The Role of Butyrate in Attenuating Pathobiont-Induced Hyperinflammation

Abstract

An excessive hyperinflammatory response-caused septic shock is a major medical problem that is associated with pathogenic bacterial infections leading to high mortality rates. The intestinal microbiota and the associated elaborated metabolites such as short chain fatty acid butyrate have been shown to relieve pathogenic bacterial-caused acute inflammation. Butyrate can down-regulate inflammation by inhibiting the growth of pathobionts, increasing mucosal barrier integrity, encouraging obligate anaerobic bacterial dominance and decreasing oxygen availability in the gut. Butyrate can also decrease excessive inflammation through modulation of immune cells such as increasing functionalities of M2 macrophages and regulatory T cells and inhibiting infiltration by neutrophils. Therefore, various approaches can be used to increase butyrate to relieve pathogenic bacterial-caused hyperinflammation. In this review we summarize the roles of butyrate in attenuating pathogenic bacterial-caused hyperinflammatory responses and discuss the associated plausible mechanisms.

Keywords: Butyrate; Hyperinflammation; Macrophages; Pro-inflammatory cytokines; Regulatory T-cells; Septic shock.

Figure 1. Butyrate-promoting mucin production. Butyrate produced from fibers by bacterial fermentation. Butyrate stimulates goblet cells to produce mucins. Butyrate also stimulates colonocytes to produce AMPs and IgAs.

Figure 2. Increased anti-microbial effect of macrophages by butyrate. Butyrate activates AMPK which blocks mTOR activity. Butyrate also blocks mTOR activity through inhibiting PI3K/Akt and MAPK activities. The mTOR blocks LC3, which stimulates ROS to increase phagocytosis. The mTOR can increase the production of IL-6 and TNF-α, which activate mTOR upsteam pathways PI3K/Akt and MAPK to form feed-forward regulation loop.

AMPK, adenosine monophosphate-activated protein kinase; LC3, microtubule-associated protein 1A/1B-light chain 3.

Figure 3. Butyrate limits pathogen expansion through regulating oxygen availability. Butyrate decreases gut oxygen availability though activation of PPAR-γ pathway, Tregs and commensal E. coli. Limited oxygen availability decreases pathogen expansion.

Figure 4. Anti-septic effect of butyrate. Pathogens can cause excessive inflammation, which can result in septic shock. Butyrate can limit both pathogens infection through mucosal barrier and oxygen availability, and excessive inflammation through activation of M2 macrophages, Tregs and inhibition of neutrophils.