**4. An inhibitor of ileal bile-acid transporter (IBAT)**

In a gnotobiotic experiment wherein feces of patients with chronic constipation, especially those with delayed intestinal transit time, were transplanted into germ-free mice, short chain fatty acids and secondary bile acids, which are metabolites of the gut microbiota, were identified to be factors that promote intestinal peristalsis, and the administration of butyric acid or DCA activated serotonin signals in the gut and restored the decreased intestinal peristalsis of these gnotobiotic mice [31]. In addition, the amount of bile acids in the feces of patients with chronic constipation and irritable bowel syndrome was found to be decreased, suggesting that improving this decrease in the bile-acid concentration in the large intestine may be a suitable therapeutic strategy.

Elobixibat, the first inhibitor of IBAT, expressed in epithelial cells in the terminal ileum and suppresses the reabsorption of bile acids, thereby causing bile acids to flow into the lumen of the large intestine (**Figure 2**). Elobixibat is effective as a therapeutic agent for chronic constipation as it induces a secondary bile-acid signal, causing water to be secreted into the lumen of the large intestine and thus promoting gastrointestinal peristalsis [3, 4]. These physiological effects of bile acids are thought to be mediated by the TGR5 receptor localized in intestinal cells. The analysis of bile acids in feces has indicated an increase in DCA levels after the administration of Elobixibat compared to those before administration [23]. Intestinal neuroendocrine cells (EC cells) are considered to be the main TGR5 receptorexpressing cells, and TGR5 receptor-deficient mice have been demonstrated to have decreased intestinal peristalsis [32]. The binding of bile acids to the TGR5 receptor expressed on the luminal side of EC cells is hypothesized to activate serotonin synthesis signals and enhance secretion, leading to the activation of peristalsis. The reactivity of the TGR5 receptor to different bile acids varies; the TGR5 receptor has high reactivity with LCA and DCA and low reactivity with CDCA and CA [33].

#### **Figure 2.**

*Ileal bile-acid transporter (IBAT) inhibitor (elobixibat) and its effect on the function of the large intestine. Elobixibat inhibits IBAT expressed in epithelial cells in the terminal ileum and partially suppresses bile-acid reabsorption. The flow of bile acids into the lumen of the large intestine activates TGR5 receptors, causing the secretion of water into the lumen of the large intestine and thus promoting gastrointestinal peristalsis.*

TGR5 receptor expression is also reported to be affected by gut microbiota [12]. In other words, the dose dependence of the efficacy of Elobixibat may be strongly influenced by the intestinal bile-acid profile and intestinal flora of each individual. In addition, Elobixibat activates bile-acid metabolism, and in future studies, it is necessary to consider the effects of Elobixibat on the whole body, including effects on cholesterol metabolism and fatty liver.

An observational study that used the Japanese version of the Patient Assessment of.

Constipation-Quality of Life (PAC-QOL) questionnaire has demonstrated that the scores of physical discomfort and psychosocial discomfort significantly decreased in patients with constipation after the treatment with Elobixibat for 4 weeks, indicating the possibility that Elobixibat could affect the gut-brain axis [34].

#### **5.** *Akkermansia muciniphila* **and bile-acid signals for well-being**

Well-being is a key word in the WHO's definition of health: a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity. Thus, medical care aimed at wellbeing is necessary. Recent reports have revealed the involvement of gut microbiota and bile-acid metabolism in extending healthspan and lifespan [35]. The gut microbiota of two different mouse models of progeria was characterized by intestinal dysbiosis with alterations including an increase in the abundance of Proteobacteria and Cyanobacteria and a decrease in the abundance of Verrucomicrobia compared to the gut microbiota of control mice. Fecal microbiota transplantation from wild-type mice enhanced healthspan and lifespan in both progeroid mouse models, and transplantation with the Verrucomicrobia *Akkermansia muciniphila* was sufficient to exert beneficial effects. Furthermore, an analysis of gut microbiota metabolites revealed that various bile acids were reduced in the progeroid mouse models, and this dysregulation in bile acids was improved by transplantation with *Akkermansia muciniphila* [35].

#### *Role of Gut Microbiota in Bile-Acid Metabolism DOI: http://dx.doi.org/10.5772/intechopen.100440*

Morita et al. [36] reported that *Akkermansia* was more abundant in individuals from Ogimi and *Lachnospiraceae*, *Collinsella*, *Peptococcus*, and S24–7 were more abundant in individuals not from Ogimi. Ogimi is a village located in the northern region of Okinawa's main island and has a population of approximately 3,000; it is known as the village of longevity in Japan. Grajeda-Iglesias et al. [37] recently demonstrated that *Akkermansia muciniphila*, especially if it is pasteurized, causes major changes in metabolism, elevating the concentrations of several metabolites that have been previously associated with positive effects on health in mouse models. Pasteurized *Akkermansia muciniphila* was more efficient than live *Akkermansia muciniphila* in elevating the intestinal and circulatory concentrations of polyamines, short-chain fatty acids, 2-hydroxybutyrate, and multiple bile acids, all of which may have a positive impact on human health.

Bile-acid analysis by LC–MS/MS has enabled the identification of new metabolites related to health and longevity. Detailed metagenomic analysis and intestinal metabolite analysis of Japanese centenarians recently revealed a novel bile-acid metabolite, isoallo-lithocholic acid, which has a bactericidal effect on specific intestinal bacteria [38]. Although details of the effect of *Akkermansia muciniphila* on bile-acid metabolism are not fully understood, our previous analysis using a high-fat diet load mouse model suggests that the bacterium promotes the deconjugation of conjugated bile acids and suppresses the production of secondary bile acids [29]. A double-blind comparative study in obese individuals has already been conducted to investigate whether *Akkermansia muciniphila* improves the intestinal environment [39]. They demonstrated that Akkermansia muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected after three months of supplementation [39].

The neuroprotective effect of tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid and naturally produced in the liver by conjugation of taurine to UDCA, has been recently elucidated [40]. Several studies have shown that TUDCA has neuroprotective action in several models of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease [40]. Currently, there is one registered clinical trial with TUDCA in Alzheimer's disease, in the United States (Clinical Trials registration: NCT03533257).

Additionally, countermeasures against sarcopenia are important clinical issues in research aimed at improving well-being. Maintaining muscle strength with diet and exercise is important to prevent sarcopenia, and recent studies have shown that TGR5 present in the skeletal muscle plays an important role in muscle maintenance [41, 42]. Exercise-induced stimulation enhances TGR5 receptor expression in the skeletal muscle, and the increased after-meal levels of bile acids in the blood act as ligands for the TGR5 receptor, helping maintain muscle and prevent sarcopenia. Furthermore, TGR5 signaling in the muscle activates muscle metabolism and enhances glucose clearance, which also has a positive effect on glucose metabolism [41, 42]. Countermeasures against so-called frail complexes, such as sarcopenia, locomotive syndrome, and frailty, are extremely important clinical issues in supporting medical care aimed at improving well-being. It should be emphasized that the gut microbiota-bile acid-receptor signal is a novel therapeutic and prophylactic target molecule for improving frailty.
