Small intestinal bacterial overgrowth and intestinal methanogen overgrowth in gastrointestinal malignancies

Introduction

Small intestinal bacterial overgrowth (SIBO) can be defined as a disorder, where an excessive number of colon-specific bacteria are present in a small intestine, which physiologically is not abundantly colonised [1].

Intestinal methanogen overgrowth (IMO), originally described as methane- dominant SIBO, involves an overgrowth of archaea, particularly Methanobrevibacter smithii, which produce methane. Unlike bacteria, archaea belong to a distinct biological domain, leading to the differentiation of IMO as a separate condition [2–4]. The clinical manifestations of IMO differ from those of SIBO, primarily due to the production of methane by methanogens, which impacts gastrointestinal motility.

In a healthy individual, easily digestible starch breaks down and fully absorbs in a proximal part of a small intestine and is not available for bacteria in a distal part of ileum and a colon for fermentation. In SIBO/IMO that threshold of major fermentation and gas production is moved towards the initial part of a small intestine due to an excessive number of bacteria and/or archaea. This shift results in both easily and poorly digestible starch being available for fermentation by the overgrown microorganisms [5]. In SIBO, the main gas produced during the fermentation of carbohydrates is hydrogen (H₂). In contrast, in IMO archaea utilize the H₂ produced in fermentation to form methane [3]. Treatment involves pharmacotherapy, probiotics and nutritional intervention. Due to the complexity, it requires a multidisciplinary approach. In most patients, full recovery is challenging to attain, with the disease often alternating between periods of remission and relapse.

Current research on SIBO frequently fails to adequately distinguish between its various subtypes, including SIBO and IMO. This lack of differentiation undermines therapeutic approaches specific to each subtype. Further research is essential to elucidate these distinctions and enhance the precision of clinical management strategies.

Pathophysiology and risk factors

Physiologically, there are many defensive mechanisms which are responsible for maintaining balanced microbial environment (eubiosis) and prevent excessive colonisation of microorganisms. These include among others: gastric acid, physiological motility of a small intestine (including migrating motor complex), pancreatic enzymes, bile, intestinal integrity and immunity (mucus, secretory IgA), ileocecal valve, physiological gastrointestinal tract anatomy and commensal gut microbiota [1, 6–8]. Impairment of these mechanisms can result in intestinal dysbiosis and SIBO [9]. The onset of SIBO is frequently linked to a delay of orocecal transit time. It impairs the usual clearance of bacteria from the digestive tract and prolongs the time where food residues are accessible by bacteria and archaea for fermentation. Other most common causes of the development of SIBO include alteration of gastric acid secretion and a reflux of contents from the large intestine to the small intestine due to dysfunction of the ileocecal valve [10].

Small intestinal bacterial overgrowth is frequently associated with a wide range of comorbid conditions and diseases, as supported by existing research. A literature review published in 2024 [8] proposes the categorization of conditions linked to SIBO into 12 groups:

Numerous studies demonstrate significant associations between SIBO and a wide range of conditions, but itis worth mentioning that many of the conditions discussed are linked to gut microbiota status rather than directly to SIBO, these studies collectively underscore the profound role of gut microbiota in overall health [11, 12] (Table 1).

Clinical presentation of SIBO

The signs and symptoms of SIBO can develop due to nutrient malabsorption, changes in intestinal permeability, inflammation, and immune activation caused by abnormal bacterial fermentation in the small intestine [12, 24]. Abdominal pain, bloating, gas, distension, flatulence, and diarrhoea are frequently observed symptoms among patients with SIBO, present in more than two-thirds of individuals. The frequency and severity of symptoms are likely influenced by both the level of bacterial overgrowth and the degree of mucosal inflammation. Gastrointestinal problems can also result in malabsorption, which can lead to weight loss/inability to gain weight, steatorrhea, vitamin deficiencies, hypoalbuminemia, anaemia, and malnutrition [1,12]. Small intestinal bacterial overgrowth symptoms are not only limited to the digestive system, but can include extraintestinal symptoms: fatigue, skin changes, headaches, arthralgia [8], depression, anxiety, and brain fog [25, 26].

The vague nature of these symptoms makes it challenging to clinically differentiate SIBO from other conditions [12, 27].

There are four types of SIBO:

In the literature, several studies examine the frequency of SIBO symptoms in various conditions due to its common association, but the evidence of frequency of symptoms in SIBO itself is missing. In a cohort of patients with Crohn’s disease, the most frequently reported symptoms of SIBO were abdominal pain (37.3%), diarrhoea (30.9%), flatulence (19.1%), and bloating (16.4%) [31].

