**4. Functions of gut microbiota**

A mature, healthy gut microbiota has significant functions in the human body [4]: protection against pathogens by colonizing mucosal surfaces and production of various antimicrobial substances; development and modulation of the immune system; digestion and nutrient metabolism; control of cellular proliferation and differentiation; modification of insulin resistance and its secretion; and facilitation of dynamic communication between the gut and multiple organs [33, 34].

In Ref. to its role in enhancing the immune system, immunological immaturity is observed in germ-free and laboratory mice compared with wild mice, and humans residing on farms exhibit greater functional microbial diversity and a lower susceptibility to chronic inflammatory diseases [35]. The gut microbiota has also been described as an important immunoregulator of bone's remodeling processes [36, 37].

One of the most relevant roles of gut microbiota is the metabolism of dietary elements into bioactive food components. Indigestible carbohydrates are metabolized into short-chain fatty acids (SCFAs), such as acetic, propionic, and butyric acids,

which are mainly produced due to fermentation by Bacillota, Bacteroidota, and other anaerobic bacteria. These compounds supply significant energy for intestinal epithelial cells, strengthen the mucosal barrier, contribute to intestinal homeostasis, and reduce inflammation [38]. Moreover, the gut microbiota participates in the biosynthesis of certain essential amino acids and vitamins and is involved in the synthesis of bile acids, cholesterol, and conjugated fatty acids [17]. On the other hand, other microbial derived-metabolites, such as trimethylamine N-oxide (TMAO), have been associated with cardiovascular disease [39].

Therefore, understanding the metabolic pathways of derived microbial compounds is crucial for establishing a link to the metabolism of the healthy host or to the pathogenesis of metabolic diseases.

## **5. Gut microbiota in obesity and type 2 diabetes mellitus**

#### **5.1 Obesity**

Obesity is a complex and multifactorial disease with significant morbidity and mortality, and it is a major public health problem, particularly in the developed world [40]. Among the risk factors contributing to obesity (genetic, behavioral, socioeconomic, and environmental), the gut microbiota has been recognized as a major contributor [3]. More than 10 years ago, a differential gut bacterial composition linked to increased Bacillota and a reduction in Bacteroidota was demonstrated in genetically obese (ob/ob) mice compared with lean (ob/+) and wild-type (+/+) mice that had been fed with the same polysaccharide-enriched diet [41]. Moreover, after transplanting the obese and lean microbiomes to germ-free recipients, the phenotypes of the mouse donors were reproduced.

Numerous studies have been designed to identify significant differences in the bacterial gut microbiota composition between lean and obese individuals [42] and to describe the impact of the bariatric surgery approach to obesity [43]. Regarding bacteria, the Bacillota/Bacteroidota ratio has been discarded because it was proven ineffective as a differential marker of the microbiota in patients with obesity, given that an expansion of Bacillota leads to a proportional reduction of the other phyla [44]. The bariatric surgery approach will be discussed in a later section.

According to the following meta-analysis, which reviewed the composition of the gut microbiota in obese and non-obese individuals [45], no significant differences were found in alpha diversity. On the other hand, at the genus level, lower relative proportions of *Bifidobacterium* and *Eggerthella* (Actinomycetota) were observed in the obese group compared with the non-obese. The genera of *Acidaminococcus*, *Anaerococcus*, *Catenibacterium*, *Dialister*, *Dorea*, *Eubacterium*, *Megasphaera*, *Roseburia*, *Streptococcus* (all belonging to the Bacillota phylum), *Fusobacterium* (Fusobacteriota), *Prevotella* (Bacteroidota), *Escherichia-Shigella*, and *Sutterella* (Pseudomonadota) were significantly higher in the obese individuals. On the other hand, Verrucomicrobiota (*Akkermansia muciniphila*), *Faecalibacterium*, *Methanobrevibacter smithii*, and *Lactobacillus* species have a lower presence in obesity [46].

