Clinical significance of perioperative probiotic intervention on recovery following intestinal surgery

Abstract

Restoring the balance of gut microbiota has emerged as a critical strategy in treating intestinal disorders, with probiotics playing a pivotal role in maintaining bacterial equilibrium. Surgical preparations, trauma, and digestive tract reconstruction associated with intestinal surgeries often disrupt the intestinal flora, prompting interest in the potential role of probiotics in postoperative recovery. Lan et al conducted a prospective randomized study on 60 patients with acute appendicitis, revealing that postoperative administration of Bacillus licheniformis capsules facilitated early resolution of inflammation and restoration of gastrointestinal motility, offering a novel therapeutic avenue for accelerated postoperative recovery. This editorial delves into the effects of perioperative probiotic supplementation on physical and intestinal recovery following surgery. Within the framework of enhanced recovery after surgery, the exploration of new probiotic supplementation strategies to mitigate surgical complications and reshape gut microbiota is particularly intriguing.

Key Words: Probiotic; Surgery; Inflammation; Gut microbiota; Intestinal mucosal barrier; Enhanced recovery after surgery

Core Tip: The application of probiotics during the perioperative period is still under clinical investigation. Through their complex mechanisms, probiotics can promote postoperative recovery of intestinal peristalsis, alleviate inflammatory responses, maintain intestinal mucosal barrier function, and expedite patient rehabilitation. Given the variability of individual intestinal microbiota and the functional differences among probiotic strains, personalized probiotic therapy stands out as a significant direction for future research in accelerated rehabilitation surgery.

INTRODUCTION

The gut microbiota is a vast and intricate ecosystem, comprising between 600000 to 3.3 million genomes that exist in a symbiotic relationship with the host[1]. Dubbed as an “organ”, gut microbiota aids in food digestion, regulates intestinal endocrine functions, maintains nutritional and energetic homeostasis, and supports the development of the human metabolic system. Additionally, it coordinates immunity and detoxifies harmful substances in the host[2]. Significant alterations in the microbiota’s quantity and diversity can lead to gut dysbiosis, potentially causing acute or chronic dysfunction in some bodily systems[3,4].

Probiotic, also known as live microorganisms, enhance the stability of gut microbiota. Through a balanced gut microbiome, they indirectly improve the body’s metabolism, immune system, and even mental health. Since Lilly and Stillwell[5] first introduced probiotic therapy in 1965, it has sparked extensive clinical research by investigators across numerous diseases, including inflammatory bowel disease[6], intestinal tumors[7], liver cirrhosis[8], Alzheimer’s disease or cognitive impairment[9], lung diseases[2], and chronic kidney disease[10] etc.

For highly invasive intestinal surgeries[11], probiotic supplementation may emerge as a pivotal factor in enhanced recovery after surgery protocols. This approach aims to expedite postoperative intestinal healing and mitigate complications by stabilizing the intestinal microbiota[12]. Lan et al[13] administered oral probiotics (Bacillus licheniformis capsules) to patients who underwent emergency appendectomy. They found that probiotics aided in the restoration of intestinal function after the appendectomy, effectively reducing levels of C-reactive protein, interleukin-6, and procalcitonin, thereby mitigating the body’s inflammatory response. This editorial evaluates the clinical value of probiotics in postoperative intestinal recovery, focusing on intestinal motility, systemic inflammation, and barrier protection functions.

MECHANISMS OF PROBIOTICS IN RESTORING INTESTINAL MOTILITY

Intestinal motility is influenced by various factors, including the intestinal environment, bile acid metabolism, mucus secretion, and immune and nervous system functions[14]. A significant decrease in the abundance of probiotics such as Bifidobacterium and Lactobacillus is associated with impaired gastrointestinal motility. Bifidobacterium and Bacteroides metabolites like acetate and butyrate to interact with G-protein coupled receptors 41 and 43 or act directly on colonic smooth muscle to improve intestinal motility[15-17]. Probiotics can also enhance intestinal motility by regulating intestinal nervous system. Specifically, Limosilactobacillus reuteri facilitates gut movement through the intermediate conductance calcium-dependent potassium channel[18]. Additionally, intestinal neurons are stimulated to enhance gut contractility via Lactobacillus rhamnosus GG-mediated formyl peptide receptor 1[19] and Clostridium butyricum-mediated toll-like receptor 2[20]. Recent research has shown that supplementing with Bifidobacterium longum harboring the abfA gene cluster can improve the intestinal motility gene abfA, and then strengthen the digestion of arabinose, increases beneficial metabolites, and ultimately leads to better gastrointestinal motility[21]. Probiotics can also promote intestinal activity by regulating the endocrine system and intestinal secretions[21]. Modifying the intestinal luminal environment with specific probiotics may thus improve gut motility, benefiting post-surgery patients.