Diagnostics

Diagnostics of SIBO may include invasive and not invasive tests. There is no validated gold standard method for diagnosis. Aspiration of the small bowel fluid, followed by culturing and counting bacteria is currently considered to be most reliable in the diagnosis of SIBO. The sample is taken during endoscopy from duodenum. Moreover, small bowel aspiration is generally more time-consuming than the breath test when considering the entire procedure. Although the aspiration itself takes 10–15 minutes, it involves endoscopy, sedation, and preparation, which adds up to the total time [32]. The bowel aspiration method is invasive and expensive and there is a risk of cross-contamination caused by improper techniques for sampling collection, therefore it is rarely used in the clinical practice. A concentration of H₂ ≥ 10 ^ 3 CFU/ml in a culture can be used for SIBO diagnosis according to the North American Consensus [29, 33].

The most common method for SIBO and IMO diagnosis is breath tests with 75 g glucose (GBT) or 10 g lactulose [3, 12]. Breath tests are based on the principle that H₂ and methane cannot be produced by a human, but these gases are exclusively produced by bacteria through a fermentation process. Gas produced by these microorganisms after consumption of carbohydrates diffuse into circulation, is transported into the lungs where it can be measured in the exhaled air. As per the North American Consensus, hydrogen-dominant SIBO can be diagnosed with breath testing that shows a rise in H₂ of 20 ppm or more above baseline within 90 minutes. Methanogen overgrowth (IMO) is defined as methane reaching 10 ppm or more at any point during the test. Despite common use of the North American Consensus guidelines, the Rome Consensus Conference recommends a more conservative cut-off of a 10 ppm rise in H₂ within 60 minutes, highlighting the importance of linking breath test results with clinical symptoms enhancing diagnostic accuracy [34]. There is no universally agreed-upon standard for cut-off values in breath tests for diagnosing SIBO [29]. Small intestinal bacterial overgrowth can be diagnosed by both methods: small bowel aspiration and a breath test, whereas IMO can be only diagnosed by a breath test [29].

Differences in oral-caecal transit time seems to be one of the biggest limitations of breath tests as it increases the risk of false-positive results. There is no consensus with regard to which substrate – lactulose or glucose – is recommended [29]. Lactulose does not absorb in a small intestine, therefore is more sensitive for detection of bacteria/archaea overgrowth in comparison to glucose, which is rapidly absorbed in the proximal part of a small intestine [29, 35]. Glucose breath tests are more specific, but less sensitive in comparison to lactulose breath testing (LBT). On the other hand, LBT are less specific, but more sensitive and are associated with a higher risk of false-positive results [27], particularly in patients with faster intestinal transit and diarrhoea states [29]. A meta-analysis from 2020 reported LBT with 42.0% sensitivity and 70.6% specificity, compared to 54.5% sensitivity and 83.2% specificity for glucose, showing a slight advantage for glucose. Clinically, both are viable, though lactulose is often favoured for patients with diabetes or suspected small bowel dysmotility as glucose may affect motility and underdetect distal SIBO [36].

Preparation before the breath tests is an essential element of achieving the most accurate results. The North American Consensus provided a guideline, in which antibiotics (4 weeks prior to testing) and promotility drugs and laxatives (1 week prior to testing) should be avoided. It is also important to maintain a fasting period of 8–12 hours prior to a test and eliminate complex carbohydrates 24 hour prior to testing as it affects directly the level of H₂ and may result in a high H₂ baseline. As smoking also results in an increase of H₂ concentration in the exhaled air, it is important to avoid it on a test day [27, 33].

SIBO and IMO treatment

Small intestinal bacterial overgrowth treatment principles include eliminating the underlying cause, antibiotic therapy and diet modifications to prevent nutritional deficiencies [8, 37]. According to the American College of Gastroenterology Clinical Guideline, the use of antibiotics is recommended in SIBO to eradicate bacterial overgrowth and to resolve symptoms [12]. Unfortunately, there are limited data on guidelines for antibiotic strategies in SIBO, and in most cases it remains empiric. According to the American Gastroenterological Association [37] Clinical Practice Update from 2020, SIBO treatment with antibiotics should aim to modulate intestinal microbiota to alleviate symptoms, instead of focusing solely on eradication.

The most often used antibiotic for SIBO eradication is rifaximin. It is considered an eubiotic as it preserves microbiota in a colon, increasing the number of Lactobacillus and Bifidobacterium spp. and supports intestinal barrier integrity [11, 27]. It has a wide antibacterial activity for both aerobic and anaerobic, Gram-positive and Gram-negative bacteria. According to meta-analysis from 2017, in doses of 600–1600 mg daily administered over 5–28 days, rifaximin seems to be effective and safe in SIBO treatment [37]. The overall eradication rate of SIBO was 70.8% and turned out to be more effective than other systemic antibiotics like metronidazole or tetracyclines [27, 38].

