THE INTESTINAL MICROBIOME IN PATIENTS UNDERGOING BARIATRIC SURGERY: A SYSTEMATIC REVIEWⅢ

Conventional bariatric procedures include VG or gastric sleeve, gastric RYGB, and BPD. SG involves removing approximately 75–80% of the stomach, leaving a small tubular-shaped pouch. RYGB involves creating a small stomach pouch, usually about 30 ml in volume, and a gastrojejunostomy between the pouch and the jejunum. The ingested food bypasses approximately 95% of the stomach, the entire duodenum, and part of the jejunum. BPD is a disassortative procedure involving a subtotal gastrectomy plus a long intestinal detour with mixing of bile and nutrients2. 

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Bariatric surgery is substantially recommended by weight loss experts for individuals with a BMI of 40 or 35 kg/m² with associated comorbidities. All bariatric surgery procedures result in a drastic reduction in food intake and calories consumed15. In addition to the anatomical alteration, many patients have preexisting factors that influence post-surgery outcomes, such as gut microbiota, surgical conversion, and AT. With altered gastric physiology, the speed of food transit from the stomach to the ileum changes, and both RYGB and VG decrease the effects of gastric acid on ingested food2,16. These changes are disparate according to the surgical technique chosen. Usually, the greatest weight loss occurs after RYGB, with a percentage of approximately 62.58% at 5 years and 63.52% at 10 years 7,16. 

The first study of the microbiota after bariatric surgery occurred in 2009, which included data from three obese individuals, three after gastric bypass, and three with normal weight, and noted an abundance of H2 -H2-producing bacteria groups. In the same year, another study was done together with the first longitudinal analysis of the gut microbiota of 30 obese individuals undergoing gastric bypass. The results showed that there was a lower Bacteroidetes/Prevotella ratio before surgery and a higher Bacteroidetes/Prevotella ratio after surgery17. In the literature review, Debédat et al., in 2019, demonstrated that the intestine is a highly plastic and specialized organ for large surgical removal of the ileum that leads to increased proliferation of cells, thus increasing glucose uptake and utilization. 

The secretory cells also increase, leading to increased production of intestinal hormones such as glucagon-derived peptide (GLP-2). Postprandial GLP-1 secretion is increased, which may contribute to improved insulin secretion. GLP-2, co-expressed with GLP-1 in intestinal L cells and released after nutrient intake, has a beneficial trophic role in the small intestine with stimulation of crypt cell proliferation, increased intestinal weight, and villus growth in both jejunum and small intestine2,6-8,16. When exploring metabolomic pathways linked to metabolites that could be influenced by bariatric surgery, the surgical intervention reduced the tricarboxylic acid cycle, glycine, serine, and threonine metabolism, glyoxylate and dicarboxylate, and tyrosine metabolism. These results suggest that BCAAs and aromatics, as well as energy metabolism, were negatively regulated with bariatric surgery18. Although beneficial effects of BCAA supplementation have been described, some clinical trials show increased BCAA levels in obesity and people with insulin resistance8,11,21. 

The RYGB technique induces a reduction in serum BCAAs, further validating how bariatric surgery aids in insulin resistance and glucose metabolism. BCAA levels decreased significantly only in patients who lost at least 10 kg of body weight after bariatric surgery, but not in patients with similar weight loss induced by a restrictive diet, suggesting the role of a bariatric surgery-dependent mechanism in BCAA reduction6. The VG technique in particular demonstrated an increased capacity for amino acid biosynthesis after surgery, a mechanism that could be linked to improved glucose control6,11. Some patients undergoing bariatric surgery have reported improvements in metabolic syndrome parameters, including reduced waist circumference, reduced triglycerides, reduced fasting glucose, increased high-density lipoprotein, and reduced blood pressure. Many of the explanations for this change in gut architecture are due to altered food intake, hormonal modification, bile acids (BAs), and changes in inflammation levels5,8,17. 

Some of these have been associated with metabolic syndrome parameters and increased Veillonella, which is inversely correlated with waist circumference and positively correlated with the percentage of weight loss. Escherichia, Akkermansia, Enterococcus, and Carnobacterium positively correlated with percent weight loss, and Bifidobacterium and Sutterella negatively correlated5,20,26. Recently, a meta-analysis by Guo et al. reported the change in two genera, Escherichia and Akkermansia, after bariatric surgery. Changes in bacterial genera, such as Eubacterium spp., Ruminococcaceae spp., and Faecalibacterium spp., are associated with improvement in metabolic factors, including HbA1c. In addition, the recommended healthy diet after bariatric surgery may also play a role in increasing MGR, in contrast to obesity, whose microbiota richness is reduced10,16. 

