Prescription Opioids induce Gut Dysbiosis and Exacerbate Colitis in a Murine Model of Inflammatory Bowel Disease

Sharma, Umakant; Olson, Rohini; Erhart, Federico Nicolas; Zhang, Li; Meng, Jingjing; Segura, Bradley J.; Banerjee, Santanu; Sharma, Madhulika; Saluja, Ashok K.; Ramakrishnan, Sundaram; Abreu, María T.; Roy, Sabita

doi:10.1093/ecco-jcc/jjz188

Cited by 45 publications

(39 citation statements)

References 61 publications

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“…Recent studies have, therefore, investigated how the interactions between gut microbiota and the immune system influence the development of IBD. It is proposed that a compromised mucosal immune function, including an increase in intestinal permeability or epithelial cell injury, may enable an abnormally high concentration of pathogens to be transmitted to underlying lamina propria, consequently triggering a persistent inflammation response in genetically susceptible individuals [ 107 ].…”

Section: Intestinal Microbiota and Ibdmentioning

confidence: 99%

Dietary Regulation of the Crosstalk between Gut Microbiome and Immune Response in Inflammatory Bowel Disease

Yao

Fan

et al. 2021

Foods

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Inflammatory bowel disease (IBD), a chronic, recurring inflammatory response, is a growing global public health issue. It results from the aberrant crosstalk among environmental factors, gut microbiota, the immune system, and host genetics, with microbiota serving as the core of communication for differently-sourced signals. In the susceptible host, dysbiosis, characterized by the bloom of facultative anaerobic bacteria and the decline of community diversity and balance, can trigger an aberrant immune response that leads to reduced tolerance against commensal microbiota. In IBD, such dysbiosis has been profoundly proven in animal models, as well as clinic data analysis; however, it has not yet been conclusively ascertained whether dysbiosis actually promotes the disease or is simply a consequence of the inflammatory disorder. Better insight into the complex network of interactions between food, the intestinal microbiome, and host immune response will, therefore, contribute significantly to the diagnosis, treatment, and management of IBD. In this article, we review the ways in which the mutualistic circle of dietary nutrients, gut microbiota, and the immune system becomes anomalous during the IBD process, and discuss the roles of bacterial factors in shaping the intestinal inflammatory barrier and adjusting immune capacity.

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Section: Intestinal Microbiota and Ibdmentioning

confidence: 99%

Dietary Regulation of the Crosstalk between Gut Microbiome and Immune Response in Inflammatory Bowel Disease

Yao

Fan

et al. 2021

Foods

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“…Our earlier study has shown that morphine could exaggerate DSS-induced mucosal inflammation syndrome 15 . As shown in Figure 7 , the EVs that are derived from intestinal organoid, rather than morphine-treated organoid, could efficiently alleviate colitis.…”

Section: Resultsmentioning

confidence: 93%

Immune modulation mediated by extracellular vesicles of intestinal organoids is disrupted by opioids

et al. 2021

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Extracellular Vesicles (EVs) are effective mediators of intercellular communications between enterocytes and immune cells. The current study showed that EVs isolated from mouse and human intestinal organoids modulated inflammatory responses of various immune cells including mouse bone-marrow derived-macrophages, dendritic cells, microglia cells, and human monocytes. EVs suppressed LPS-elicited cytokine production in these cells while morphine abolished EVs’ immune modulatory effects. Microarray analysis showed that various microRNAs, especially Let-7, contributed to EV-mediated immune modulation. Using murine models, we showed that injection of EVs derived from intestinal organoids reduced endotoxin-induced systemic inflammation and alleviated the symptoms of DSS-induced colitis. EVs derived from morphine-treated organoids failed to suppress the immune response in both these models. Our study suggests that EVs derived from intestinal crypt cells play crucial roles in maintaining host homeostasis and opioid use is a risk factor for exacerbating inflammation in patients with inflammatory diseases such as sepsis and colitis.

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“…Regarding opioid-induced dysbiosis, to date, most of the data originate from preclinical studies, in which mice were exposed to morphine for different time periods [128,129,131,[133][134][135]. However, in some experiments, other opioid agents were used, such as loperamide [136,137] or hydromorphone [138], and there are some common patterns in the microbial composition of animals irrespective of the type of opioid used, allowing to draw some general conclusions on the effect of opioids on microbiota. Moreover, some of these changes have also been observed in non-human primates [139], as well as in opioid user cirrhotic patients compared to those not on opioids [140], or in heroin addicts [141], further supporting the complexity and translational relevance of the results.…”

Section: The Role Of Mors In the Gut Microbiota: Dysbiosis Opioid Tolerancementioning

confidence: 99%

“…Hence, opioid-induced microbial alterations can generate a pro-inflammatory milieu, which can compromise the gut epithelial barrier and allow luminal aggressive factors (bacteria, bile acids) to penetrate into the gut wall and trigger an immune response, further amplifying the initial inflammation. Gut inflammation in response to opioid administration is typically characterized by enhanced intestinal permeability, the activation of Toll-like receptor-2 (TLR-2), TLR-4, and elevated levels of various pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17) in the intestine, mesenteric lymph nodes, and remote organs [128,133,134,138].…”

Section: The Role Of Mors In the Gut Microbiota: Dysbiosis Opioid Tolerancementioning

confidence: 99%

“…Moreover, the genetic deletion of TLR-2 had a more pronounced inhibitory effect on the development of opioid tolerance than deletion of TLR-4 (which is primarily activated by the Gram-negative cell wall component lipopolysaccharide) [128]. Among the Gram-positive bacteria Enterococcus may be of particular relevance, as it blooms in the gut of opioid-treated animals [129,133,134,138] and can also be detected in the peritoneal organs of these animals due to impaired epithelial barrier and bacterial translocation [133]. Further evidence for the importance of this pathogen is that infection with Enterococcus faecalis augmented the development of morphine tolerance in mice [129].…”

Section: The Role Of Mors In the Gut Microbiota: Dysbiosis Opioid Tolerancementioning

confidence: 99%

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On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

et al. 2020

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There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.

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Prescription Opioids induce Gut Dysbiosis and Exacerbate Colitis in a Murine Model of Inflammatory Bowel Disease

Cited by 45 publications

References 61 publications

Dietary Regulation of the Crosstalk between Gut Microbiome and Immune Response in Inflammatory Bowel Disease

Dietary Regulation of the Crosstalk between Gut Microbiome and Immune Response in Inflammatory Bowel Disease

Immune modulation mediated by extracellular vesicles of intestinal organoids is disrupted by opioids

On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

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