As Methanobrevibacter smithii is resistant to many antibiotics [32] treating IMO with a combination of rifaximin and neomycin seems to show better results. In a prospective clinical trial [39], patients with methane levels ≥ 3 ppm according to LBT received one of the following treatments: 500 mg of neomycin, 400 mg of rifaximin or both for 10 days. The combination of both antibiotics was more effective than rifaximin or neomycin alone. Approximately 30–40% of SIBO patients experience persistent symptoms despite antibiotic treatment, often due to coexisting issues like food intolerances or disaccharide deficiencies. Identifying contributing factors, such as lactose intolerance or pancreatic insufficiency, requires thorough evaluation and appropriate diagnostic testing. Further research is necessary to refine treatment strategies and improve outcomes for patients with incomplete responses to therapy [40].

The growing rate of treatment failures has driven the search for alternative therapies. The application of herbs with antibacterial properties can be incorporated into common practice, demonstrating potential for clinical benefits, particularly in cases of CH4-SIBO. Faecal microbiota transplantation from a healthy donor is being considered as an option for SIBO, particularly in cases of recurrence or antibiotic-resistant bacterial strains [41, 42].

Encapsulated faecal microbiota transplantation (FMT) demonstrates efficacy and safety as a therapeutic intervention for SIBO, significantly ameliorating gastrointestinal symptoms and enhancing gut microbiota diversity in comparison to placebo. However, larger randomized controlled studies with longer follow-up periods are needed to confirm these results and to incorporate FMT into common clinical practice in SIBO management [43]. In the field of oncology, FMT provides a direct approach to modulating the gut microbiota. Current studies suggest potential benefits in addressing cancers linked to intestinal dysbiosis, reducing treatment-associated complications, and improving immunotherapy outcomes. However, the role of FMT in cancer management remains insufficiently explored, emphasizing the necessity for well-designed, large-scale randomized controlled trials to establish its therapeutic efficacy and evaluate long-term outcomes. There is a notable absence of research examining the therapeutic potential and effectiveness of FMT in SIBO among cancer patients, highlighting a critical gap in the current literature [44].

Nutritional deficiencies and malnutrition in SIBO and IMO

Small intestinal bacterial overgrowth is a frequently overlooked condition which might cause impaired nutritional status. The adverse effects of SIBO on nutritional status can involve various factors, such as microbial metabolism, inflammation and damage to the intestinal mucosa, altered food intake due to gastrointestinal symptoms [45–47]. This can lead to malabsorption of vitamin B₁₂, fat-soluble vitamins (A, D, E) and rarely protein, resulting in weight loss [48, 49]. Moreover, SIBO is associated with many clinical conditions, such as scleroderma, inflammatory bowel diseases or coeliac disease, which can affect nutritional status themselves [8]. Due to the lack of a clear clinical picture and the frequent coexistence of other diseases, assessing the impact of SIBO on the body’s nutritional parameters is difficult. It also remains unclear whether the specific subtypes of SIBO might influence particular nutritional deficiencies.

One of the most important pathophysiologic effects of SIBO in terms of nutrient deficiencies is mucosal damage and inflammation of the epithelium [44, 50]. The inflammatory changes are nonspecific and may lead to varying degrees of villous flattening, decrease in a level of brush border enzymes and reduction in the intestinal absorptive surface area [51, 52]. Another factor affecting poor absorption in SIBO is the competition between bacteria and the host for micronutrients. One of the most frequently described deficiencies in the literature is deficiency of vitamin B₁₂ and iron [12]. Lakhani et al. [53] showed that thiamine deficiency among patients after Roux-en-Y gastric bypass surgery is common. On the other hand, bacteria can also synthesize various vitamins, especially folate [24]. It remains unclear whether the host can absorb it. Small intestinal bacterial overgrowth can lead to elevated folate levels, although this effect is not observed in clinical practice. As bacteria can synthesize various vitamins like foliate, SIBO can lead to elevated folate levels, although this effect is not observed in clinical practice, and it remains unclear whether the host can absorb it [24].

The gut microbiome plays a crucial role in the biotransformation of bile acids by performing deconjugation, dehydroxylation, and reconjugation of these molecules [54]. In SIBO, there is a shift in these reactions, which causes proximally generation of free bile acids. As a result, there is disruption of fat and fat-soluble vitamins (vitamin A, D, E) digestion and absorption [24], except vitamin K. Its deficiency is rarely observed in SIBO, probably due to bacterial synthesis of menaquinones [55].

It is well-known that cancer patients are a high-risk group of developing malnutrition due to metabolic alterations, systemic inflammation and symptoms which affect food consumption [56]. Theoretically, SIBO may worsen the nutritional status of cancer patients due to impaired absorption. Far more research on nutritional status of cancer patients with SIBO will be necessary to elucidate this problem.

In light of the aforementioned statements, it seems appropriate to consider routine screening of patients for SIBO and nutritional status.

