The Role of the Intestinal Microbiome in Inflammation and Cancer

Background: Changes in the microbiome have been described in many diseases and are thought to play a role in their pathogenesis and progression. In this article, we approach the topic critically and discuss the areas in which the development of microbiome-based clinical applications may soon be expected.

Methods: We selectively review the literature on disease-associated microbiome signatures and therapeutic modulation of the microbiome. We discuss clinical studies as well as relevant preclinical studies that reveal causal relationships between the microbiome and disease.

Results: The intestinal microbiome undergoes dynamic regulation by lifestyle factors such as the diet. Particularly in inflammatory and malignant neoplastic diseases, changes in the microbiome have been identified that contribute to the progression of disease in animal models. Studies have also shown that the response to systemic antitumor therapy is regulated by the microbiota. In view of this, initial clinical trials have been conducted that document the efficacy of fecal microbiome transfer and of selective approaches to microbiome modulation in the treatment of several inflammatory and malignant diseases.

Conclusion: Evidence from animal models and initial clinical studies indicates that therapeutic modulation of the microbiome can be of benefit to patients suffering from a number of inflammatory and malignant diseases. The further translation of research of this kind into clinical applications will require the validation of these data in controlled trials and the development of targeted approaches to microbiome modulation.

Cite this as: Zeissig S, Frost F, Haller D, Stallmach A, Vehreschild MJGT, Schneider KM: The role of the intestinal microbiome in inflammation and cancer. Dtsch Arztebl Int 2025; 122: 567–72. DOI: 10.3238/arztebl.m2025.0142

The intestinal microbiome comprises the vast community of microorganisms in the gastrointestinal tract and is highly compartmentalized with regard to its composition and function (luminal versus mucosal, small intestine versus large intestine) (1). With over 4600 different species and an estimated 170 million bacterial proteins, bacteria contribute to microbial diversity on a large scale (2). Most of the biomass is found in the colon (around 4 × 10¹³ bacteria) (1, 3). Functionally, the microbiota plays a central role in, among other things, the development of the immune system, the digestion of complex carbohydrates, vitamin and bile acid metabolism, intestinal and systemic hormone regulation, colonization resistance, and intestinal barrier regulation (1, 3).

After birth, the sterile gut is initially colonized by only a few bacterial species. Nutritional factors subsequently play a crucial role in the dynamic development of a diverse, resilient, and highly individualized microbiota from infancy to adulthood (1, 3). The composition and function of the intestinal microbiome, however, undergo continuous modulation throughout life by environmental factors, particularly diet, but also drugs, physical activity, smoking, and various other factors (1, 3). Dietary changes at any age can alter the microbiome within hours (1, 3) and may also be utilized therapeutically, for example, by using enteral nutrition to treat patients with Crohn’s disease (4). Plant-based diets are enriched in dietary fiber and secondary plant substances as compared with mixed diets. Faecalibacterium, Prevotella, Roseburia, Bifidobacterium, and Akkermansia are types of bacteria which are increasing in abundance as a result of Mediterranean and plant-based diets. They produce short-chain fatty acids through the fermentation of dietary fibers (5). A protein-rich and high-fat mixed diet is associated with Bacteroides, Bilophila, Blautia, and Fusobacterium, amongst others, and promotes the formation of branched-chain fatty acids and secondary bile acids (5). A plant-based diet is linked to a lower risk of metabolic and oncological diseases, although the specific contribution of the microbiome to these associations remains unclear. Initial human trials combining a dietary intervention followed by autologous microbiome transplantation via fecal microbiome transfer (FMT) indicate that the microbiome acts as a key mediator between dietary effects and the host’s metabolic regulation (6).

Evidence from animal models indicates that the effect of the microbiome on organ and cellular functions is linked to certain time-limited developmental windows. For instance, the development and maturation of some important immunological processes are attributable to specific interactions in early childhood between the microbiome and the host (windows of opportunity). It is therefore assumed that disruptions to these symbiotic interactions in childhood and early adulthood can result in persistent changes to the immune system and thus promote chronic inflammatory responses (7, 8). For example, mice raised under germ-free conditions demonstrate persistent immune and barrier defects, as well as susceptibility to immune-mediated diseases, even after microbial colonization during adulthood (7, 8). In line with these findings, a temporal relationship has also been confirmed between improved hygiene standards and the increasing incidence of immune-mediated diseases in Western countries, a concept known as the hygiene hypothesis. Furthermore, there is also a link between repeated treatment with antibiotics in childhood and an increased incidence of immune-mediated disorders such as chronic inflammatory bowel diseases (CIBD), asthma, diabetes mellitus, and obesity (7, 8, 9, 10, 11).

