*6.2. FODMAP Diet*

Recent studies have demonstrated that functional GI symptoms can be induced by colonic gas production in patients with visceral hypersensitivity. In those patients, shortchain fermentable carbohydrates increase small intestinal water volume, resulting in increased colonic gas production. Therefore, dietary restriction of short-chain fermentable carbohydrates (low-FODMAP diet) should theoretically ameliorate the symptoms of IBS. In pre-clinical studies, the low-FODMAP diet (LFD) altered the gut microbial composition, resulting in reduced fecal lipopolysaccharide of Gram-negative bacteria. In contrast to a high-FODMAP diet, there is a significant reduction of *Akkermancia muciniphila* and *Actinobacteria* [156]. Therefore, it could be beneficial in reducing gut mucosal inflammation and restoring the barrier function of the gut, ultimately leading to the alleviation of visceral pain [156].

In a clinical setting, the FODMAP diet has led to a reduction in IBS severity, with decreased frequency of pain episodes (*p* < 0.01) and increased quality of life [157]. In another study by Pedersen et al., LFD resulted in a greater reduction of disease severity but no improvement in quality of life [158]. In a double-blind, placebo-controlled trial on 40 patients with IBS by Hustoft et al., LFD with fructans lowered the severity of nausea, vomiting, and flatulence [159]. Overall, up to 86% of IBS patients improve clinically in terms

of GI symptoms, as well as abdominal pain, bloating, and constipation, while following the diet [160].

#### *6.3. Fecal Microbiota Transplantation*

Fecal microbiota transplantation (FMT) involves the transfer of microbial flora from a healthy donor stool to the recipient's intestinal tract to normalize the target intestinal microbiota composition and function. One of the most notable examples of the use of FMT in clinical practice is *Clostridium difficile* infection (CDI), which often occurs in patients whose microbiota has been suppressed by prolonged antibiotic therapy. Recent evidence suggests that the gut microbiota composition is linked to the occurrence of abdominal pain and its frequency, duration, and intensity in the general population [161]. Moreover, in an animal model of colitis, FMT administration to control rats resulted in long-lasting visceral hypersensitivity [162]. Several mechanisms have been proposed through which FMT might affect chronic pain, including competition with pathogenic bacteria, protection of the intestinal barrier, or stimulation of the intestinal immune system [163]. An open-label study on FMT in humans with IBS showed marked improvement in abdominal pain that was associated with the abundance of *Akkermansia muciniphila* [164].

Moreover, allogenic FMT resulted in a significant decrease in symptoms of IBS (*p* = 0.02), which was not present in the autologous FMT group (*p* = 0.16) [165]. Furthermore, a metagenomic sequencing study revealed that following FMT the taxonomic profile of the recipient shifts towards a donor-like profile, inducing long-term changes in the gut microbiota, which mirror the clinical effect of the treatment [166].

In order to perform successful FMT, several criteria must be met. Firstly, donor selection should be strict, excluding those at risk of harboring an infectious agent. Moreover, recipients must not receive major immunosuppressive therapy, or suffer from serious comorbidities that would put them at risk [167]. While FMT is relatively safe, some of the studies suggest its potential drawbacks. One study suggested that FMT might be associated with diarrhea, abdominal cramping, belching, and nausea within 3 h post-FMT [168]. Moreover, there exists a possibility of development of long-term adverse effects due to alteration of the gut microbiota. More long-term, follow-up studies are required to address this issue [169].