Nutritional approach

In addition to medical consultations, it seems to be beneficial, based on current knowledge, to incorporate a dietitian consultation into standard practice for SIBO patients as the dietitian can assess their nutritional status and create an individualized dietary intervention plan. Dietary recommendations in SIBO and IMO are not unambiguous. Recently, elimination diets have become popular for treating SIBO. The data on diets for SIBO are largely based on IBS research [12]. The primary focus of dietary adjustments for SIBO is minimizing fermentable substances, therefore low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet is commonly used and seems to be the best approach in SIBO according to the literature. Diet is focusing on eliminating low fermentable oligosaccharides, disaccharides, monosaccharides and polyols. The low FODMAP diet involves three phases: elimination, reintroduction, and individualization. The elimination phase (4–6 weeks) restricts high-FODMAP foods, followed by a reintroduction phase (6–10 weeks) to test individual tolerance while tracking symptoms. Finally, the individualization phase reintroduces tolerable FODMAP foods in suitable amounts, tailored to the patient’s symptom severity. It is essential to highlight that the low FODMAP diet is an elimination diet and is inherently unbalanced, which may lead to adverse alterations in the intestinal microbiota, particularly with extended use. Reducing the intake of FODMAP-rich foods may result in decreased energy intake and potential deficiencies in essential nutrients, including fibre, calcium, iron, zinc, folic acid, B vitamins, and vitamin D [26].

Other frequently recommended: gluten-free diet and avoiding various fibre fractions or dairy products [12]. However, there are no documented efficacy data of these approaches for the eradication of SIBO.

The literature also mentions the elemental diet as a potential method for treating SIBO. This is a medical food diet characterized by a high degree of hydrolysis of individual nutrients. As a result, it is easily absorbed by the body and does not cause additional strain on the digestive tract. Only one open-label single-arm study has examined the role of the elemental diet in SIBO [57]. The study included 124 participants, with the diet intervention of the Vivonex Plus formula, administered for 14 days, and in some participants extended to 21 days. Normalization of breath test results was achieved in 85% of patients, indicating a high efficacy of the elemental diet. This may be related to the rapid absorption of the formula’s ingredients, leaving little substrate for bacteria residing in the small intestine, thus reducing their abundance [58]. Due to a non-randomized study plan, this trial should be interpreted with caution.

Unfortunately, despite the potentially high efficacy of the elemental diet, there are many contraindications to its use. It is based on consuming industrially processed liquid foods while excluding traditional foods. This can be a significant challenge for patients in practice and may lead to eating disorders. Due to its restrictive nature, it is should not be recommended for cancer patients. The use of elimination diets by individuals diagnosed with SIBO without indications and supervision of a dietitian may be a factor contributing to the development of malnutrition. FODMAPs, gluten or dairy products are extensive groups of products that provide essential substances for health, such as B vitamins, calcium, and magnesium. There is a paucity of scientific data confirming the use of these dietary exclusions. Therefore, it seems that their use is highly risky and should be aimed at supplementing microelements.

Gut microbiota

Increasingly, research into gastrointestinal (GI) cancer pathogenesis and treatment is focusing on the role of the ‘brain-gut axis’. The term ‘brain-gut axis’ means a bidirectional communication between the gut and the brain by the central nervous system (CNS), the autonomic nervous system – sympathetic and parasympathetic, and what is most important – the gut microbiota [59]. The largest number of microorganisms in our body colonize the digestive tract, mainly the large intestine, which provide a suitable living environment and rich food for the microbiota. There are many studies confirming that dysbiosis of the intestinal microbiome occurs in gastrointestinal cancers as well as intestinal barrier dysfunction, which leads to entry of harmful antigens, microbes and its metabolites into circulation [60]. Furthermore, as a result of the activity of the microbiota, neuroactive molecules can be synthesized and secreted in the gut, crossing the blood-brain barrier and affecting the functioning of the CNS. It is thought that neural and humoral pathways may transmit signals from tumor cells to the brain, and then through the brain influence tumor growth in peripheral tissues. Recent findings suggest that neuronal signalling molecules may be involved in the tumorigenesis and progression of GI cancers [61]. Hasuda et al. [62] analyzed the composition of the intestinal microbiome in patients with esophageal cancer and found that the number of Streptococcus was significantly higher, while the number of Faecalibacterium was significantly lower compared to healthy volunteers.

Gastric cancer is strongly associated with Helicobacter pylori infection, which may also influence gut microbiome dysbiosis [63]. Chen et al. [64] discovered changes in abundance of Enterococcus, Megasphaera, Corynebacterium, Roseburia, and Lachnospira in guts in surgical and non-surgical gastric cancer patients. The study conducted by Zhang et al. [65] found that Lactobacillus and Megasphaera could be predictive markers for gastric cancer.

Ren et al. [66] reported that 13 bacterial species, including Gemmiger and Parabacteroides, were more abundant in the gut in patients with early hepatocellular carcinoma. Butyrate-producing microbes were decreased, while microbes producing lipopolysaccharide (LPS) were increased. Butyrate, as well as ursodeoxycholic acid, impede tumor development and progression. Moreover, overconsumption of FODMAP rich high-fructose corn syrup was found to promote the liver lipid synthesis and change the microbial composition with higher prevalence of Bacteroides in non-alcoholic steatohepatitis, which increases the risk of NAFLD-hepatocellular carcinoma (NAFLD-HCC) [67, 68]. The abundance of Escherichia coli in hepatocellular carcinoma patient’s faeces is much higher than that in faeces from healthy controls [69].