#### **5.2 Type 2 diabetes mellitus**

The etiology of type 2 diabetes mellitus (T2DM) involves a combination of genetic variants and environmental factors shared with obesity, in which most individuals are *Gut Microbiota and Bariatric Surgery DOI: http://dx.doi.org/10.5772/intechopen.107175*

either overweight or obese. Insulin resistance is followed by a compensatory higher biosynthesis and insulin secretion.

Although there are some inconsistencies among studies, it appears that in the early stages of T2DM, before patients have been treated with anti-hyperglycemic drugs, the gut microbiota could have loss of butyrate-producing taxa, a marked reduction of *Akkermansia*, and an increase in proinflammatory bacterial genera such as Bacteroidota [47, 48].

The effects of metformin on the gut microbiota have been studied in patients with T2DM, demonstrating a higher relative abundance of *Akkermansia*, *Butyrivibrio*, *Bifidobacterium*, and *Megasphaera* compared with individuals without T2DM [49]. On the other hand, those with non-metformin treated T2DM had a higher relative abundance of Clostridiaceae and a lower abundance of *Enterococcus casseliflavus* compared with individuals without T2DM. The authors found significant associations between metformin intake and gut microbiota composition.

Additional studies [50, 51] have also observed shifts in gut microbiota in patients treated with metformin by increasing the abundance of *Akkermansia* and SCFAproducing bacteria, which activate intestinal gluconeogenesis, resulting in lower glycemic levels. *Akkermansia* participates in maintaining the cohesion of the mucin layer by reducing translocation of proinflammatory lipopolysaccharides and controlling fat deposition, adipose tissue metabolism, and glucose homeostasis. SCFAs, especially butyrate and propionate, trigger intestinal gluconeogenesis, benefitting glucose and energy homeostasis and reducing hepatic glucose production, appetite, and body weight.

Nevertheless, further large-scale studies are necessary to evaluate the interactions between the changes in gut microbiota and the effects of metformin to establish a potential target intervention from a microbiological perspective.

### **6. Impact of bariatric surgery on gut microbiota**

As has been described throughout the present book, bariatric surgery (BS) is indicated as treatment for reducing body mass index (BMI) in severe obesity (BMI ≥40 Kg/m2 or ≥ 35 Kg/m2 ) with at least one obesity-related disease [52]. This surgery improves glycemic control because of weight loss and calorie restriction, along with increased insulin sensitivity and secretion [53]. Several changes in gut microbiota composition depending on the type of surgery have been observed.

The procedures vary, although the most common are sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). While SG is a restrictive approach based on stomach reduction, RYGB combines restrictive and malabsorptive approaches by reducing the stomach and anatomically reorganizing the biliary and digestive tracts [54]. These procedures alter the anatomy of the digestive and biliary tract, hormonal status, and the amount and choice of nutrients ingested, which could modify the composition of the microbiota and the quantity of several microbial metabolites [54, 55]. However, whether the evolution of the microbiota is the cause or the consequence of weight loss and improvement of obesity-related diseases (or whether the changes are more related to the specificities of the surgical procedure) remains to be determined.

One of the most relevant lines of research proposes to predict weight loss after BS by examining the basal composition of the gut microbiota. Previous studies have indicated that BS modifies the gut microbiota profiles [56, 57]. Changes in alpha diversity do not appear to be clear, but beta diversity analyses consistently show more profound changes for the RYGB approach with an expansion of the phylum

#### **Figure 2.**

*Bacterial taxa with differential abundance according to linear effect size discriminant analysis (LEfSe). This representation shows the significant taxa ordered according to the magnitude of the differences [LDA score (only taxa with LDA > 4 are shown)]. A, comparison of microbiota composition between baseline and 3 months after SG surgery (n = 14). B, comparison of microbiota composition between baseline and 3 months after RYGB surgery (n = 26) (from: Salazar et al. [58]).*

Pseudomonadota. Redistribution of the bile acid circuit, whose antibacterial activity limits the expansion of gamma-Proteobacteria in the small intestine, appears to be the main cause of the increase in the members of this phylum found in samples from patients undergoing RYGB [58].

