TABLE 4.

Effects of opioid on gut microbiome and other systems.

Species	Opioid administration	Sample size	Effects on microbiome	Effects on microbial metabolites, immune and barrier system	Citations
Human	Active substance users (Heroin Methamphetamine Ephedrine)	Patients with substance use disorders n = 45 Control group n = 48	↑Species diversity index and the abundance of Thauera, Paracoccus, and Prevotella No changes specific to heroin, methamphetamine or ephedrine	NA	Xu et al., 2017
	Opioids use	Neither C. difficile infection nor colonization n = 25 C. difficile infection n = 3 C. difficile colonization n = 1	↑Alpha diversity	NA	Vincent et al., 2016
	Opioids use disorders	Cohort I(in-patient): On opioids n = 62, Not on opioids n = 82. Cohort II(out-patient): On opioids n = 72, Not on opioids n = 72	↓Autochthonous taxa (Ruminococcaceae and Clostridiales XIV) and Bacteroidaceae	↑Metabolism of aromatic amino acids ↑Degradation of branched-chain amino acids	Acharya et al., 2017
		With opioid use disorder n = 45 Without opioid use disorder n = 54	↑Bifidobacterium	NA	Barengolts et al., 2018
Mouse	Morphine Implanted pellet	25 mg morphine n = 5 30 mg naltrexone n = 5 Morphine + naltrexone n = 5 Placebo n = 5	↓Alpha-diversity ↑Enterococcus faecalis, Flavobacterium, Fusobacterium, Sutterella and Clostridium	↓Bile acids ↑Phosphatidylethanolamines and saturated fatty acids	Wang F. et al., 2018
		25 mg subcutaneous morphine sulfate pellet n = 7-8 Twice-daily intraperitoneal (i.p.) injections of escalating doses of morphine sulfate (10, 20, 30, 40 mg/kg, n = 7–8	Intermittent morphine ↑Ruminococcus spp. ↓Lactobacillus spp. Sustained morphine ↑Genera Clostridium ↑Family Rikenellaceae	NA	Lee K. et al., 2018
		Placebo +placebo microbiome n = 5 Placebo +morphine microbiome n = 5 Morphine + placebo microbiome n = 5 Morphine + morphine microbiome n = 5	↓Bacteroidetes, Lactobacillus and Clostridium ↑Firmicutes (Enterococcaceae, Staphylococcaceae, Bacillaceae, Streptococcaceae, and Erysipelotrichaceae)	↓Primary and secondary bile acids in the gut not in the liver ↑Level of coprostanol and cholesterol
		Poly-microbial sepsis mice model induced by cecal ligation and puncture (CLP) treated by 25 mg slow-release morphine pellet Placebo n = 5 Morphine n = 5 Placebo+CLP n = 5 Morphine+CLP n = 5	↑Firmicutes phylum (specifically the G+ bacterial species, Staphylococcus sciuri, Staphylococcus cohnii, Staphylococcus aureus, Enterococcus durans, Enterococcus casseliflavus, Enterococcus faecium, and Enterococcus faecalis) ↑Translocation of Gram-positive gut bacteria	↑CLP mice mortality, bacterial dissemination, IL-17A, IL-6.	Meng et al., 2015
		WT and m-opioid receptors (MOR) knockout (MORKO) mice administrated with 75 mg morphine pellets for 24 h n = 9–10	Chronic morphine compromises barrier function of gut epithelium Bacterial translocation to mesenteric lymph node (MLN) and liver	Disrupts tight junction organization between small intestinal epithelial cells; Disrupts tight junction organization between small intestinal epithelial cells.	Meng et al., 2013
	15 mg/kg morphine injection b.i.d. for 8 days	Saline group n = 6 Morphine group n = 7	↓Actinobacteria ↓Firmicutes ↓Bifidobacteriaceae ↓Lactobacillaceae	Disrupted gut epithelial barrier and promoted systemic Bacterial translocation; ↑TLR2 and TLR4 expression; ↑Sustained chronic systemic inflammation.	Zhang L. et al., 2019
Rat	10 mg/kg morphine i.p.	Morphine group n = 28 Saline group n = 7	No significant differences in alpha diversity Morphine group ↓Alloprevotella, Desulfovibrio, and Rikenella ↑Allobaculum and Parasutterella Saline group ↓Corynebacterium, Clostridium_XlVa, Corynebacterium, and Parasutterella ↑Desulfovibrio	NA	Zhang et al., 2020
Indian-origin rhesus macaques	Intramuscular injection	Morphine group n = 4 Simian immunodeficiency virus (SIV) group n = 4 Morphine+SIV group n = 6	No significant differences in microbial diversity ↑Methanobacteriaceae ↓Streptococcaceae streptococcus and Pasteurellaceae Aggregatibacter	↓Primary bile acids ↑Secondary bile acids and sphingolipid metabolites	Sindberg et al., 2019