Gut Microbiota: Influence on Carcinogenesis and Modulation Strategies by Drug Delivery Systems to Improve Cancer Therapy

Zheng D., Li R., An J., Xie T., Han Z., Xu R., Fang Y., Zhang X.

While microbial-based therapy has been considered as an effective strategy for treating diseases such as colon cancer, its safety remains the biggest challenge. Here, probiotics and prebiotics, which possess ideal biocompatibility and are extensively used as additives in food and pharmaceutical products, are combined to construct a safe microbiota-modulating material. Through the host-guest chemistry between commercial Clostridium butyricum and chemically modified prebiotic dextran, prebiotics-encapsulated probiotic spores (spores-dex) are prepared. It is found that spores-dex can specifically enrich in colon cancers after oral administration. In the lesion, dextran is fermented by C. butyricum, and thereby produces anti-cancer short-chain fatty acids (SCFAs). Additionally, spores-dex regulate the gut microbiota, augment the abundance of SCFA-producing bacteria (e.g., Eubacterium and Roseburia), and markedly increase the overall richness of microbiota. In subcutaneous and orthotopic tumor models, drug-loaded spores-dex inhibit tumor growth up to 89% and 65%, respectively. Importantly, no obvious adverse effect is found. The work sheds light on the possibility of using a highly safe strategy to regulate gut microbiota, and provides a promising avenue for treating various gastrointestinal diseases.

Inamura K.

Immunotherapy, which shows great promise for treating patients with metastatic malignancies, has dramatically changed the therapeutic landscape of cancer, particularly subsequent to the discovery of immune checkpoint inhibitors. However, the responses to immunotherapy are heterogeneous and often transient. More problematic is that a high proportion of patients with cancer are resistant to such therapy. Much effort has been expended to identify reliable biomarkers that accurately predict clinical responses to immunotherapy. Unfortunately, such tools are lacking, and our knowledge of the mechanisms underlying its efficacy and safety is insufficient. The microbiota is increasingly recognized for its influence on human health and disease. Microbes create a pro- or an anti-inflammatory environment through complex interactions with host cells and cytokines. Emerging evidence indicates that microbes alter the efficacy and toxicity of immunotherapy by modulating the host's local and systemic immune responses. It is therefore critically important to exploit the microbiota to develop biomarkers as well as to identify therapeutic targets that can be applied to cancer immunotherapy. This review provides insights into the challenges that must be addressed to achieve these goals.

Nadeem M.S., Kumar V., Al-Abbasi F.A., Kamal M.A., Anwar F.

Inflammatory bowel diseases (IBDs) are chronic problems of gastrointestinal tract (GIT) with poorly understood aetiology. Patients with any of the two common entities, Crohn's disease (CD) or ulcerative colitis (UD) have significant increased risk of gastrointestinal and extra-intestinal malignancies. Particularly, the colorectal cancer (CRC) and lymphomas are the most frequently associated cancers with IBD. Although the incidence of CRC has declined in the European countries during last 30 years yet the risk among IBD patients remains higher than the healthy people. In the present study, we have described many common factors influencing the onset and advancement of IBD and CRC including the alterations in gut microbiota, changes in the interleukin pathways and tumour necrosis factor. The other common factors are patient age, race, genetics, family history, diet composition, obesity and level of vitamins and minerals in the body. These multiple factors contribute to the higher incidence of CRC among IBD patients.

Wang X., Cao Z., Zhang M., Meng L., Ming Z., Liu J.

Probiotic self-coated with biofilms achieve strikingly enhanced oral availability and intestinal colonization in a porcine model.

Dong X., Pan P., Zheng D., Bao P., Zeng X., Zhang X.

A strain of bioinorganic hybrid bacteriophage was screened to enhance the antitumor immune response of colorectal cancer.

Yu X., Lin C., Yu J., Qi Q., Wang Q.

