Lactobacillus rhamnosus GG soluble mediators ameliorate early life stress-induced visceral hypersensitivity and changes in spinal cord gene expression

Abstract

Visceral hypersensitivity is a hallmark of many functional and stress-related gastrointestinal disorders, and there is growing evidence that the gut microbiota may play a role in its pathophysiology. It has previously been shown that early life stress-induced visceral sensitivity is reduced by various probiotic strains of bacteria (including Lactobacillus rhamnosus GG (LGG)) alone or in combination with prebiotic fibres in rat models. However, the exact mechanisms underpinning such effects remain unresolved. Here, we investigated if soluble mediators derived from LGG can mimic the bacteria’s effects on visceral hypersensitivity and the microbiota–gut–brain axis. Rats were exposed to maternal separation (MS) from postnatal days 2–12. From weaning onwards both non-separated (NS) and MS offspring were provided drinking water with or without supplementation of standardized preparations of the LGG soluble mediators (LSM). Our results show that MS led to increased visceral sensitivity and exaggerated corticosterone plasma levels following restraint stress in adulthood, and both of these effects were ameliorated through LSM supplementation. Differential regulation of various genes in the spinal cord of MS versus NS rats was observed, 41 of which were reversed by LSM supplementation. At the microbiota composition level MS led to changes in beta diversity and abundance of specific bacteria including parabacteroides, which were ameliorated by LSM. These findings support probiotic soluble mediators as potential interventions in the reduction of symptoms of visceral hypersensitivity.

Treatment with Bacterial Biologics Promotes Healthy Aging and Traumatic Brain Injury Responses in Adult Drosophila, Modeling the Gut–Brain Axis and Inflammation Responses

“…A modest weight loss was detected for flies on control M-9 media. LGG and IAB treated flies did not show significant changes, indicating that flies found both treatments palatable ( Supplementary Figure S2 ) [ 3 , 12 , 47 , 48 ].…”

“…Finally, the preliminary results on IAB’s impact on the age-related dysregulation of the fly immune system requires further investigation. Implications of a therapeutic delay or potential reversing of immune system dysfunction has vast implications for the treatment of chronic human diseases, including neurodegeneration [ 22 , 36 , 37 , 39 , 40 , 47 ].…”

A role for gut microbiota in early-life stress-induced widespread muscle pain in the adult rat

“…It is well-established that early-life stress affects gut microbiome, 24 – 29 a dysbiosis that persists into adulthood. 24 , 25 , 29 Importantly, in addition to local effects, such as visceral pain 30 , 31 and gut permeability, 26 , 27 gut dysbiosis has been implicated in several systemic pathologies, including altered behavior (e.g. depression and anxiety), 24 , 32 , 33 Parkinson’s disease, 34 increased hypothalamic pituitary adrenal axis (HPA) activity, 35 systemic lupus erythematosus 36 and systemic inflammation.…”

“…However, it is known that early-life stress (maternal separation), produces a change in beta diversity (i.e. a change in microbial composition, or dysbiosis), for example a deficiency in Lactobacillus , 26 , 40 Staphylococcus and Mucispirillum , 29 Clostridium , Bilophia 30 and increases in Bacteroides , 29 Alloprevotella and Acetivibrio . 30 Other studies have observed additional changes in gut microbiome following early-life stress and with 5,000 – 10,000 bacterial species it is going to be challenging to determine which bacterial species contribute to local or systemic hyperalgesia.…”

Animal models of visceral pain and the role of the microbiome

“…A number of studies have now demonstrated that maternal separation in rodents results in adult offspring demonstrating long-term visceral hypersensitivity ( Coutinhoet al, 2002 , Schwetzet al, 2005 , Renet al, 2007 with accompanying intestinal microbial alterations ( Eutameneet al, 2007 , O’Mahonyet al, 2009 , O’Mahonyet al, 2020 , Distruttiet al, 2013 , De Palmaet al, 2015 ). Previous work has shown that animals exposed to neonatal stress through maternal separation demonstrate altered gene expression in both the colon and spinal cord that could be linked to pain ( Distruttiet al, 2013 , McVey Neufeld et al, 2020 ). Microarray examination paired with functional analysis revealed that less than 3% of colonic genes showed up- or down-regulated mRNA gene expression in pups exposed to maternal separation, with many of these genes falling into the category of metabolism or pain/inflammation categories.…”