In pancreatic cancer patients, studies show an overall decrease in gut microbial diversity, a decreased number of Firmicutes and number of Proteobacteria, specifically Klebsiella pneumonia, pathogenic Enterobacteriaceae – and LPS producing taxa [70].

Other studies have shown that an increased number of Escherichia coli, Enterococcus, Bacteroides, and Clostridium can enhance abnormal crypt foci which increases the risk of developing colorectal cancer. Mainly Escherichia coli and Bacteroides fragilis appear to promote tumorigenesis in colorectal cancer (CRC) by inducing DNA damage and cellular inflammation [71].

Probiotics and prebiotics

The probiotics and prebiotics can be elements of the therapy of microbial imbalance in gastrointestinal cancers. However, there are limited data about probiotic treatment of SIBO in cancer patients. The study conducted by Liang et al. [72] is the only probiotic trial specific to gastric and CRC patients. The authors found that administering Bifidobacterium triple viable (Bifico) capsule containing different probiotic strains belonging to Enterococcus, Bifidobacteria and Lactobacillus genera was effective in combating SIBO and alleviated gastrointestinal cancer-related symptoms. In a group of patients with severely impaired immune function, careful assessment is required.

SIBO and IMO in gastrointestinal cancer

Prevalence of SIBO is estimated to vary between 25% and 22% and is affected by age and co-existing conditions [1]. Some data indicate that SIBO prevalence is higher in certain types of gastrointestinal cancer. Evidence suggests that SIBO is more prevalent in specific gastrointestinal cancers [73], potentially due to dysfunction of the defensive mechanisms previously described, but also cancer itself. Cancer induces notable alterations in microbial composition, particularly within the tumour microenvironment, where conditions such as hypoxia, necrosis, and increased vascular permeability facilitate bacterial invasion and proliferation [74]. Along with the medications and surgical procedures used in its treatment, cancer can lead to gastrointestinal dysmotility, which is a known risk factor for SIBO [75].

Chemotherapeutics can alter gut microbiome directly or through effects on the epithelial cells [76] and can result in dysbiosis. In the study by Cong et al. [77], notable differences were found in the gut microbiome of patients who underwent surgery alone vs. those who received chemotherapy (specifically oxaliplatin and tegafur, a fluorouracil precursor). The patients who had surgery showed a reduced abundance of Bacteroidetes and Firmicutes, suggesting a decrease in microbiota diversity compared to those treated with chemotherapy. According to the study performed in a Chinese population, SIBO is more common in patients with gastrointestinal cancer. Sixty five percent of a study group consisting of 112 patients with gastric cancer and 88 with CRC tested positive for SIBO based on the glucose hydrogen breath test. The authors conclude that the most probable reason for bacterial overgrowth in a gastric cancer group was using protein-protein interaction (PPI) medications and changes in gastric acid secretion resulting in impairment of its anti-bacterial properties [72]. Paik et al. [78] investigated SIBO in post-gastrectomy patients. They performed GBT and measured both H₂ and methane. A significantly higher prevalence of SIBO was observed in patients who underwent gastrectomy in comparison to healthy controls (77.6% vs. 6.7%). The authors suggest that SIBO is strongly linked to postprandial intestinal symptoms and might lead to worsening of late hypoglycaemia in patients after gastrectomy. They also point SIBO as a new therapeutic target in post-gastrectomy patients for the management of intestinal symptoms.

Heneghan et al. [79] examined the prevalence of SIBO in patients with oesophageal and gastric cancer, who were disease-free at least 18 months after surgical resection. The study found that 38% of patients had SIBO, which was associated with malnutrition and low faecal elastase concentration (< 200 µg/g). Deng et al. [80] was assessing the prevalence of SIBO and gastrointestinal symptoms in a group of patients with colon cancer after surgical treatment. Small intestinal bacterial overgrowth prevalence in the experimental arm was significantly higher in comparison to the healthy control group (41.86% vs. 6.67%, p < 0.05) as well as gastrointestinal symptoms score (p < 0.05). According to Rao et al. [22], in a group of patients who underwent colectomy, the prevalence of SIBO was also significantly higher than in the healthy control group (62% vs. 32%). Larsen et al. [81] was assessing the aetiology of chronic loose stools in patients after right-sided hemicolectomy. Small intestinal bacterial overgrowth was present in 74% of patients, but loose stools were linked with bile acid malabsorption (BAM) in this group, and presumably not with SIBO. Liang et al. [72] suggests that SIBO can lead to deterioration clinical symptoms in patients with gastrointestinal cancer.