Methodology

A PubMed-based literature search was conducted for randomized controlled trials (RCTs) and meta-analyses assessing fecal microbiome transfer and probiotic or prebiotic therapies in the context of inflammatory or malignant diseases. Another PubMed-based literature review was also performed for animal studies on microbial contributions to inflammatory or malignant diseases.

The role of the microbiome in the pathogenesis of inflammation and cancer

As presented in detail in the eMethods, articles published in recent years have demonstrated changes to the intestinal microbiome, known as dysbiosis, in a large number of inflammatory, metabolic, degenerative, and malignant diseases (3). Many of these disease-associated microbiome signatures (pathobiomes) have so far not been independently validated, and it is not fully understood whether they are associated with the disease itself or its risk factors, comorbidities, sequelae, or its drug treatment (3). While clinical investigations have so far often been restricted to describing associations between diseases and changes to the microbiome, preclinical experiments involving animal models could demonstrate that the intestinal microbiome and disease-associated changes to its composition and function can contribute significantly to the pathogenesis of inflammatory, metabolic, and malignant processes and can also regulate responses to systemic anticancer treatments, such as immune checkpoint blockade (12, 13). Please refer to the eMethods for a detailed account of these studies.

From theory to practice—the role of the microbiome in diagnostics and therapy

The microbiome in clinical diagnostics

The development of inexpensive sequencing-based microbiota analyses led to reports of a rapidly growing number of supposedly characteristic microbiome signatures in a variety of different diseases. Many of these signatures were reported in small cohorts only and have so far not been independently validated. The use of microbiome signatures for diagnostic purposes (Figure) has therefore not yet been implemented in routine clinical practice. At the same time, the widely marketed stool microbiome analysis tests have no diagnostic validity due to considerable inter-individual differences in microbiota composition and the highly dynamic nature of the individual microbiome. As a result, such investigations should not be conducted outside of controlled clinical studies. This could well change in the future. For instance, robust and validated stool-based microbiome signatures have been reported for colorectal cancer which at the moment, however, still do not represent a suitable alternative to fecal immunochemical tests with respect to their diagnostic precision but potentially could be of additional value (14). Another field of extensive research interest is the quest for microbiome-based signatures which predict response to inflammatory-modulating treatment or cancer therapy. This would require robust signatures of sufficient diagnostic precision obtained in different cohorts which, however, are currently not yet available (Figure).

Figure

Opportunities and prerequisites of the potential use of the microbiome in the future for diagnostic assessment and treatment, using colon cancer as an example

The microbiome as a preventive and therapeutic target

Helicobacter pylori-associated inflammatory (gastritis) and malignant (gastric cancer, mucosa associated lymphoid tissue [MALT] lymphoma) diseases are prime examples of how strategies of antimicrobial prevention (gastric cancer) or treatment (gastritis, early stages of MALT lymphoma) have been established by demonstrating a link between bacterial colonization and human pathology followed by the identification of a causal relationship. Thus, eradication of H.-pylori can reduce the risk of gastric cancer (15), while HPV vaccination and HCV eradication can contribute towards the prevention of associated cancers (16, 17). An important conclusion emanating from these successful achievements is that they are based on many years of research which clearly proves both the association between individual bacteria/viruses and pathologies and the causality of this association, and establishes concepts of a more (HPV, HCV) or less (H. pylori) selective treatment approach. The hurdles for therapeutic microbiome modulation are set even higher than their diagnostic benefit (Figure). The spectrum of potential interventions ranges from broad approaches, such as FMT or antibiotic treatment, to selective measures, such as the application of individual bacterial species or their targeted elimination by bacteriophages.

