Lactobacillus paracasei-derived extracellular vesicles attenuate the intestinal inflammatory response by augmenting the endoplasmic reticulum stress pathway

Abstract

Lactobacillus paracasei is a major probiotic and is well known for its anti-inflammatory properties. Thus, we investigated the effects of L. paracasei-derived extracellular vesicles (LpEVs) on LPS-induced inflammation in HT29 human colorectal cancer cells and dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. ER stress inhibitors (salubrinal or 4-PBA) or CHOP siRNA were utilized to investigate the relationship between LpEV-induced endoplasmic reticulum (ER) stress and the inhibitory effect of LpEVs against LPS-induced inflammation. DSS (2%) was administered to male C57BL/6 mice to induce inflammatory bowel disease, and disease activity was measured by determining colon length, disease activity index, and survival ratio. In in vitro experiments, LpEVs reduced the expression of the LPSinduced pro-inflammatory cytokines IL-1α, IL-1β, IL-2, and TNFα and increased the expression of the anti-inflammatory cytokines IL-10 and TGFβ. LpEVs reduced LPS-induced inflammation in HT29 cells and decreased the activation of inflammation-associated proteins, such as COX-2, iNOS and NFκB, as well as nitric oxide. In in vivo mouse experiments, the oral administration of LpEVs also protected against DSS-induced colitis by reducing weight loss, maintaining colon length, and decreasing the disease activity index (DAI). In addition, LpEVs induced the expression of endoplasmic reticulum (ER) stress-associated proteins, while the inhibition of these proteins blocked the anti-inflammatory effects of LpEVs in LPS-treated HT29 cells, restoring the pro-inflammatory effects of LPS. This study found that LpEVs attenuate LPS-induced inflammation in the intestine through ER stress activation. Our results suggest that LpEVs have a significant effect in maintaining colorectal homeostasis in inflammation-mediated pathogenesis.

Lactobacillus reuteri-derived extracellular vesicles maintain intestinal immune homeostasis against lipopolysaccharide-induced inflammatory responses in broilers

“…IL-10 and TGF-β mainly mediate the negative regulation of inflammatory responses by suppressing the production of pro-inflammatory cytokines [ 55 , 56 ]. Similar suppression of pro-inflammatory cytokines and activation of anti-inflammatory cytokines induced by L. paracasei -derived EVs have also been observed with LPS-challenged human colon cancer cells [ 15 ]. Furthermore, several studies have demonstrated that probiotics-derived EVs controlled inflammatory responses by modulating the cytokine production in the host’s immune cells [ 31 , 42 ].…”

“…Only recently has it been increasingly interested in the mechanism of EVs secretion by which probiotics and commensal microbiota communicate with the host. Previous studies have revealed that EVs derived from several probiotics and commensal bacteria, such as Bacteroides fragilis [ 42 ], Akkermansia muciniphila [ 43 ], Escherichia coli Nissle 1917 [ 44 ], Bifidobacterium longum [ 45 ] and Lactobacillus paracasei [ 15 ], exerted similar effects as their parental bacteria. Consistent with these studies, we discovered that L. reuteri BBC3 could produce relatively high quantities of EVs, and treatment of broiler chicks with LrEVs reproduced the protective effects of L. reuteri BBC3 on LPS-induced lower performance and intestinal injury and inflammation.…”

“…Li et al [ 13 ] showed that L. plantarum WCFS1 secreted EVs with an average size of 101 nm. EVs derived from L. acidophilus and L. paracasei have also been isolated and characterized [ 14 , 15 ]. Recently, several studies also demonstrated the existence of EVs in L. reuteri strains [ 14 , 16 ].…”

Probiomimetics—Novel Lactobacillus‐Mimicking Microparticles Show Anti‐Inflammatory and Barrier‐Protecting Effects in Gastrointestinal Models

“…these effects seem to be related to multiple mechanisms, such as the reduction of NO‐production and the amelioration of endoplasmic reticulum stress. [ 51 ]…”

Endoplasmic Reticulum Stress and Intestinal Inflammation: A Perilous Union

“…Prevalence of Fusobacterium activates UPR and promotes inflammation in UC patients (72). Probiotic bacteria such as Lactobacillus paracasei ameliorated intestinal inflammation through ER stress-UPR pathway (73). On the contrary, Lactobacillus acidophilus mitigated intestinal inflammation by suppressing NF-kB and thereby inhibiting ER stress (74).…”