Ma et al. [82] assessed a prevalence of SIBO in pancreatic carcinoma and in cholangiocarcinoma patients. Small intestinal bacterial overgrowth was present in 63.3% of patients with pancreatic cancer, 46.7% in a group with cholangiocarcinoma, in comparison to 13.3% in a group of healthy individuals. Moreover, the authors indicated a possible link between SIBO and a higher risk of the incidence of these cancers, due to a positive association between SIBO prevalence and the expression of TLR-4 protein.

Small intestinal bacterial overgrowth is prevalent in gastrointestinal cancers, with rates varying by cancer type and treatment. Factors such as microbial dysbiosis, tumor-related changes, and treatment-induced gastrointestinal dysfunction contribute to its development. Recognizing and managing SIBO in cancer patients is essential as it worsens symptoms, impacts nutrition, and may influence clinical outcomes.

SIBO and IMO vs. cancer treatment

During last decades it has become increasingly important to not only prolong survival of cancer patients but also maintain or improve their quality of life [83]. Moreover, modern therapies such as targeted therapy or immunotherapy, causing significant side effects such as endocrine, skin, cardiological or gastroenterological complications, have resulted in the involvement of many specialists in the treatment of cancer patients [84, 85].

Gastrointestinal symptoms are very common in cancer patients, particularly in digestive tract neoplasms and may worsen during or after cancer treatment. Some of them are managed very well with novel therapies, like vomiting which is no longer a significant problem with the use of setrons and NK1 antagonists. The other may be omitted in standard medical history or questionnaires and not addressed during medical controls/check-ups like early satiety, mucus discharge, steatorrhea, urgency of defecation, regurgitation, borborygmi, tenesmus etc. It was revealed in the facilitating open couple communication, understanding and study (FOCCUS) [86] that common terminology criteria for adverse events, routinely used by oncologists in a daily practice, was frequently recording less severe toxicity than gastrointestinal symptoms rating scale which was evaluating 25 GI symptoms. Gastroenterological cancers account for approximately 20% of all cancer diagnoses and with the increasing number of cases and prolonged survival of patients cured or living with a controlled disease, identifying GI disorders and their treatment is becoming more important.

In the group of patients after pancreatic resection in 2014–2019, 61% of whom were treated for pancreatic cancer, as many as 67% had GI symptoms after the end of hospitalization [86]. Diarrhoea was the most common symptom (30%), followed by nausea and vomiting (25%) and loss of appetite and weight (16%) and patients after pancreaticoduodenectomy were more likely to have those disorders. Interestingly, only 19% of all treated patients and 27% of symptomatic patients were referred for GI diagnostics. Small intestinal bacterial overgrowth was confirmed in only 1.2%, exocrine pancreatic insufficiency (EPI) was diagnosed in 4% and delayed gastric emptying in 2%. These results are in contradiction to the previously mentioned analysis by Ma et al. [82], probably due to the retrospective nature of the trial and the lack of diagnostic tests for SIBO in all symptomatic patients. This cohort study also did not assess the impact of GI symptoms on the delay and tolerance of chemotherapy, which is indicated in most patients after surgical treatment of pancreatic cancer.

As mentioned earlier, SIBO was frequently diagnosed in patients after gastrectomy (38–77%) [79], regardless of age, gender, time since surgery, body mass index or the results of laboratory tests assessing the patients’ nutritional status. Although differences in the incidence of SIBO were found among different types of gastrectomy: 20% after total gastrectomy, 50% after Billroth I, and 24.2% after Billroth II gastrectomy, these results were not statistically significant. Small intestinal bacterial overgrowth caused postprandial symptoms and intensified late hypoglycaemia as an expression of late dumping syndrome after gastrectomy. In Heneghan et al. study [79], all SIBO patients after gastrectomy had symptoms of malabsorption, even though only 17% of them had EPI and 11.7% had BAM.

Patients undergoing surgery for CRC are more likely to be SIBO-positive in breath tests than the healthy population. Treatment with rifaximin improves symptoms, particularly diarrhoea (p < 0.05) in all SIBO-positive patients after CRC resection and 33% of them had turned SIBO-negative in the second GBT.

In a study assessing patients after right hemicolectomy for CRC with symptoms of chronic loose stool, incidence of SIBO was high (73%), but with no difference compared to the control arm (74%). As mentioned earlier, the predisposition to the development of SIBO in these patients is very high due to the removal of the defence mechanism – ileocecal valve. However, these patients suffered more often from BAM (82%) compared to asymptomatic controls (37%) and, contrary to previous hypotheses, the researchers found that BAM in these patients was not secondary to SIBO (type 3 BAM) but resulted directly from resection of the terminal ileum (type 1 BAM).

Many patients suffer from complex GI symptoms after anticancer therapy [73]. Some of them may result from concomitant diseases or diseases undetected before oncological treatment, such as IBS, other cancer, side effects of drugs such as PPIs or L-thyroxine, therefore a special diagnostic algorithm was proposed [85].