eFigure

Well-established relationships between microbial organisms and cancer

Fecal microbiota transfer

Fecal microbiota transfer (FMT), i.e., the oral, rectal, or endoscopic transplant of stool, with or without prior treatment with antibiotics or bowel cleansing, allows the delivery of a complex microbiota with its beneficial effects to recipients, even without knowledge of which microbial taxa are responsible for these protective effects. Recurrent Clostridioides difficile infection (CDI) is a widely recognized example for the successful use of FMT in clinical studies. C. difficile can be isolated in the intestinal microbiota of 3 to 5% of healthy adults (18). Oral ingestion of spores increases hospital colonization rates to 20 to 40% (19). Changes to the microbiome by antibiotic treatment result in an overgrowth of C. difficile which is associated with an increased risk of symptomatic CDI. Around 20% of those affected develop disease recurrence, of which almost one third suffer from multiple recurrences (19). The underlying problem are niches in the gut microbiota which allow the colonization and proliferation of C. difficile. FMT addresses this problem by transplanting a complex microbiota which is highly effective against recurrent CDI. Thus, the primary endpoint of resolution of diarrhea in recurrent CDI (rCDI) without relapse after ten weeks was reached in 81% of participants treated with a combination of vancomycin followed by FMT, compared with only 31% of those who received vancomycin alone (Table 1 [20]).

Table 1

Selection of completed trials on therapeutic microbiome modulation in infectious and inflammatory diseases

Encouraged by the success rates of FMT with regard to CDI, the efficacy of FMT has meanwhile been investigated in non-infectious diseases (21). An interesting example of this is hepatic encephalopathy (HE) secondary to cirrhosis of the liver, where a clear contribution by the intestinal microbiota to the disease process has been reported. Well established forms of treatment, such as the prebiotic lactulose or the antibiotic rifaximin, modulate the microbiota to afford protective effects (22, 23). Examinations of patients with acute or chronic liver disease have shown that lactulose promotes intestinal expansion of Bifidobacteria which metabolize the disaccharide to acetate and so acidify the gut lumen. This is associated with a reduction in systemic infections and lower in-hospital mortality (22). The antibiotic rifaximin-alpha has also been approved for prevention of hepatic encephalopathy (HE) recurrence. A placebo-controlled RCT has demonstrated improvement in HE grade and score resulting from the reduction of mucus-degrading bacteria and reinforcement of the intestinal barrier (23). In line with this, patients in the rifaximin group were less likely to develop infections than those on placebo (odds ratio 0.21; 95% confidence interval: [0.05; 0.96]). Based on the documented role of microbiota in HE, a phase II RCT investigating FMT for the prevention of HE recurrence has now also been conducted (Table 1). FMT was safe, and no FMT-related serious adverse events were reported (primary endpoint). As a secondary endpoint, a reduced incidence of HE was evident in the FMT groups in comparison with the placebo group (24).

Several placebo-controlled RCTs have meanwhile been conducted on patients with IBD and, in particular, ulcerative colitis, to assess the efficacy of FMT (Table 1). The majority of these trials show a positive impact of FMT on disease activity, which have also been confirmed in meta-analyses (Table 1) (25, 26, 27, 28). It was also revealed that these effects were considerably dependent on donor material – an issue which can be addressed by using multi-donor preparations. Continued administration is required to ensure efficacy of FMT therapy, in line with the concept that changes of microbial composition in patients with CIBD indeed contribute to disease process yet do not represent the cause of disease (Table 1). Initial FMT trials have also been conducted in other inflammatory diseases, such as acute pancreatitis, although results so far have been negative (29).

Based on the observation that a response to immune checkpoint inhibitors (ICI) can be elicited in an animal model using stool transfer from humans to mice (eSupplement), initial unblinded phase I trials investigating this question were conducted in patients with malignant melanoma. These trials investigated whether FMT using stool from donors who had responded to anti-PD-1 antibody therapy could elicit a clinical response in recipients with primary or secondary failure to respond to such treatment. An objective response to the ICI was subsequently observed in a subset of patients (Table 1), (30, 31). Since then, FMT trials have also obtained promising initial results in first-line ICI therapy (Table 2), (32).

Table 2

Selection of trials on therapeutic microbiome modulation in malignant diseases

The challenges of FMT lie in identifying suitable donors, ensuring the longitudinal stability of donor microbiota, and preventing the transmission of infectious pathogens (Box). The latter of these aspects in particular is a significant obstacle to its use in clinical practice. FMT is subject to the German Medicines Act which only allows compassionate use of FMT if the preparation is manufactured under medical supervision for immediate use. An FMT-based product has so far not been approved in the EU, and its use is restricted to clinical trials. Interest in FMT remains unbroken, however, with currently more than 130 recruiting trials covering a wide variety of diseases, ranging from IBD and primary sclerosing cholangitis (PSC) to liver cirrhosis and cancer therapy (clinicaltrials.gov). An EU directive issued in 2024 which classified FMT as a “Substance of Human Origin” acknowledges the high demand. This directive will, for the first time, classify FMT as a transplant under regulatory law in Germany. This could significantly simplify the availability and reimbursement of FMT by health insurance providers and so allow nationwide access yet does not solve the problem of identifying suitable donors.

