Opioid-induced dysbiosis of maternal gut microbiota during gestation alters offspring gut microbiota and pain sensitivity

Abstract

There has been a rapid increase in neonates born with a history of prenatal opioid exposure. How prenatal opioid exposure affects pain sensitivity in offspring is of interest, as this may perpetuate the opioid epidemic. While few studies have reported hypersensitivity to thermal pain, potential mechanisms have not been described. This study posits that alterations in the gut microbiome may underly hypersensitivity to pain in prenatally methadone-exposed 3-week-old male offspring, which were generated using a mouse model of prenatal methadone exposure. Fecal samples collected from dams and their offspring were subjected to 16s rRNA sequencing. Thermal and mechanical pain were assessed using the tail flick and Von Frey assays. Transcriptomic changes in whole brain samples of opioid or saline-exposed offspring were investigated using RNA-sequencing, and midbrain sections from these animals were subjected to qPCR profiling of genes related to neuropathic and inflammatory pain pathways. Prenatal methadone exposure increased sensitivity to thermal and mechanical pain and elevated serum levels of IL-17a. Taxonomical analysis revealed that prenatal methadone exposure resulted in significant alterations in fecal gut microbiota composition, including depletion of Lactobacillus , Bifidobacterium , and Lachnospiracea sp and increased relative abundance of Akkermansia, Clostridium sensu stricto 1 , and Lachnoclostridium . Supplementation of the probiotic VSL#3 in dams rescued hypersensitivity to thermal and mechanical pain in prenatally methadone-exposed offspring. Similarly, cross-fostering prenatally methadone-exposed offspring to control dams also attenuated hypersensitivity to thermal pain in opioid-exposed offspring. Modulation of the maternal and neonatal gut microbiome with probiotics resulted in transcriptional changes in genes related to neuropathic and immune-related signaling in whole brain and midbrain samples of prenatally methadone-exposed offspring. Together, our work provides compelling evidence of the gut-brain-axis in mediating pain sensitivity in prenatally opioid-exposed offspring.

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

“…We expect this incongruence, whereby these beneficial genera are tied to both tolerance and its attenuation, could reflect that a variety of taxa, not just these two genera, can bolster gut integrity similarly and support trophic networks of the microbiota to resist or counter morphine's adverse effects (Figure 2D, Table 2). Importantly, these capabilities may not necessarily be defined by or limited to related taxa, or even guaranteed to be expressed equally by every strain within a given species (Supplemental Figure 8 and Table 2; 168,169 . Functional redundancy of SCFA production by the microbiota could ensure resiliency to perturbation [170][171][172][173] .…”