Oncological patients undergoing radiotherapy suffer from GI symptoms in 30–60%, but fortunately less than 10% have ≥ G3 toxicity. Concomitant chemotherapy increases this number to 14% or even to 26% if mitomycin is used [83]. The most common causes of GI symptoms after irradiation include SIBO (38%) and BAM (21%), while EPI is less frequent (5%) [73].

In daily practice antibiotics for SIBO are usually used empirically if low-fibre diet and antidiarrheal agents are failing to improve symptoms [87]. White et al. [88] presented a pilot study evaluating feasibility of dietary intervention and investigation of diarrhoea cause during pelvic radiotherapy – lactose intolerance, SIBO and BAM. They proved that such approach is possible and acceptable to patients without disruption of anticancer treatment. Investigators conclude that the intervention group suffered less from GI symptoms and had better quality of life although these results must be interpreted with caution. This study analyzed patients treated with radiochemotherapy for bladder cancer and cervical cancer but without randomization to the cancer site. The imbalance of diagnoses in the control and experimental groups might have influenced the severity of GI symptoms because patients treated for bladder cancer received a higher dose of radiotherapy and more toxic chemotherapy and they did not receive brachytherapy. Further studies of better randomization are needed to confirm these findings.

As assessed by researchers from the UK, who analyzed patients undergoing radiotherapy in the pelvic area, a standardized algorithm for the management of gastroenterological symptoms does not require the supervision of gastroenterologists if nurses are properly trained. Patients who, based on a carefully designed questionnaire, are suspected of having SIBO, should be referred for diagnosis and undergo appropriate treatment, with possible impact on their quality of life [89]. There is no optimal treatment strategy for SIBO after radiotherapy. Usually, the treatment does not differ from the management of SIBO unrelated to oncological treatment. Antibiotics active against Gram (–) bacteria are used for about 2 weeks, or probiotics and prebiotics. The use of rifaximin may be particularly important due to its lack of absorption from the gastrointestinal tract, which may reduce the emergence of resistant bacterial strains [84]. Chronic diarrhoea after radiotherapy should be differentiated at least from BAM, fat malabsorption, rapid intestinal transit or lactose intolerance, possibly according to the algorithm mentioned above because up to 2/3 of GI symptoms after radiotherapy may not be correlated with the irradiation if endoscopy is performed [83, 85, 90].

Modern radiotherapy methods can reduce the occurrence and severity of radiation-induced intestinal toxicity and enable achievements of gastrointestinal dose limits (e.g., < 120 ml of small bowel loops receiving > 15 Gy) by using a precise method such as intensity-modulated radiotherapy, image-guided radiotherapy, stereotactic body radiotherapy, high-dose-rate brachytherapy [83, 91]. Other methods of limiting the gastroenterological toxicity of radiotherapy include avoiding irradiation of the entire duodenal circuit, fasting for 2 hours before the radiotherapy fraction, spacers injected between healthy organs and the irradiated neoplasm, the use of ACEIs (angiotensin-converting-enzyme inhibitors), statins and probiotics, but these methods have not been confirmed in randomized trials.

There are only few studies assessing the frequency of SIBO in patients undergoing chemotherapy for GI cancers and there is a paucity of data on the impact of SIBO on chemotherapy tolerance. Due to the frequent use of chemotherapy drugs that cause diarrhoea (irinotecan, 5-fluorouracil and its prodrug – capecitabine), the diagnosis of co-occurring SIBO seems to be particularly difficult in GI cancers and, at the same time, very important for improving treatment tolerance. In a Brazilian study evaluating patients receiving chemotherapy for GI malignancies [91], 57.6% of patients reported diarrhoea, but SIBO was diagnosed in only 9% of them. The limitation of this trial was the small number of patients included [45] and the fact that many of them did not accept to undergo two breath tests during the chemotherapy treatment.

The British FOCCUS study [86] prospectively evaluated 119 patients receiving chemotherapy for GI cancers, looking for reversible causes of gastroenterological symptoms. Interestingly, it was found that even before oncological treatment, patients suffered from undiagnosed disorders causing GI symptoms, such as EPI (9%), vitamin B₁₂ deficiency (12%) or thyroid dysfunction (20%). Additionally, further reversible causes were diagnosed during chemotherapy such as urinary tract infection (17%), BAM (43%) and SIBO (54%).

Gastroenterological symptoms also frequently occur during modern systemic anticancer therapies. Immunotherapy is a treatment based on antibodies (antiCTLA4, antiPD1, antiPDL1 etc.) that unlock the activity of the patient’s immune system, that is used in a rapidly growing number of malignancies like kidney cancer, melanoma, lung cancer, bladder cancer, Hodgkin lymphoma and others [84]. Unfortunately, this therapy, although efficient, is not free from side effects and GI toxicity is the second most common after dermatological complications. Up to 20–50% of patients suffer from diarrhoea, 1–10% have enterocolitis and approximately 10% have hepatopathy.