PROBIOTICS IN REDUCING INFLAMMATION

Probiotics found in fermented foods possess a robust redox system and antioxidant capabilities, which effectively mitigate inflammatory responses[22]. Studies indicate that lactic acid bacteria, a type of probiotic, exhibit significant antioxidant activity primarily by reestablishing the host’s antioxidant gut microbiota, scavenging free radicals, regulating the production of antioxidant enzymes, and chelating pro-oxidant metal ions[23]. Treatment with the probiotic Akkermansia muciniphila has been shown to reduce chronic inflammation by deactivating downstream signals of lipopolysaccharide/binding protein and increasing anti-inflammatory factors such as α-tocopherol and β-sitosterol[24]. Furthermore, Zhang et al[25] discovered that Lactobacillus plantarum and its metabolite indole-3-lactic acid improve intestinal inflammation. Lactobacillus johnsonii and its metabolites inhibit the activation of the mitogen-activated protein kinases signaling pathway and the polarization of M1 macrophages, thereby reducing the secretion of proinflammatory cytokines[26]. The administration of probiotics is emerging as a novel approach in preventing and treating intestinal inflammation. Current studies are exploring various methods such as artificial enzyme modification, nanoparticle decoration, or genetic engineering to enhance probiotic viability, improve anti-inflammatory efficiency, and stabilize the inflammatory environment within the intestine[27-29].

PROTECTION OF INTESTINAL MUCOSAL BARRIER FUNCTION BY PROBIOTICS

The intestinal barrier, spanning approximately 400 m², evolves through the synergistic interplay between the gastrointestinal epithelium and microbiota. This vital interface not only prevents the invasion of viruses and microorganisms but also ensures the balanced absorption and excretion of nutrients[30-32]. The normal gut flora regulates the expression and distribution of tight junction proteins, which mediate epithelial cell adhesion[33]. Furthermore, bacteria within the intestinal mucus utilize the mucus as an energy source and its metabolic byproducts to maintain the composition and thickness of the mucus layer[34,35]. Disruption of this barrier is recognized as a pathophysiological change and a contributing factor in the development of various diseases, including irritable bowel syndrome, inflammatory bowel disease, and the early-stage colon cancer[30,36,37]. The consequences of such disruption can be far-reaching, extending to extraintestinal conditions such as neurological disorders[38], musculoskeletal injuries[39], cardiovascular diseases, and diabetes[40].

The evidence regarding the modulation of intestinal permeability by probiotics remains inconclusive. However, studies suggest that probiotics can selectively regulate mucosal T-cell expression[41] and lymphocyte-derived interleukin-22 secretion[42], suppressing mucosal inflammation and enhancing bactericidal activity to promote epithelial restoration. Additionally, probiotics compete with pathogens for survival resources, utilize common receptors for epithelial adhesion to inhibit infection, and increase the output of antimicrobial proteins[43]. They also activate immune defenses through host pattern recognition receptors, enhancing resistance to infection[42]. Notably, Lactobacillus rhamnosus GG secretions protect human colonic smooth muscle cells[44], and certain probiotics promote intestinal epithelial repair[45], strengthening tight junction proteins through increased butyrate production[42]. However, some probiotic strains, such as lactic acid bacteria[46] and Bifidobacterium longum[42], may lack intestinal mucosal protective functions. Overall, probiotic administration holds significant potential in safeguarding intestinal mucosal barrier function.

