Postoperative infection, surgical site infections (SSIs) in particular, is the most common reason for readmission, which contributes to the increased cost of health care (Merkow et al., 2015). In general, GI surgery is subjected to a greater risk of postoperative infection compared with other surgical procedures because the GI tract is inhabited by a wide cluster of microorganisms. Traditionally, postoperative infection is often caused by inadequate preoperative topical or intestinal disinfection, which can be prevented by antibiotics as prophylaxis the day before surgery, even without mechanical bowel preparation (Espin Basany et al., 2020). However, complete depletion of gut and skin microbiota is not possible and has potential negative effects. Many postoperative infections arise from the patient’s gut microbiota, usually after unintended inhibition of beneficial bacteria and translocation of antibiotic-resistant pathogenic bacteria (Deitch, 2012; Yu et al., 2014). Conversely, a diverse and protective gut microbiota provides an important biological layer against infectious complications, because commensal bacteria contribute to colonization resistance against both endogenous and exogenous pathogens through competitive inhibition, production of antimicrobial peptides, and activation of the host immune system (Ducarmon et al., 2019; Isles et al., 2022).

Lifestyle factors, underlying diseases, medications, antibiotics, and surgical procedures can perturb gut microbiota leading to loss of colonization resistance and increased susceptibility to the invasion of pathogenic bacteria. Besides, many in−hospital infections originate from the patient’s gut microbiota when the beneficial bacterial population is suppressed (Wang et al., 2019). Preoperative dysbiosis of gut microbiota is associated with higher rates of postoperative infectious complications, including abdominal/pelvic infections and pulmonary infections, in CRC patients (Liu et al., 2021). The increased relative abundance of Klebsiella in postoperative CRC patients is significantly and positively associated with infectious diseases, such as bacterial invasion of epithelial cells and Staphylococcus aureus infection, revealed by the correlation analysis between differentiated metabolic pathways and genera (Cong et al., 2018). The causative bacteria of surgical site infections are identified to be P. aeruginosa, Staphylococcus aureus, and Enterococcus spp., which are also enriched in the fecal microbiota of postoperative CRC patients (Ohigashi et al., 2013). A gut microbiota-based model base on six genera (Hungatella, Epulopiscium, Fusobacterium, Ruminococcaceae_ucg_009, Actinomyces, and Ralstonia) is used to predict surgical site infections after ileocolonic resection for Crohn’s disease (CD) patients with an AUC of 0.78 (Julien et al., 2022).

The effect of perioperative modulation of gut microbiota by probiotic or synbiotic on postoperative infectious complications has been evaluated in clinical trials ( Table 1 ). A meta-analysis shows that perioperative probiotic or prebiotic supplements may reduce the overall incidence of infectious complications, including wound infections, respiratory infections, and urinary tract infections, in patients undergoing GI surgery, and the most used strains are Lactobacillus and Bifidobacterium (Yang et al., 2017). Their role in postoperative infections may be due to the perioperative stabilization of gut microbiota and alleviation of the systemic inflammatory response (Kotzampassi et al., 2015; Polakowski et al., 2019). Using probiotics or prebiotics as a potential alternative to maintaining the beneficial structure of gut microbiota throughout the whole process of hospitalization may be a promising strategy to reduce the risk of postoperative infections and can be included in enhanced recovery after surgery. However, the results of existing clinical studies are inconsistent, which may be due to disparities in type, dosage, and administration strategies (timing and duration) of probiotics/prebiotics, thus large-scale randomized clinical trials are needed to confirm the efficacy and safety of probiotics/prebiotics in surgical patients.

Anastomotic leak (AL) is one of the most potentially devastating complications that can develop after major surgical bowl reconstruction and has plagued surgeons for decades. Although surgical technique and postoperative care have been improved over the past several decades, AL continues to occur and can lead to peritonitis, sepsis, and even death (Caulfield and Hyman, 2013; Shogan et al., 2013). After anastomosis is performed, the repairing process of the GI tract is immediately initiated and divided into three phases, including the lag phase, the fibroplasia phase, and the maturation phase (Sajid et al., 2012). Ultimately, the healing process results in the repair of the intestinal epithelial barrier with the involvement of complex molecular and cellular interactions of host cells, luminal proliferative components, and gut microbiota (Kurashima and Kiyono, 2017). Among these factors contributing to anastomotic healing, gut microbiota remains largely overlooked and should be focused on. Indeed, germ-free mice have a reduced regenerative response of the epithelia and a hampered healing process of the intestinal barrier compared with conventional mice (Hooper et al., 2001). In addition, conventionalized germ-free rats show a significantly better wound healing of intestinal anastomoses than germ-free animals and rats that are colonized by either Lactobacillus acidophilus or E. coli (Okada et al., 1999), suggesting that the effect of gut microbiota on the healing of intestinal anastomoses depends on differences in the types of bacteria. Therefore, gut microbiota can either assist or hinder intestinal wound healing through cooperation or competition between different microbial species (Koliarakis et al., 2020). Further studies focusing on gut microbiota could be one such avenue for uncovering the elusive pathogenesis of AL.