Bacterial vectors, as microscopic living 'robotic factories', can be reprogrammed into microscopic living 'robotic factories', using a top-down bioengineering approach to produce and deliver anticancer agents. Most of the current research has focused on bacterial species such as Salmonella typhimurium or Clostridium novyi. However, Escherichia coli Nissle 1917 (EcN) is another promising candidate with probiotic properties. EcN offers increased applicability for cancer treatment with the development of new molecular biology and complete genome sequencing techniques. In this review, we discuss the genetics and physical properties of EcN. We also summarize and analyse recent studies regarding tumour therapy mediated by EcN. Many challenges remain in the development of more promising strategies for combatting cancer with EcN.

Relman D.A.

Relationships between hosts and host-associated microbial communities are complex, intimate, and associated with a wide variety of health and disease states. For these reasons, these relationships have raised many difficult questions and claims about microbiome causation. While philosophers and scientists alike have pondered the challenges of causal inference and offered postulates and rules, there are no simple solutions, especially with poorly characterized, putative causal factors such as microbiomes, ill-defined host effects, and inadequate experimental models. Recommendations are provided here for conceptual and experimental approaches regarding microbiome causal inference, and for a research agenda.

Chen H., Zhang F., Li R., Liu Y., Wang X., Zhang X., Xu C., Li Y., Guo Y., Yao Q.

Berberine (BBR) is an isoquinoline alkaloid, which has been used in the treatment of intestinal mucositis. However, BBR on chemotherapy-induced mucositis in cancer patients remains largely unknown. Here, we investigated the effect of BBR on intestinal mucositis induced by 5-fluorouracil (5-Fu) using rat model. We detected the degree of intestinal mucosal damage and inflammatory response in 5-Fu treated rats with or without BBR administration, and investigated the changes of fecal metabolites and gut microbiota using 1H NMR spectroscopy and 16S rRNA. The mechanism was further explored by fecal microbiota transplantation (FMT). Results showed that BBR treated rats displayed less weight loss, lower diarrhea score and longer colon length in 5-Fu treated rats. Meanwhile, BBR treatment significantly increased the expression of Occludin in ileum and decreased the d-lactate content in serum. Moreover, the expression of IL-1β, IL-6 and TNF-α in ileum were suppressed by BBR treatment. The pattern of fecal metabolism changed obviously after treated with 5-Fu, which was reversed by BBR. Importantly, BBR significantly increased the levels of butyrate and glutamine in feces from 5-Fu treated rats. In terms of gut microbiota, BBR enriched the relative abundance of Firmicutes and decreased Proteobacteria at the phylum level. Meanwhile, BBR increased the propotion of unclassified_f_ Porphyromonadaceae, unclassified_f_ Lachnospiraceae, Lactobacillus, unclassified_o_ Clostridiales, Ruminococcus, Prevotella, Clostridium IV, and decreased Escherichia/Shigella at the genera level. Furthermore, principal component analysis (PCA) showed that fecal transplantation led to changes in fecal metabolites. Fecal transplantation from BBR treated rats had low diarrhea score, reduced inflammatory response in ileum, and relieved intestinal mucosal injury, which may be caused by the increased of butyrate level in fecal metabolites. In conclusion, our study provides evidence that BBR regulates fecal metabolites to ameliorate 5-Fu induced intestinal mucositis by modifying gut microbiota.

Chen W., Wang S., Wu Y., Shen X., Guo Z., Li Q., Xing D.