THE IMPACT OF PROBIOTICS ON GASTROINTESTINAL FUNCTION RECOVERY AFTER INTESTINAL SURGERY

Intestinal surgery often impairs intestinal mucosal barrier function, triggering inflammation and ischemia-reperfusion injury. Especially, the resection and reconstruction of the intestine alter the structure of gut microbiota, affecting digestion, nutrient absorption, and immune function[47]. Since 1954, Anlyan et al[48] emphasized the importance of maintaining a healthy gut microbiota during surgery, recommending aseptic measures and intestinal sterilization to prevent infections and microbiota dysbiosis. In response to the adverse effects of surgery on intestinal function, probiotic intervention emerges as a promising strategy. As shown in Table 1, probiotics expedite post-surgical intestinal function recovery, mitigate post-operative infections and inflammatory responses, and safeguard the intestinal mucosal barrier[13,49-74]. Research has demonstrated that regular administration of probiotics pre- and post-operatively can significantly restore gastrointestinal motility, resulting in earlier postoperative recovery of bowel exhaust and defecation, reduced fever, and abdominal discomfort, ultimately leading to shorter hospital stays[13,49-52,61,66,71]. Notably, for patients undergoing neoadjuvant chemotherapy, probiotic therapy has been shown to alleviate chemotherapy-induced intestinal complications, and receive greater therapeutic benefits for these patients[60,75]. Furthermore, Mizuta et al’s study revealed that probiotic intervention can also improve hematological parameters and promote nutritional recovery[60].

Table 1 Effect of probiotic intervention on postoperative rehabilitation of intestinal surgery.

