*6.1. Probiotics and Prebiotics*

Probiotics are living microorganisms that can provide health benefits to the host [140]. A growing body of research supports the thesis that probiotics are effective in modifying the balance of the gut microbiota [141,142]. Some of their proven beneficial effects include improved digestion, boosted immunity, and decreased cholesterol levels [143]. Some of the more recent studies suggest that probiotics might be effective in alleviating the symptoms of chronic intestinal disorders, such as Crohn's disease [144].

Several preclinical animal studies have demonstrated the beneficial effects of probiotics on visceral pain [145–147]. In multiple studies, probiotics exerted beneficial effects on visceral hypersensitivity. In rats, probiotic VSL#3 decreased visceral hypersensitivity potentially through the mast cell-PAR2-TRPV1 pathway, which then affects the release of potent mediators that affect the enteric nerves and smooth muscles [145]. Moreover, supplementation with *Clostridium butyricum*, a commensal bacterium, may inhibit colonic inflammation in a mouse model of IBS through its action on nod-like receptor pyrin domain-containing protein 6 [146]. In a similar model, *Roseburia hominis* alleviated visceral hypersensitivity and prevented the expression of occludin from decreasing [147]. Moreover, in rats, *B. infantis* 35624 significantly reduced visceral pain, suggesting that it may be effective in treating symptoms of IBS [148].

Several human studies have also revealed the benefits of using probiotics for chronic pain. A randomized, double-blind study on 101 pediatric patients suffering from IBS (NCT01180556) revealed that a 4-week supplementation of *L. reuteri* DSM 17938 reduced both the frequency and the intensity of abdominal pain in children [149]. Moreover, a probiotic mixture of *Bifidobacterium infantis* M-63, breve M-16V, and longum BB536 (NCT02566876) was successful in attenuating the symptoms of abdominal pain in IBS but not in functional dyspepsia. Likewise, the intervention group noted the markedly higher quality of life improvement in comparison with a placebo (48% vs. 17%, *p* = 0.001) [150]. A 2009 review by Newlove-Delgado et al. retrospectively investigating the use of probiotics in children with recurrent abdominal pain suggested that those preparations are likely to improve pain symptoms in the short term, that is, up to 3 months (OR = 1.63; 95% CI = 1.07–2.47) [151]. By contrast, a randomized, placebo-controlled trial by Spiller et al. failed to identify any clinical benefit, including intestinal pain and discomfort, of *S. cerevisiae* I-3856 supplementation at a dose of 1000 mg per day, in comparison to a placebo [152].

Prebiotics are fibers and other non-digestible ingredients that benefit the host by selectively boosting the growth and activity of select microorganisms in the colon, mainly lactobacilli and bifidobacteria. They are considered either as an addition to probiotics or an alternative to them. Several pre-clinical dissertations have emerged underlining the beneficial role of prebiotics in terms of attenuating chronic pain, such as PDX/GOS reducing chronic visceral pain induced by intracolonic zymosan injection in rats [153]. In human studies, a prebiotic galacto-oligosaccharide mixture supplemented for 2 weeks reduced abdominal pain associated with GI disorders in adults. The treatment arm reported significantly lower scores for bloating, flatulence, and pain. However, there was no improvement in quality of life throughout the study [154]. Lastly, a study on the symbiotic containing *Bacillus coagulans* on 88 pediatric patients showed a reduction of abdominal pain that was present after treatment (60% vs. 39.5%, *p* = 0.044) but not after 12 weeks of follow-up [155].
