Microbiota regulates visceral pain in the mouse

Abstract

The perception of visceral pain is a complex process involving the spinal cord and higher order brain structures. Increasing evidence implicates the gut microbiota as a key regulator of brain and behavior, yet it remains to be determined if gut bacteria play a role in visceral sensitivity. We used germ-free mice (GF) to assess visceral sensitivity, spinal cord gene expression and pain-related brain structures. GF mice displayed visceral hypersensitivity accompanied by increases in Toll-like receptor and cytokine gene expression in the spinal cord, which were normalized by postnatal colonization with microbiota from conventionally colonized (CC). In GF mice, the volumes of the anterior cingulate cortex (ACC) and periaqueductal grey, areas involved in pain processing, were decreased and enlarged, respectively, and dendritic changes in the ACC were evident. These findings indicate that the gut microbiota is required for the normal visceral pain sensation.DOI: http://dx.doi.org/10.7554/eLife.25887.001

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

“…Most convincingly, converging evidence from GF mice indicates that the amygdala transcriptome is hyperactive in the absence of a microbiota. [36,37] This hyperactive state is consistent with the altered phenotype of GF mice in regards to both social and fearrelated behaviors, [101,110] pain sensitivity, [119] as well as elevated stress-induced HPA axis responses (see Figure 4). [8,10] More broadly, the studies outlined below suggest that microbiota-toamygdala signalling may result in functionally relevant changes in the amygdala.…”

“…Social deficits in mice (less interest in social interaction, poor memory for social partners) [110,113] Reversal of social deficits in murine models of ASD [111,115] Reversal of antibiotic-induced social deficits in mice [113] Reduced risk for ASD [116] , reduced symptom severity in children with ASD (open pilot) [117] Transplant of standardized human gut microbiota to children with ASD improved ASD symptoms in open-label pilot [118] Pain Visceral hypersensitivity in mice [119] Visceral hypersensitivity in healthy mice [94,120,135] Reversal of visceral hypersensitivity in stressed mice [122] Increased risk for IBS in humans [51] Positive effects on pain in IBS patients [127] Reversal of stressinduced visceral hypersensitivity in rats [121] Reversal of antibiotic-induced visceral hypersensitivity in mice [135] Positive effects on IBS symptoms in humans [127] Transplant from IBS donors increases GI symptoms (accelerated gastrointestinal transit, increased intestinal permeability) in mice [125,126] Transplant from healthy donors reduces GI symptoms (constipation, diarrhea, indigestion, abdominal pain) in children with ASD (open-label pilot) [118] www.advancedsciencenews.com www.bioessays-journal.com been several studies reporting no effect of probiotics on these measures, [99] these disparate results may be explained by straindependent effects or a moderating effect of symptom severity because it has been reported that the beneficial effects are greatest for those with the most negative symptoms at baseline. [100] …”

“…[57] For example, microbiota depletion has been shown to induce visceral hypersensitivity in adulthood for both GF mice [119] and mice exposed to antibiotics early in life. [120] On the other hand, stress-induced visceral hypersensitivity can be reversed by treatment with either probiotics [121] or antibiotics.…”

Beneficial effect of butyrate‐producing Lachnospiraceae on stress‐induced visceral hypersensitivity in rats

“…The absence or disruption of gut microbes can significantly influence visceral pain perception, leading to visceral hypersensitivity. In particular, germ‐free mice exhibited increased visceral pain responses when exposed to colorectal distension (CRD) stimuli, and visceral hypersensitivity was normalized after microbial colonization . Furthermore, rats receiving early‐life antibiotic treatment also displayed visceral hypersensitivity in adulthood and altered microbiota profiles .…”

Microbiota and Neurodevelopmental Trajectories: Role of Maternal and Early-Life Nutrition

“…Furthermore, they showed increased blood-brain barrier permeability [24]. Functionally, such changes translate to increased stress response [14, 16], changes in anxiety [25] and fear recall [26], cognitive deficits [27], social changes [21, 28] and visceral pain responses [29]. Thus, the complete absence of microbial colonization in early life has dramatic effects on offspring’s brain development and function.…”