Ref.	Probiotic species	Start time	Duration	Surgical method	Clinical index	Infection or inflammation index	Intestinal injury index
Lan et al[13]	Bacillus licheniformis capsules	Postoperation: 1st day	Postoperation: 5 days	Laparoscopic appendectomy	Positive	Positive	Positive
Xu et al[49]	12.5% glucose solution + bifidus-triple viable preparation	Preoperative: 7th day	Preoperative: 7 days	Colorectal cancer excision	Positive	Positive	Positive
Liu et al[50] and Liu et al[51]	Lactobacillus plantarum, Lactobacillus acidophilus and Bifidobacterium longum	Preoperative: 6th day. Postoperation: 1st day	Preoperative: 6 days; postoperation: 10 days	Colorectal cancer excision	Positive	Positive	Positive
Liu et al[52]	Lactobacillus plantarum, Lactobacillus acidophilus-11 and Bifidobacterium longum-88	Preoperative: 6th day. Postoperation: 1st day	Preoperative: 6 days; postoperation: 10 days	Radical resection of colorectal tumors and liver metastases	Positive	Positive	Positive
Horvat et al[53]	The combination of pro- and prebiotics was the multi-strain/multi-fiber Synbiotic 2000™	Preoperative: 3rd day	Preoperative: 3 days	Colorectal cancer excision	NA	Positive	NA
Zhang et al[54]	Bifid triple viable probiotics	Preoperative: 3rd-5th days	Preoperative: 3-5 days	Colorectal cancer excision	NA	Positive	Positive
Zhu et al[55]	Jinshuangqi tablets	Preoperative: 5th day. Postoperation: 2nd day	Preoperative: 5 days; postoperation: 7 days	Laparoscopic radical surgery for colorectal cancer	NA	Positive	Positive
Zhang et al[56]	Viable Bifidobacterium	Preoperative: 5th day	Preoperative: 5 days	Colorectal cancer excision	NA	Positive	Positive
Xia et al[57]	Lacidophilus and high-purityoligosaccharide	Preoperative: 1st day	Preoperative: 1 day	Colorectal cancer excision	NA	Positive	Positive
Kotzampassi et al[58]	Lactobacillus acidophilus, Lactobacillus plantarum, Bifidobacterium lactis and Saccharomyces boulardii	Preoperative: 1st day. Postoperation: 1st day	Preoperative: 1 day; postoperation: 15 days	Colorectal cancer excision	Positive	Positive	NA
Enayet et al[59]	Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, and fructo-oligosaccharides	Preoperative: 3rd days. Postoperation: 1st day	Preoperative: 3 days; postoperation: 7 days	Intestinal surgery for children under 5 years old	NA	Positive	NA
Mizuta et al[60]	Bifidobacterium longum BB536	Preoperative: 7th-14th day. Postoperation: 1st day	Preoperative: 7-14 days; postoperation: 14 days	Colorectal cancer excision	Negative	Positive	Positive
Yang et al[61]	Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis	Preoperative: 5th day. Postoperation: 1st day	Preoperative: 5 days; postoperation: 7 days	Colorectal cancer excision	Positive	Negative	NA
Consoli et al[62]	Saccharomyces boulardii	Preoperative: 7th day	Preoperative: 7 days	Colectomy	Negative	Positive	NA
Polakowski et al[63]	Synbiotics	Preoperative: 8th day	Preoperative: 7 days	Colon cancer resection	Positive	Positive	NA
Zaharuddin et al[64]	Lactobacillus acidophilus, Lactobacillus lactis, Lactobacillus casei subsp, Bifidobacterium longum, Bifidbacterium bifidum and Bifidobacterium infantis	Postoperation: 28th	Postoperation: 6 months	Colorectal cancer excision	NA	Positive	NA
Aisu et al[65]	Enterococcus faecalis T110, Clostridium butyricum TO-A and Bacillus mesentericus TO-A	Preoperative: 3rd-15th day. Postoperation: The day of drinking	NA	Colorectal cancer excision	NA	Positive	NA
Park et al[66]	Bifidobacterium animalis subsp, lactis HY8002, Lactobacillus casei HY2782, and Lactobacillus plantarum HY7712	Preoperative: 7th day	Preoperative: 7 days; postoperation: 21 days	Resection of sigmoid carcinoma	Positive	Positive	NA
Wang et al[67]	Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis	Postoperation: Admission date	From admission to discharge	Colorectal cancer excision and Hip or knee replacement	Positive	Positive	NA
Bajramagic et al[68]	Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus rhamnosus, Bifidobacterium lactis, Bifidobacterium bifidum, Bifidobacterium breve, and Streptococcus thermophilus	Postoperation: 3rd day	Postoperation: 1 year	Colorectal adenocarcinoma resection	Positive	NA	NA
Kakaei et al[69]	Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus plantarum, Bifidobacterium breve, Bifidobacterium longum, and Streptococcus thermophilus	Preoperative: 1st day	Preoperative: 1 day; postoperation: 30 days	Colorectal cancer excision	Negative	NA	NA
Flesch et al[70]	Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus casei and Bifidobacterium	Preoperative: 5th days. Postoperation: 1st day	Preoperative: 5 days; postoperation: 14 days	Colorectal cancer excision	NA	Positive	NA
Tan et al[71]	Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus lactis, Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium infantis	Preoperative: 7th day	Preoperative: 7 days; postoperation: By the time of recovery of intestinal function or discharge	Colon cancer resection	Positive	Negative	NA
Komatsu et al[72]	Lactobacillus casei strain Shirota	Preoperative: 7th-11th day	Preoperative: 7-11 days; postoperation: 2-7 days	Laparoscopic colorectal resection	NA	Positive	NA
Sadahiro et al[73]	Bifidobacteria	Preoperative: 7th day. Postoperation: 5th day	Preoperative: 7 days; postoperation: 10 days	Colon cancer resection	NA	Negative	NA
Mangell et al[74]	Lactobacillus plantarum 299v	Preoperative: 8th day. Postoperation: 1st day	Preoperative: 8 days; postoperation: 5 days	Colectomy	NA	Negative	Negative

NA: Not available.