Fusobacteriaceae, Clostridiaceae, and Enterobacteriaceae species increased significantly, while Bifidobacteriaceae and Peptostreptococcaceae decreased in abundance after RYGB. At the same time, there was an increase in microbiota richness, mainly due to Proteobacteria, with an increased association between the gut microbiota and white AT gene expression. Firmicutes phyla were associated with improved trunk fat mass and glycated hemoglobin6,19. In addition, the RYGB showed an increase in the abundance of typically oral tract bacteria such as Fusobacteria, Veillonella, and Granulicatella, and these changes may be substantiated due to pH changes, as when it is elevated in the distal gut, this can affect the gut microbiota.

The food flow was also modified, with less nutritive substance in the distal intestine under post-RYGB conditions. In this regard, oxygen plays an important role, as the shortening of the intestinal length in RYGB can lead to the growth of facultative anaerobes such as Gammaproteobacteria and a reduction of some obligate aerobes21. However, the VG technique did not show significant changes, and the changes in the microbiota induced by surgery occur more gradually and do not completely remodel the microbial genera present in the gut. Finally, when comparing the two techniques, the RYGB has been shown to modify the gut microbiome significantly19. 

Bypass surgery increases intestinal gluconeogenesis and improves insulin resistance; the increased GLUT1 transporter on the membrane of enterocytes improves glucose uptake, and this occurs mainly to support the increased tissue. The hyperplasia of intestinal cells also explains the increased amounts of glucagon-derived peptides that assist glucose utilization. The sodium-glucose co-transporter (SGLT1) also assists in lowering plasma glucose; this is due to the sodium present in the bile. With this, gastrectomy delayed glucose absorption and did not show intestinal hyperplasia8. However, there is a controversy in the results about this bacterial proportion, as some studies with obese patients show changes in the amounts of microorganisms after surgery, while others show the opposite effect. 

The bacterial clusters at a few months after surgery changed progressively, and at 3 months, it was possible to observe that the bacteria that made up the microbiome were no longer the same. The changes were not sustained in the long term, returning to the initial preoperative values after 12 months, but the improvement in metabolism persisted. Thus, at 12 months after surgery, the bacterial profile was similar to that of the preoperative one5,19. Other postoperative subjects did not have this rapid change in the microbiome after surgery, but improvement in metabolism was achieved after 1 year. 

These differences show that microbiome change alone is not able to sustain the benefits achieved in the long term, as bacterial groups act synergistically to enhance or degrade metabolism21. Shao et al. conducted research with rats that underwent the bariatric surgery procedure of VG type and RYGB. After a postprocedural observation for 1, 3, 6, and 9 weeks, they found the effectiveness of bariatric surgeries was associated with their effects on the gut microbiota, as there was a change in the composition, gene content, and fermentation profiles of microbes in the gut, promoting decreased overall adiposity, rapid improvement in glucose metabolism, and remission of obesity comorbidities after the procedure.

The phenotype of circulating microorganisms and biomarkers occurs disparately and throughout the body. To investigate the existence of biomarkers that are associated with different outcomes in each surgical technique, it was found that the bacterial genus Veillonella might be the most characteristic biomarker of the RYGB procedure, while Blautia might be the biomarker of VG surgery. Evaluating the postoperative microbiota profile, the RYGB technique was shown to alter the microbiome more abundantly. 

Thus, the signal transduction pathway was benefited as well as the degradation and metabolism of xenobiotics. Other pathways altered after surgery were decreased amino sugar and nucleotide sugar metabolism, alanine, aspartate, and glutamate metabolism, and glycolysis/glyconeogenesis19,20. There is a direct influence between certain bacterial species and surgical techniques. It was found that in RYGB, in addition to weight loss, changes in the profile of the microbiota were made possible. Firmicutes phyla were associated with better levels of glycated hemoglobin and improved AT in the trunk. In contrast, the VG technique demonstrated a link to Akkermansia muciniphila species, which are related to improved metabolism, decreased adiposity, and inflammation. A. muciniphila produces metabolites derived from its fermentation that serve as a substrate for other bacteria19. 