The gut microbiota participates in the physiological process of intestinal wound healing and epithelial repair through a variety of molecular mechanisms. Members of the gut microbiota can interact with different intestinal epithelial lineages through innate immune receptors, such as toll-like receptor (TLR) 4 and 2, by recognizing gut microbial components, such as lipopolysaccharide and flagellin, thus modulating homeostasis in the gut and playing an important role in the epithelial repair after injury (Burgueno and Abreu, 2020). Metabolites produced by gut microbiota are also involved in the intestinal epithelial repair. Butyrate, one of the SCFAs derived from the bacterial fermentation of dietary fibers, regulates colonocyte proliferation, strengthens the gut barrier, limits pathogen growth, and suppresses inflammatory response (Martin-Gallausiaux et al., 2021). Several animal studies have shown that exogenous butyrate administration improves the healing of colonic anastomoses and enhances colonic anastomotic strength in rats (Rolandelli et al., 1997; Mathew et al., 2010; Bosmans et al., 2017). Besides, perioperative supplementation of inulin and galactooligosaccharides, which modulate the gut microbiota to increase the production of butyrate through enhancement of butyrate-producing bacteria, improve anastomotic healing and reinforce the gut barrier in mice (Hajjar et al., 2021). Moreover, SCFAs produced by gut microbiota may be a mechanism of intestinal resistance to colonization by P. aeruginosa, which has been identified as an AL-related pathogen (Levison, 1973; Williamson and Alverdy, 2021). These data indicate the importance of functional gut microbiota to ensure adequate healing, but the stress of perioperative events and surgery itself may induce a shift of gut microbiota to a pathologic phenotype, which leads to an AL.

Previous studies have investigated the causal relationship between AL and gut microbiota. Anastomotic injury, without preoperative MBP or antibiotic prophylaxis, contributes to remarkable compositional and functional changes in the anastomotic tissue-associated microbiota with a 200-fold and 500-fold increase in the relative abundance of Escherichia-Shigella and Enterococcus, respectively (Shogan et al., 2014). However, these alterations were not observed in the stool microbiota (Shogan et al., 2014), suggesting that certain bacteria having adhesive properties invade the anastomotic site, which may potentially complicate or accelerate anastomotic healing.

Clinically relevant animal models of AL are created to investigate the responsible gut microbiota-related mechanisms involved in the pathogenesis of AL. A novel model of AL, in which rats are exposed to preoperative radiation as in patients with advanced rectal cancer and undergo a distal colon resection followed by intestinal inoculation with P. aeruginosa, a common pathogen in the gut following radiation exposure, is developed (Olivas et al., 2012). Only those rats that are both exposed to radiation and colonized by P. aeruginosa occur AL. Sequencing of retrieved P. aeruginosa strains from the leaking anastomotic tissues demonstrates that the appearance of a single nucleotide polymorphism mutation in the mexT gene leads to a stop codon and subsequent a non-functional truncated protein, which induces P. aeruginosa in vivo transformation to more destructive phenotype with enhanced abilities of collagen degradation, invasion, and cytotoxicity. This study indicates that interactions between pathogen and host stimulate and contribute to the development of bacterial virulence and subsequent AL. More molecular detail on the microbiota-dependent pathogenesis of AL also has been identified. A commensal bacterium, E. faecalis, contributes to the pathogenesis of AL by degrading collagen and activating host matrix metalloproteinase 9 (MMP9) (Shogan et al., 2015). Rat receiving a low colonic reconstruction and segmental devascularization develop a 50% incidence of AL. The leaking anastomotic tissues are colonized by E. faecalis strains with high collagenase activity. In contrast, the healed anastomotic tissues harbor low collagenase E. faecalis strains. Both eliminations of E. faecalis strains by direct topical antibiotics and pharmacological suppression of intestinal MMP9 activation prevent AL. Mechanically, high collagenase-producing strains directly cleave collagen I and indirectly break down collagen IV by converting tissue MMP9 to its active form, which is dependent on the collagenase-encoding genes gelE and sprE. Fusobacterium nucleatum (F. nucleatum) also can induce colon AL by activating epithelial cells to express MMP9 (Shi et al., 2022). Recent studies using FMT demonstrate a causal role of the preoperative and postoperative gut microbiota in AL. FMT using postoperative stool samples from AL patients leads to poor anastomotic healing in rats (Jin et al., 2022). Mice receiving preoperative stool samples from AL patients with CRC also display poor surgical healing, which is correlated with two bacterial strains, Alistipes onderdonki (A. onderdonkii) and Parabacteroides goldsteinii (P. goldsteinii), and A. onderdonkii supplementation leads to a higher rate of leaks in mice (Hajjar et al., 2022). Overall, some individual pathogens, including E. faecalis, P. aeruginosa, F. nucleatum, and A. onderdonkii, have been implicated in the pathogenesis of AL by promoting the breakdown of collagen ( Figure 2 ). A short course of dietary prehabilitation decreases postoperative collagenolytic Enterococcus and reduces AL in mice (Hyoju et al., 2020). Although the effect of probiotics or synbiotics on the AL is not satisfactory in most clinical cases according to limited reports ( Table 1 ), P. goldsteinii plays an anti-inflammatory effect and improves wound healing in a murine AL model (Hajjar et al., 2022), representing a potential probiotic that may enhance postoperative recovery in patients at risk of developing AL.