*Gut Microbiota and Bariatric Surgery DOI: http://dx.doi.org/10.5772/intechopen.107175*

In 2022, Salazar et al. [58] observed that BS caused a decrease in the genera *Roseburia*, *Faecalibacterium*, *Ruminococcus*, and *Bifidobacterium* and an increase in *Escherichia/Shigella* and *Akkermansia*. As observed in other studies [59], differences between samples at baseline and at the end of follow-up were much more profound in the RYGB group: the phyla Pseudomonadota, Bacteroidota, Verrucomicrobiota, and Fusobacteriota experienced a significant increase in number at 3 months after RYGB surgery, inversely to Bacillota and Actinomycetota. However, the changes were considerably less marked in the SG group, with a slight enrichment of certain Bacillota, such as *Streptococcus*, *Parvimonas*, *Hungatella*, *Lactobacillus*, and *Desulfovibrio*, along with a decrease in Bacteroidota and Negativicutes. Lastly, and despite these differences in bacterial composition, the authors emphasized that weight loss was uniform in both groups, independent of the initial gut microbiota composition (**Figure 2**).

#### **6.1 Type 2 diabetes mellitus remission**

Regarding T2DM remission after BS, discordant results have been published according to a meta-analysis review [60]. This discordance could be explained by the design of the studies, the sample size and statistical power to assess differences, as well as the duration of follow-up. In addition, the authors note that different remission criteria were used in the literature reviewed, which could have possibly led to discrepancies in the interpretation of the available evidence. However, other researchers have explored the possibility that remission of diabetes after RYGB and SG surgery may be associated with interindividual differences in microbiota composition.

Although post-surgical changes in gut microbiota richness and composition were observed, these were independent of T2DM remission status, and no specific postoperative gender signature was identified that discriminated patients who reached this metabolic outcome [59]. However, a distinct genus signature pre-RYGB was observed in patients with total T2DM remission (**Figure 3**).

Murphy et al. [61] found that body weight reduction, dietary changes, and T2DM remission were similar 1 year after both RYGB and SG. RYGB surgery resulted in an

#### **Figure 3.**

*Gut bacteria genera at the preoperative period in obese patients classified according to T2D remission after RYGB. These figures represent comparison at the preoperative period of gut bacteria genus profile between patients classified, after RYGB, according to presence (blue boxes; n = 8) and absence of T2D remission (red boxes; n = 6). There was a higher relative abundance of (a) Asaccharobacter (p = 0.038) and (B) Atopobium (p = 0.047) and a lower relative abundance of (C) Gemella (p = 0.018), (D) Coprococcus (p = 0.029), and (E) Desulfovibrio (p = 0.030) in the patients with T2D remission than in patients without, ( from: Al-Assal K et al. [59]).*

increased Bacillota and Actinomycetota phyla, but a decreased Bacteroidota phyla. On the other hand, the SG procedure resulted in an increased Bacteroidota phyla. An increase in *Roseburia* species was observed among those who achieved diabetes remission in both types of surgery, although greater changes in gut microbiota metabolism occurred after RYGB than after SG. Contrary to the findings of Al-Assal et al. [59], those with persistent diabetes postoperatively had more *Desulfovibrio* species before surgery.

Similar results were addressed in Davies et al. [62], a higher abundance of *Eubacteriaceae* and *Alistipes putredinis* was observed before surgery in those individuals with T2DM remission post-intervention. After BS, *Lachnospiraceae* and *Roseburia* species were more abundant in those who had achieved T2DM remission.

The differential bacterial abundance was analyzed in 8 patients who underwent RYGB with complete resolution of diabetes as reported by Salazar et al. in 2022 [58], showing a significant increase of Verrucomicrobiota phyla (*Akkermansia*) and Fusobacteriota (*Fusobacterium*) after surgery, whereas the relative abundance of the phyla Bacillota (*Faecalibacterium*, *Erysipelotrichia*, *Gemmiger*, and *Lactobacillus*) and Actinomycetota (*Bifidobacterium*) decreased.