Surgical interventions in the intestine are prone to postoperative infections and bacteremia, emphasizing the importance of enhancing intestinal microenvironment and barrier function prior to surgery to mitigate the highly invasive nature of abdominal procedures[11]. Despite the use of bowel preparation, including preoperative fasting, prophylactic antibiotics, and mechanical bowel lavage, which aim to reduce intestinal bacterial infections, postoperative infective complications remain inevitable. These preparations, however, may alter the gut microbiota composition, leading to a decrease in microbiota diversity and an increased risk of pathogen proliferation[47,76,77]. The intervention of probiotics may mitigate the adverse effects of intestinal preparation measures on gut microbiota disruption, stabilize the intestinal flora, and has also been demonstrated to alleviate intestinal mucosal inflammation, reduce blood bacterial load, and mitigate the risk of septicemia, wound infections, and other infective complications[13,49-59,61-63,65,66], offering a promising approach to enhance surgical outcomes. Furthermore, according to Aisu et al’s findings[65], the absence of probiotic consumption has been identified as an independent risk factor for surgical site infection. Moreover, for extraintestinal inflammatory diseases, early supplementation with Bifidobacteria, particularly multi-strain probiotics, significantly reduces proinflammatory cytokine levels, minimizes complications such as infections, and safeguards intestinal integrity[78-80]. Additionally, probiotic consumption protects the body from invasion by external pathogens[81,82], further emphasizing their importance in preventing infection.

Supplementation of probiotics during the perioperative period significantly improves the intestinal microecology and enhances the intestinal mucosal barrier function. Studies have shown that an increase in the abundance of probiotics (Bifidobacteria and Lactobacilli) supplemented in feces, coupled with a decrease in the prevalence of Escherichia coli[49-51,54,55]. Compared to the placebo group, markers of intestinal mucosal barrier injury, including endotoxin, blood d-lactate, intestine fatty acid binding protein, ileal bile acid-binding protein, and urinary lactulose/mannitol ratios, were significantly reduced following probiotic intervention[49-52]. This suggests that probiotic supplementation can inhibit intestinal mucosal barrier injury and promote the repair of intestinal epithelial structures[57]. Additionally, for patients with liver metastases from colon cancer, probiotic administration can protect the hepatic barrier and mitigate liver ischemia-reperfusion injury[52,83].

Probiotics, leveraging their capacity to modulate gut microbiota in the treatment of extraintestinal diseases, may mitigate the surgical impact on underlying comorbidities like cardiovascular disease[84] and type 2 diabetes[85], thereby accelerating recovery. Furthermore, probiotic consumption post-colorectal surgery can inhibit colon cancer-related gut bacteria[66], and research indicates their potential as preventive/therapeutic agents for colorectal cancer[86]. However, the role of probiotics in reducing recurrence remains to be observed.

Many studies revealed that probiotic intervention during perioperative periods of non-intestinal surgeries, including esophagectomy[87], cholangiocarcinoma, radical resection of ampullary tumors[88,89], pancreatic surgery[90], hepatic surgery[91], and liver transplantation[92], can reduce post-operative infection complications and abdominal discomfort. Highlighting the ‘universal’ benefits of probiotic therapy, their administration in patients with multiple severe injuries can also prevent infections and promote recovery[93].

The current research on preventive probiotic interventions is primarily focused on colorectal cancer surgeries, with limited understanding of their prophylactic effects in other gastrointestinal surgical procedures. Lan et al’s findings on emergency appendectomy underscore the potential of probiotics in early recovery of inflammation[13]. Future research should expand the sample size of prospective studies as discussed by Lan et al[13], but also to broaden the scope of research centers. Moreover, the diversity of clinical indicators for gastrointestinal function should be enriched, encompassing assessments of the abundance of various intestinal microbiota as well as intestinal immunity and relevant clinical index examination methods.

Current probiotic supplementation is largely empirical, often constrained by individual variations in mucosal microbiota and their colonization efficiency[94]. Notably, intestinal mucosal recovery following probiotic supplementation pales in comparison to autologous fecal microbiota transplantation[95]. Various probiotic strains possess unique intestinal functional benefits[96]. Future research should aim to identify specific probiotic species, dosages, and treatment durations that are particularly effective for postoperative recovery, while also developing novel personalized probiotic therapies tailored to individual gut microbiota compositions.

CONCLUSION

Enhanced recovery after surgery has gained widespread acceptance and application. Probiotics, particularly in the perioperative context, demonstrate immense potential in balancing intestinal microbiota, accelerating gut function recovery, mitigating inflammatory and antibiotic usage, thus fostering postoperative rehabilitation. Future research should focus on clinical prospective studies to refine personalized probiotic supplementation strategies, further accelerating patient recovery and alleviating societal and economic burdens.