Taken together, these animal data suggest that bacterial phenotypes can be reshaped in vivo by injured tissue, which may have a profound effect on the recovery from GI surgery. Targeting the gut microbiota as a modifiable factor may be a novel strategy for the prevention of AL.

GI dysmotility is common after major GI reconstruction. This dysmotility can range from malabsorption, which is associated with increased motility, to postoperative ileus (POI). Gut microbiota plays a significant role in the regulation of GI physiology, particularly GI motility (Zheng et al., 2022).

Altered gut microbiota after GI surgery substantially contributes to changes in GI motility. POI is one of the most frequent complications after GI surgery. Mice treated with oral antibiotics show a moderate alleviation in small intestinal POI, whereas POI is improved by antibiotic treatment in the colon (Pohl et al., 2017). Besides, there is a big difference in the quantity and composition of the gut microbiota between the small and large intestines (Mowat and Agace, 2014; Martinez-Guryn et al., 2019), indicating the essential role of gut microbiota in the induction of POI. In the clinical setting, CRC patients with ileus have a lower α-diversity and a higher Firmicutes to Bacteroidetes ratio of gut microbiota compared with CRC patients without ileus (Jin et al., 2020). The relative abundance of Proteobacteria is high in CRC patients with ileus, whereas the relative abundances of Bacteroidetes, Firmicutes, and Fusobacterium are high in CRC patients without ileus. At the genus level, Escherichia-Shigella, Ralstonia, and Veillonella are significantly greater in the group with ileus than that without ileus. For POI, CRC patients with a low abundance of Faecalibacterium have a high risk of POI, and Faecalibacterium as a biomarker has an AUC value of 0.74 for the prediction of POI and an AUC value of 0.67 for the prediction of POI that occurs 6 months after discharge from hospital (Jin et al., 2020). Preoperative probiotic treatment improves bowel movement in the guinea pig with POI, probably by restoring the beneficial bacterial species Bifidobacterium bifidum and Bifidobacterium longum and increasing butyrate production (Shin et al., 2021). Moreover, a meta-analysis of 21 randomized controlled trials shows that prophylactic supplements of probiotics or synbiotics can effectively shorten the time of first flatus, first defecation, and first diet and reduce the incidence of POI in patients receiving GI cancer surgery (Tang et al., 2022). In contrast, preoperative stimulation of the efferent loop with probiotics does not affect the appearance of POI in patients undergoing loop ileostomy closure, which may be due to the previous existence of POI after colorectal cancer surgery (Rodriguez-Padilla et al., 2021). Nevertheless, perioperative gut microbiota modulation by supplementation of probiotics or synbiotics may be used to improve the recovery of GI motility after GI surgery ( Table 1 ), but the underlying mechanisms and what changes in gut microbiota resulting from bowel preparation and surgery contribute to GI dysmotility remain to be elucidated.