Box

Legal framework for fecal microbiome transfer

From FMT to defined microbiome products

In the long term, FMT will most likely be replaced by more selective approaches to microbiome modulation. Here, the example of CDI can be drawn upon to illustrate these developments. Thus, based on the success of FMT, RBX2660, a FMT-like product manufactured from human stool and comprising living bacteria, was developed and approved in the USA in 2022 by the FDA for rectal administration to treat rCDI after a positive placebo-controlled RCT (Table 1) (33). SER-109, another microbiome product, was approved for rCDI the following year. SER-109 consists of Firmicutes spores and after a successful placebo-controlled RCT (Table 1) was approved in the USA by the FDA for the oral prevention of recurrence of rCDI (34). Live bacterial products (LBP, probiotics), on the other hand, did not demonstrate any convincing efficacy in the prevention of CDI recurrence (35). With SER-287, a therapeutic agent based on Firmicutes spores, was also developed for the treatment of ulcerative colitis. However, after a promising phase Ib RCT (clinical remission in week 8: placebo/placebo 0%, vancomycin/SER-287 18%), negative results were demonstrated in the phase IIb RCT (Table 1, [36]).

Meta-analyses rate the level of evidence for the efficacy of LBP in IBD as weak to inadequate (37, 38, 39, e1). However, E. coli Nissle plays a leading role as an alternative to 5-aminosalicylates for the maintenance of remission in ulcerative colitis (e2). Evidence for the use of prebiotics (substrates, such as dietary fiber, which stimulate bacterial growth) is also limited at the moment (e3). The same applies for acute and chronic pancreatitis for which trials on probiotics have so far remained unsuccessful (e4, e5).

In the meantime, LBPs have already undergone successful testing in checkpoint inhibition. So far, two phase I clinical trials have assessed the Clostridium butyricum strain CBM588 in patients with metastatic renal cell carcinoma. In an initial unblinded, single-center trial, 30 treatment-naive patients were stabilized on the ICI nivolumab and ipilimumab and randomized 2 to 1 to receive either CBM588 or placebo (e6). The secondary endpoint of progression-free survival was significantly longer in the group receiving CBM588, at 12.7 months, as compared with the group without CBM588 (2.5 months) (Table 2). A second trial applied the same design, randomizing patients 2 to 1 to receive treatment with cabozantinib and nivolumab with either CBM588 or placebo (e7). The secondary endpoint of objective response was higher under CBM588 at 74% than under placebo (20%, p = 0.01, Table 2). Both trials were unblinded phase I studies with insufficient statistical power for efficacy analysis and thus require validation by means of blinded studies with adequate sample size. The key starting point of both studies was the assumption that CBM588 enhances its efficacy by promoting the growth of Bifidobacteria. The primary endpoint of both studies was therefore the increase in abundance of Bifidobacteria which was not achieved in either trial. These observations underline the challenges in the translation of positive FMT findings into defined LBPs, while at the same time documenting initial successful steps along this path.

Conflict of interest statement

MV received financial support from MSD, Heel, Roche, and Tillotts. She was granted financial support by GILEAD, Tillotts, Pfizer, Bioaster, GSK, Ecraid, EUMEDICA, and Bactolife. She received lectures fees from the Academy for Infection Medicine, Astra Zeneca, bioMerieux, the German Society for Infectious Diseases (DGI), the European Society of Neurogastroenterology, Falk Foundation, FomF, GILEAD, GSK, Helios Hospitals, Hessian State Court of Justice, INfektio Forum, Janssen Cilag, Kassel University Hospital, Hessen Regional Medical Council, Ludwig Maximilan University Hospitals, Pfizer, MSD, Streamed up, St. Vincent Hospital, Ardeypharm’s Tillotts.9rojekt.

The other authors declare that there are no conflicts of interest.

Manuscript received on 6 March 2025, revised version accepted on 25 July 2025

Translated from the original German by Dr. Grahame Larkin

Corresponding author:
Prof. Dr. med. Sebastian Zeissig

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