The findings evidenced by the study from the Autonomous University of Barcelona and Chicago teaching hospitals showed that changing the microbiome alters metabolism as a whole, bacteria alter circulating biomarkers, and the relationship between gut microbiome and improved whole-body metabolism. The study looked at 26 patients, 8 of them with DM2, 9 taking metformin, 11 treated for hypertension, 10 for dyslipidemia, and only one had a history of cardiovascular disease. The profile of the microorganisms was improved, but this change could not be sustained in the long term. BAs and butyrate had their bacterial composition progressively altered as the months passed post-surgery20. Metabolites derived from bacterial metabolisms such as BAs, SCFAs, trimethylamine N-oxide (TMAO), betaine, and choline have had their activity altered, resulting in benefits to patients; high amounts of TMAO, for example, are associated with a high risk of cardiovascular diseases21. 

Regarding BCAA, there is evidence that supplementation has beneficial effects; however, these levels of obesity, insulin resistance, and DM2 are increased. BCAA-mediated insulin resistance occurs because it inhibits the phosphorylation of the insulin receptor (IRS-1). Patients with insulin resistance not only have increased levels of BCAA but also have in their microbiota good amounts of microorganisms of the species Prevotella copri and Bacteroides vulgatus, which are species related to the increased expression of genes that perform the biosynthesis of BCAA3. BAs are synthesized in the liver, stored in the gallbladder, and secreted into the duodenum in response to nutrients and their absorption requirements. They act as surfactants and are important in the breakdown and absorption of substances and stimulate the secretion of the hormone GLP-1, synthesized by the L cells of the intestine. 

They are also natural ligands of the TGR5 receptor, expressed in L cells, which are related to improved glucose utilization, consequent weight loss, and decreased inflammation6,8. BAs can regulate the composition of the gut microbiota. Therefore, they play an essential role in maintaining healthy gut microbiota, insulin sensitivity, innate immunity, and balanced lipid and carbohydrate metabolism. The erroneous bioconversion of primary BAs (PBA) into secondary BAs (SBA) results in fecal dysbiosis as well as metabolic dysfunction and is mechanistically associated with gastrointestinal carcinogenesis, including colorectal cancer and hepatocellular carcinoma17. The mechanism of BA in the face of bariatric surgery-induced improvements in body weight and metabolism includes reduced systemic and hepatic inflammation, which has, as a consequence, more efficient insulin signaling without increased GLP-1 and insulin secretion6. 

The relationship between BA metabolism and gut microbiota is in the Farnesoid X receptor (FXR). Patients undergoing gastric bypass developed a "healthy" gut microbiota, with decreased Bacteroides and increased Roseburia. Such changes were not found in FXR knockout mice and suggest an FXR-dependent signaling pathway. Another finding is that the microbiota metabolizes BAs, which are responsible for the formation of PBA and SBA that activate FXR, thus stimulating the release of gut-derived hormones such as fibroblast growth factor-19 (FGF19), which in turn stimulates BA in its synthesis, increasing host energy consumption. Therefore, elevated levels of FGF19 and BAs are found in adults undergoing gastric bypass surgery after 1 month. The same does not occur in obese adults who have received medication17. 

Patients with NAFLD have high levels of BA in plasma, as do bariatric patients, but the PBA/ABS ratio in bariatric patients tends to be lower compared to that in NAFLD patients. This finding is unrelated to postoperative weight loss since BA levels decrease after weight loss with caloric restriction and with adjustable gastric banding21,22. The intestinal anatomical alteration in the RYGB technique causes poorly digested food to reach distal parts of the small intestine with a higher concentration of BA. A similar effect is found in the SG technique. An intestinal adaptation occurs so that ileal reabsorption of BA is more efficient, justifying the increase in plasma value after bariatric surgery11,26. In other words, even if most of the experimental studies performed on this topic are with animals and observational studies are limited, it is known that bariatric surgery plays an important role in the etiopathogenesis of NAFLD. 

Therefore, the modulation of the gut microbiota after bariatric surgery and the influence on the PBA/SBA ratio in plasma induce metabolic improvements that do not necessarily depend on weight2,24. As described earlier, the microbiota has a great influence on the immune system of the human body. Obesity is a disease of low-grade inflammatory character that generates lesions in the AT, which can result in moderate and chronic systemic inflammation. They influence the production of inflammatory cytokines and chemokines that recruit inflammatory cells within the AT6,8. This increase in inflammatory processes can weaken the gut wall7, causing many obese patients to have dysbiosis of the gut microbiota14. Macrophages are the main inflammatory cells in the AT and exhibit a mixed surface marker in obese people. The continuous inflammatory cycle and abnormal metabolism are induced by the action of lymphocytes, mast cells, and neutrophils14. Some chemokines such as MCP1 also assist in the recruitment of pro-inflammatory cells23. 