It is established that the composition of the intestinal microflora is an independent predictor of the effectiveness of immunotherapy, and patients treated with antibiotics live shorter lives than others [92]. Akkermansia muciniphila turned out to be particularly important because the response to immunotherapy depended on its percentage in the stool, and its supplementation in patients previously treated with antibiotics restored sensitivity to immunotherapy [60]. Less is known about the impact of immunotherapy on the composition of the intestinal flora and its relationship to the occurrence of immune-related complications, but it appears that not every diarrhoea occurring during immunotherapy is related to it. Pembrolizumab may cause diarrhoea due to collagenous colitis, ipilimumab due to duodenal villous atrophy and nivolumab-induced diarrhoea may be associated with BAM, EPI or SIBO [84].

Other possible causes of GI symptoms during checkpoint inhibitors therapy include adrenal insufficiency or thyroid dysfunction [93]. Therefore, it should be remembered that the diagnosis of immunotherapy-induced enterocolitis is a histopathological diagnosis and therefore requires an endoscopic examination of the upper gastrointestinal tract or flexible sigmoidoscopy, preferably before the initiation of glucocorticosteroids (GCs) in the treatment of these complications. Lack of improvement after GCs may be misinterpreted as the need to intensify enterocolitis treatment, leading to ineffective implementation of more aggressive therapies, failure to diagnose, among others, SIBO, worsening of SIBO or its development due to the use of immunosuppression (and cessation of potentially effective oncological treatment) [84, 94].

On the other hand, quick exclusion of non-immune-related GI toxicities is very important for the early implementation of GCs therapy, enabling the survival of these patients, because they usually have a better effect of immunotherapy. Objective tumor response rates in patients with enterocolitis were 36% for melanoma (MM) and 35% for renal cell carcinoma (RCC), compared with 11% and 2% in patients without enterocolitis, respectively (p=0.0065 for MM and p=0.0016 for RCC) [95].

Another modern therapy used more and more often in oncology is tyrosine kinase inhibitors (TKI), which can cause diarrhoea in 1–95% of patients. The most frequently suggested mechanism of diarrhoea after TKI is excess chloride secretion, mucosal atrophy, altered gut motility, changes in intestinal microbiome (e.g. SIBO) or altered nutrient metabolism [96–99]. On the other hand, there is an interesting evaluation from Cambridge, in which 27 patients suffering from diarrhoea during TKI treatment were referred to the gastroenterologist. In 74% of these patients the secondary cause of diarrhoea was diagnosed: 50% had BAM, 40% had EPI and 10% had SIBO. Appropriate therapy in ¾ of these patients reduced the severity of symptoms and facilitated further TKI treatment [100].

The impact of immunosuppression on the development of SIBO is also not fully understood. Studies indicate that bacterial overgrowth of the small intestine is a common feature in immunodeficient paediatric patients (10 with selective IgA deficiency, four with panhypogammaglobulinemia, and three with selective T-cell deficiency), regardless of the immunological abnormality [101]. In adults, on the opposite/contrary, immunosuppression is usually iatrogenic. It was revealed that immunosuppressants and/or biological drugs do not induce SIBO in inactive Crohn’s disease [102].

In a retrospective trial of 1809 patients who have been diagnosed for SIBO by hydrogen breath test, immunoglobulin deficiency did not influence the risk of SIBO, while the use of steroids (20.6 vs. 13.6%), classical immunosuppressants – azathioprine or methotrexate (4.6 vs. 1.9%), any immunosuppressive therapy (22.3 vs. 14.1%) or the combination of steroids plus immunosuppressants (4.0 vs. 1.4%) increase this risk with the highest OR for the combination group (OR=2.92) [103].

Although the results of studies are inconsistent, SIBO appears to be common in patients treated for GI cancers and may be problematic in differential diagnosis due to non-specific symptoms overlapping with those associated with the disease and used medications.

Conclusions

Diagnosis and treatment of SIBO and IMO are challenging due to their unspecific and overlapping symptoms with other gastrointestinal disorders. The lack of a definitive diagnostic test requires a multifaceted approach, with breath tests being the most commonly used method despite their limitations. Small intestinal bacterial overgrowth treatment usually involves antibiotics, particularly rifaximin for its effectiveness and safety, alongside with dietary recommendations focusing on limiting fermentation to manage symptoms and to prevent nutritional deficiencies and malnutrition. Current data also highlight the alternative therapies like FMT-herbs or with antibacterial properties. While elimination diets and probiotics are being studied as additional treatments, their effectiveness is not yet proven, highlighting the need for personalized and well-monitored treatment plans. Nutritional management is especially important in vulnerable groups such as cancer patients, as SIBO can exacerbate malnutrition and affect treatment outcomes. Additionally, due to its higher prevalence in GI cancers, incorporating screening for SIBO and IMO into a clinical practice could be beneficial, along with appropriate treatment in case of positive results.

Further research is needed to refine diagnostic methods, optimize treatment protocols, and better understand SIBO and IMO’s impact on nutritional status and overall health in GI cancer and other patient groups.