For years, intratumor injection of bacteria have been purported to be capable of an anticancer effect. However, these bacteria are mostly pathogenic including attenuated and genetically engineered bacteria. The gut microbiota has been discovered to play a key role in immunotherapy. Many remarkable advances have been made in characterizing the immune responses to gut microbiota. Interestingly, accumulating evidence has demonstrated that immunogenic cell death (ICD) plays a key role in the anticancer effect of chemotherapy, radiotherapy, photodynamic therapy and oncolytic virotherapy. Most interestingly, the gut microbiota may impact the ICD process. Given the importance of the gut microbiota in immune responses, cancer progression and the anticancer efficacy of drugs with immune effects. We propose a mechanism in which ICD may be the possible key link between gut microbiota and the anticancer efficacy of drugs with immune effects. However, the study of the relationship between the gut microbiota and ICD is limited, and it is still not clear how gut microbiota affect the ICD pathway. In this review, we discuss the mechanism by which the gut microbiota affects ICD, and suggest that ICD may be a possible key link between gut microbiota and the anticancer efficacy of drugs with immune effects.

Choi J.H., Moon C.M., Shin T., Kim E.K., McDowell A., Jo M., Joo Y.H., Kim S., Jung H., Shim K., Jung S., Kim Y.

Lactobacillus paracasei is a major probiotic and is well known for its anti-inflammatory properties. Thus, we investigated the effects of L. paracasei-derived extracellular vesicles (LpEVs) on LPS-induced inflammation in HT29 human colorectal cancer cells and dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. ER stress inhibitors (salubrinal or 4-PBA) or CHOP siRNA were utilized to investigate the relationship between LpEV-induced endoplasmic reticulum (ER) stress and the inhibitory effect of LpEVs against LPS-induced inflammation. DSS (2%) was administered to male C57BL/6 mice to induce inflammatory bowel disease, and disease activity was measured by determining colon length, disease activity index, and survival ratio. In in vitro experiments, LpEVs reduced the expression of the LPS-induced pro-inflammatory cytokines IL-1α, IL-1β, IL-2, and TNFα and increased the expression of the anti-inflammatory cytokines IL-10 and TGFβ. LpEVs reduced LPS-induced inflammation in HT29 cells and decreased the activation of inflammation-associated proteins, such as COX-2, iNOS and NFκB, as well as nitric oxide. In in vivo mouse experiments, the oral administration of LpEVs also protected against DSS-induced colitis by reducing weight loss, maintaining colon length, and decreasing the disease activity index (DAI). In addition, LpEVs induced the expression of endoplasmic reticulum (ER) stress-associated proteins, while the inhibition of these proteins blocked the anti-inflammatory effects of LpEVs in LPS-treated HT29 cells, restoring the pro-inflammatory effects of LPS. This study found that LpEVs attenuate LPS-induced inflammation in the intestine through ER stress activation. Our results suggest that LpEVs have a significant effect in maintaining colorectal homeostasis in inflammation-mediated pathogenesis. Tiny vesicles released by a bacterial species found in the human gut can reduce symptoms of inflammatory bowel disease (IBD) and prevent disease progression. People with IBD have a decreased abundance of Lactobacilli bacteria in their gut, creating an imbalance that perpetuates the disease. Replenishment of this bacteria may become a valuable therapy. Chang Mo Moon at Ewha Womans University, Yoon-Keun Kim at MD Healthcare, both in Seoul, South Korea, and co-workers demonstrated how extracellular vesicles (EVs) released by Lactobacilli paracasei can actively prevent bowel inflammation. These EVs contain a mixture of proteins, nucleic acids and other biomolecules. The team administered EV to cultured human colorectal cancer cells and to mice with induced colitis. The EVs decreased pro-inflammatory protein activity and boosted levels of protective cellular membrane proteins via augmenting ER stress pathway.

Pleguezuelos-Manzano C., Puschhof J., Rosendahl Huber A., van Hoeck A., Wood H.M., Nomburg J., Gurjao C., Manders F., Dalmasso G., Stege P.B., Paganelli F.L., Geurts M.H., Beumer J., Mizutani T., Miao Y., et. al.

Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island. Organoids derived from human intestinal cells that are co-cultured with bacteria carrying the genotoxic pks+ island develop a distinct mutational signature associated with colorectal cancer.

Ding X., Li Q., Li P., Chen X., Xiang L., