The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

Akbarali, Hamid I.; Muchhala, Karan H.; Kang, Minho; Köşeli, Eda; Poklis, Justin L.; Xu, Qingguo; Dewey, William L.; Fettweis, Jennifer M.; Jimenez, Nicole

doi:10.21203/rs.3.rs-3084467/v1

2023

DOI: 10.21203/rs.3.rs-3084467/v1

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The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

Hamid I. Akbarali

Karan H. Muchhala

Minho Kang

et al.

Abstract: Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the gut epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that intestinal antimicrobial activity is reduced, and epithelial permeability is increased in a morphine-dependent mouse model. Antimicrobial activity and permeability are restored by fecal transplant (FMT) from morphine-naïve mice or by oral gavage of sodium butyrate. Butyrate levels are reduced in the fecal samples of morphine-tr… Show more

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Cited by 2 publications

References 70 publications

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Short-chain fatty acid, butyrate prevents morphine-and paclitaxel-induced nociceptive hypersensitivity

Jessup,

Woods,

Thakker

et al. 2023

Sci Rep

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Nociceptive hypersensitivity is a significant side effect with the chronic administration of opioids as well as chemotherapeutics. Both opioid-induced hypersensitivity (OIH) and chemotherapy-induced hypersensitivity (CIH) are characterized by an increased sensitivity to painful stimuli which can significantly reduce the quality of life for individuals on either drug(s). Here we demonstrate the nociceptive hypersensitivity associated with repeated administration of morphine (opioid) and paclitaxel (chemotherapeutic) treatment can be reversed by oral supplementation with the short-chain fatty acid (SCFA) sodium butyrate (NaBut). In two separate mouse behavioral models for nociceptive hypersensitivity, we found that thermal hyperalgesia (for OIH) and cold allodynia (for CIH) were prevented by treatment with oral butyrate (p.o, b.i.d). Electrophysiological recordings of small diameter dorsal root ganglia (DRG) neurons from morphine and paclitaxel treated mice showed an increase in neuronal hyperexcitability in both drug models which was likewise prevented by oral butyrate treatment. Using colonic conditioned media obtained from excised colon segments we found that gut mediators of morphine treated mice can induce hyperexcitability in naïve DRG neurons, but such enhanced excitability is not present when animals are co-treated with NaBut suggesting gut derived mediators modulate neuronal hyperexcitability. In-vitro NaBut treatment did not prevent morphine-induced excitability, suggesting an indirect role of butyrate in modulating neuronal hypersensitivity. These data taken together suggest that gut derived mediators affect opioid and chemotherapeutic-induced neuronal hypersensitivity that is prevented by the SCFA butyrate.

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Short-chain fatty acid, butyrate prevents morphine-and paclitaxel-induced nociceptive hypersensitivity

Jessup,

Woods,

Thakker

et al. 2023

Sci Rep

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Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study

Han,

Gao,

Wang

et al. 2024

Front. Microbiol.

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BackgroundPrevious researches have suggested a significant connection between the gut microbiota/immune cells and morphine tolerance (MT), but there is still uncertainty regarding their causal relationship. Hence, our objective is to inverstigate this causal association and reveal the impact of gut microbiota/immune cells on the risk of developing MT using a two-sample Mendelian randomization (MR) study.MethodsWe conducted a comprehensive analysis using genome-wide association study (GWAS) summary statistics for gut microbiota, immune cells, and MT. The main approach employed was the inverse variance-weighted (IVW) method in MR. To assess horizontal pleiotropy and remove outlier single-nucleotide polymorphisms (SNPs), we utilized the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) technique as well as MR-Egger regression. Heterogeneity detection was performed using Cochran’s Q-test. Additionally, leave-one-out analysis was carried out to determine if any single SNP drove the causal association signals. Finally, we conducted a reverse MR to evaluate the potential of reverse causation.ResultsWe discovered that 6 gut microbial taxa and 16 immune cells were causally related to MT (p < 0.05). Among them, 2 bacterial features and 9 immunophenotypes retained a strong causal relationship with lower risk of MT: genus. Lachnospiraceae NK4A136group (OR: 0.962, 95% CI: 0.940–0.987, p = 0.030), genus. RuminococcaceaeUCG011 (OR: 0.960, 95% CI: 0.946–0.976, p = 0.003), BAFF-R on B cell (OR: 0.972, 95% CI: 0.947–0.998, p = 0.013). Furthermore, 4 bacterial features and 7 immunophenotypes were identified to be significantly associated with MT risk: genus. Flavonifractor (OR: 1.044, 95% CI: 1.017–1.069, p = 0.029), genus. Prevotella9 (OR: 1.054, 95% CI: 1.020–1.090, p = 0.037), B cell % CD3-lymphocyte (OR: 1.976, 95% CI: 1.027–1.129, p = 0.026). The Cochrane’s Q test revealed no heterogeneity (p > 0.05). Furthermore, the MR-Egger and MR-PRESSO analyses reveal no instances of horizontal pleiotropy (p > 0.05). Besides, leave-one-out analysis confirmed the robustness of MR results. After adding BMI to the multivariate MR analysis, the gut microbial taxa and immune cells exposure-outcome effect were attenuated.ConclusionOur research confirm the potential link between gut microbiota and immune cells with MT, shedding light on the mechanism by which gut microbiota and immune cells may contribute to MT. These findings lay the groundwork for future investigations into targeted prevention strategies.

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The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

Cited by 2 publications

References 70 publications

Short-chain fatty acid, butyrate prevents morphine-and paclitaxel-induced nociceptive hypersensitivity

Short-chain fatty acid, butyrate prevents morphine-and paclitaxel-induced nociceptive hypersensitivity

Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study

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