Complex anatomical GI reconstructions, such as gastrectomy, RYGB surgery, and pancreaticoduodenectomy, can lead to fat malabsorption, dumping syndrome, and vitamin deficiencies. Patients subjected to RYGB are at an increased risk of malabsorption resulting in trace element deficiency and osteopenia (Hammer, 2012; Billeter et al., 2015). Gut microbiota seems to be an important mediator in this process because FMT from RYGB-treated mice to germ-free mice without RYGB results in weight loss and decreased fat mass when compared with mice receiving FMT from sham surgery controls, potentially by regulating the production of SCFAs (Liou et al., 2013). The energy-reabsorbing potential of the gut microbiota, indicated by the Bacteroidetes to Firmicutes ratio, is decreased following laparoscopic sleeve gastrectomy (Damms-Machado et al., 2015), and gut microbiota can also play a significant role in the effects of RYGB on energy homeostasis (Chakravartty et al., 2015). The increased relative abundance of Gammaproteobacteria is closely associated with malabsorption after RYGB (Furet et al., 2010). Although malabsorption can be treated by vitamin supplementation and dietary modifications to adapt to the changed metabolism in many cases (Bland et al., 2016), the effect of the gut microbiota in the digestion and absorption after major surgery with GI reconstruction needs a further understanding, which will provide cues for development of therapies to accelerate postoperative recovery.

The risk of colorectal cancer (CRC) may be increased after gastric bypass over time, whereas the risk of hormone-related cancers, including breast, endometrium, and prostate cancer, is associated with bariatric surgery (Derogar et al., 2013; Mackenzie et al., 2018). Besides, CRC risk is affected by sex and type of surgery. An increased risk of CRC is observed in males compared to females, especially 3 years or more after bariatric surgery, whereas CRC risk is decreased in females after RYGB but not sleeve gastrectomy (Hussan et al., 2022). Postoperative alteration of gut microbiota influences cancer risk and recurrence. Both decreases in absorptive GI mucosa and changes in the gut microbiota after bowel reconstruction contribute to disruption in the processing of bile acid (Flynn et al., 2015; Albaugh et al., 2019), which may expose colonocytes to more secondary bile acid, in particular deoxycholic acid (DCA), activating multiple signaling pathways including EGFR and Wnt in enterocytes that can lead to the development of CRC (Jia et al., 2018). Increased mucosal exposure to bile acid has been proposed to increase the risk of CRC after RYGB (Kant et al., 2014).

Gut microbiota also has been associated with CRC recurrence after surgery. Although patients undergoing surgery are often optimized with adjuvant or neoadjuvant chemoradiotherapy, up to one-third of them will get a postoperative CRC recurrence (Jeffery et al., 2007). In the traditional view, cancer recurrence is due to the postoperative blossom of shed tumor cells either at the surgical site or unknowingly present in the distal organs at the time of surgery. However, an opinion that the gut microbiota influences postoperative cancer recurrence is emerging ( Figure 3 ).

Spatial-specific gut microbiota profiles link to CRC recurrence. The composition of gut microbiota at adjacent-tumor sites of patients with CRC recurrence is different from that in patients without CRC recurrence (Huo et al., 2022). At the phylum level, the relative abundance of Fusobacteria at adjacent tumor sites is much higher in patients with CRC recurrence than that in patients without CRC recurrence (Huo et al., 2022). Gut microbiota can serve as biomarkers to predict the risk of CRC recurrence. Besides, the postoperative gut microbiota can drive shed cancer cells to a migratory and aggressive phenotype, assisting them to escape immune surveillance to promote a postoperative recurrence. Through matrix metalloproteinases or the urokinase-plasminogen system, the collagenase-producing bacteria can bind to and degrade extracellular matrix, breakdown products of which are well known to promote proliferation, migration, and invasion of cancer cells (Shogan et al., 2015; He et al., 2016; Jacobson et al., 2020). E. faecalis, a high collagenase-producing strain, cooperating with macrophages reshapes colonic epithelial cells to a mesenchymal phenotype that is similar to the phenotype seen in mesenchymal transition, which is a fundamental biological process of tumor metastasis (Belogortseva et al., 2017). Indeed, colonization of collagenase-producing E. faecalis or Proteus mirabilis promotes shed cancer cells to form a tumor in mice on a high-fat diet undergoing a colon resection and anastomosis, which can be prevented by administration of a collagenase inhibitor (Gaines et al., 2020). Thus, gut microbiota-targeted strategies may be used to reduce the risk of CRC recurrence by eliminating these bacteria or inhibiting their collagenase activities.