes , and mice deficient for PXR exhibited increased epithelial inflammatory injury and decreased tight junction protein expression.…”

Functions of the Microbiota for the Physiology of Animal Metaorganisms

“…On the one hand, bacteria may trigger host immunity if they are in too close proximity to the mucosa. Therefore, the majority of bacteria reside in the lumen or outer mucus layer [8, 9], and structure and metabolic function differ greatly between bacteria residing in the lumen and the outer layer, which is rich in mucus-related sugars [9, 10]. On the other hand, the production of mucus is stimulated by the microbiome, as various microbial molecules (e.g., lipopolysaccharides) trigger mucus production [8, 9].…”

“…Additionally, tryptophan-related compounds, which are derived from the utilization of mucus by microorganisms, influence the immunological profile of the host. Disbalances in this microorganism-mucus-host crosstalk are therefore associated with disease, for example inflammatory bowel disease (IBD) [10]. Taken together, the mucus promotes interactions between host and microbiome and thus serves as a connecting interface not only in the mammalian gastrointestinal tract, but also in the lung and other organisms such as basal metazoans.…”

“…Taken together, the mucus promotes interactions between host and microbiome and thus serves as a connecting interface not only in the mammalian gastrointestinal tract, but also in the lung and other organisms such as basal metazoans. This host-microbiome axis therefore plays a major role in health and disease of metaorganisms [10]. …”