The expression of pro-inflammatory cytokines such as IL-1α, IL-6, IL-8, MIP-1α, IFN-α, and TNF-α are significantly increased in obese women10,26. There was a reduction in adipocyte size, after bariatric surgery, accompanied by a reduction in the number of proinflammatory cytokines such as CD4, CD16+, and monocytes, resulting in a decrease in body weight and metabolic improvement. Changes in the receptors present on monocytes, such as the TLR4 receptor, which can recognize bacterial LPS, are associated with modification of the microbiota. Th1 lymphocytes have also changed their phenotype. In obesity, they had an inflammatory profile and a Th1/Th2 ratio that changed after surgery8. Consequently, as improvements in blood glucose are associated with higher amounts of Th2, in general, the profile of inflammatory secretion tends to decrease after bariatric surgery. 

The glucose levels improve within a few days after gastric bypass, and the caloric restriction after surgery leads to weight loss and also changes in anorexigenic gut hormones, such as GLP-1, CCK, PYY, OXN, and eventually glycine. The amount of weight lost also influences the remission of diabetes. Furthermore, bariatric surgery with its consequent weight loss improves insulin sensitivity, specifically when compared to gastric bypass versus a restrictive diet6,8. In addition to controlling food intake, gut hormones affect insulin secretion and resistance. GLP-1 is the most studied hormone after bariatric surgery, and patients with DM2 have decreased secretion of this hormone in the postprandial period18,26. The secretion of GLP-1 increases after bariatric surgery, improving the insulin response. 

In a literature review, Debédat et al. evidenced that after cases of hypoglycemia caused by an increase in the number of beta cells after bariatric surgery, the pancreas performed an adaptation after surgery, thus regulating possible complications8. The mass of beta cells had changed in the pancreas of patients who underwent gastric bypass, and they suffered from neuroglycopenic symptoms of postprandial hypoglycemia. However, the findings are heterogeneous; another study on obese patients found that there was an increase in pancreatic beta-cell mass before and after performing VG and gastric bypass on a total of 26 patients with severe obesity, some with DM2 and others without diabetes. Despite the improvement in glucose homeostasis, even with surgery, the beta-cell function is not recovered, and it does not start to act as in people who have always been thin, even with the weight loss of the bariatric patient2. GLP-2 also seems to assist in metabolic improvements, and its amount increases significantly after gastric bypass. 

This hormone has a protective effect on the intestinal barrier and inflammation8. Another gut hormone that bariatric surgery interferes with is ghrelin, an orexigenic peptide produced by stomach cells. Plasma levels of ghrelin increase before meals and decrease postprandial. With diet-inducing weight loss, ghrelin levels increase and this would be related to regaining the weight lost after dieting, whereas after gastric bypass, plasma levels of ghrelin are lower2. Ghrelin is lessened by VG, which also reduces weight gain and food intake and enhances response to the GLP-1 hormone. PYY hormone is an anorexigenic hormone secreted by cells in the ileum and colon in response to nutrient stimulation; it has an appetite-suppressing effect in obese individuals. Finally, foregut and anti-incretin reduce a pathophysiological increase in antiincretin signaling that normally serves to prevent postprandial hypoglycemia by neutralizing incretin-mediated insulin.

Natural Herbal Medicine For Relieving Constipation-Cistanche 

Cistanche is a genus of parasitic plants that belongs to the family Orobanchaceae. These plants are known for their medicinal properties and have been used in Traditional Chinese Medicine (TCM) for centuries. Cistanche species are predominantly found in arid and desert regions of China, Mongolia, and other parts of Central Asia. Cistanche plants are characterized by their fleshy, yellowish stems and are highly valued for their potential health benefits. In TCM, Cistanche is believed to have tonic properties and is commonly used to nourish the kidney, enhance vitality, and support sexual function. It is also used to address issues related to aging, fatigue, and overall well-being. While Cistanche has a long history of use in traditional medicine, scientific research on its efficacy and safety is ongoing and limited. However, it is known to contain various bioactive compounds such as phenylethanoid glycosides, iridoids, lignans, and polysaccharides, which may contribute to its medicinal effects.

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