Morphine mediated neutrophil infiltration in intestinal tissue play essential role in histological damage and microbial dysbiosis

Abstract

The gut microbial ecosystem exhibits a complex bidirectional communication with the host and is one of the key contributing factors in determining mucosal immune homeostasis or an inflammatory state. Opioid use has been established to induce gut microbial dysbiosis consistent with increased intestinal tissue inflammation. In this study, we investigated the role of infiltrated immune cells in morphine-induced intestinal tissue damage and gut microbial dysbiosis in mice. Results reveal a significant increase in chemokine expression in intestinal tissues followed by increased neutrophil infiltration post morphine treatment which is direct consequence of a dysbiotic microbiome since the effect is attenuated in antibiotics treated animals and in germ-free mice. Neutrophil neutralization using anti-Ly6G monoclonal antibody showed a significant decrease in tissue damage and an increase in tight junction protein organization. 16S rRNA sequencing on intestinal samples highlighted the role of infiltrated neutrophils in modulating microbial community structure by providing a growth benefit for pathogenic bacteria, such as Enterococcus , and simultaneously causing a significant depletion of commensal bacteria, such as Lactobacillus . Taken together, we provide the first direct evidence that neutrophil infiltration contributes to morphine-induced intestinal tissue damage and gut microbial dysbiosis. Our findings implicate that inhibition of neutrophil infiltration may provide therapeutic benefits against gastrointestinal dysfunctions associated with opioid use.

Exopolysaccharides Produced by Bifidobacterium longum subsp. longum YS108R Ameliorates DSS-Induced Ulcerative Colitis in Mice by Improving the Gut Barrier and Regulating the Gut Microbiota

“…Of note, Coriobacteriaceae UCG-002 , Butyricimonas , Parabacteroides , Ruminococcaceae UCG-010 , and Ruminococcaceae UCG-014 are known to produce SCFAs, primarily propionate and butyrate. ,− Moreover, the relative abundances of Enterococcus , Lachnospiraceae NK4A136 group , and Escherichia-Shigella were noticeably diminished by YS108R EPS treatment. Enterococcus , a well-studied pathogenic genus, impairs the intestinal epithelial barrier through disruption of TJ function, becoming a contributor to gut inflammation, and is heavily enriched in patients with intestinal diseases, such as CRC and CD . A study suggested that UC mice were accompanied by a decrease in the relative abundance of Lachnospiraceae NK4A136 group , which was contrary to our findings, however, it has also been reported that Lachnospiraceae NK4A136 group showed a significant inverse association with SOD and T-AOC, but a positive association with MDA …”

Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice

“…In particular, metabolic changes in morphine-tolerant mice were mitigated, raising the question of whether changes in the plasma metabolites following acute morphine intake were contributing to morphine analgesic effects and whether they could serve as tolerance indicators. The role of metabolic changes in morphine-mediated pathologies [ 43 , 51 , 52 , 53 , 54 , 55 ] demands additional studies. Our findings warrant further investigation in other morphine tolerance models and humans.…”

Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell‐derived secretome in preclinical models of morphine dependence

“…This activation could potentially occur via direct downstream signaling of the μ‐opioid receptor, 85 as well as via the activation of the TLR‐4 signaling pathway, binding to the adaptor molecule MD‐2, within the central nervous system 25,86 . Recent studies have described the role of morphine to induce peripheral inflammation, specifically by inducing dysbiosis and amplifying bacterial translocation from the intestine to the liver and mesenteric lymph nodes 87–89 . This cascade of events potentially triggers a systemic pro‐inflammatory state, 90,91 thereby underscoring a new mechanism of action in opioid dependence that merits further exploration.…”

“… 25 , 86 Recent studies have described the role of morphine to induce peripheral inflammation, specifically by inducing dysbiosis and amplifying bacterial translocation from the intestine to the liver and mesenteric lymph nodes. 87 , 88 , 89 This cascade of events potentially triggers a systemic pro‐inflammatory state, 90 , 91 thereby underscoring a new mechanism of action in opioid dependence that merits further exploration. These findings highlight the complex interplay among opioid addiction, secretome treatment, and neuroinflammation, providing information for future studies to evaluate these mechanisms.…”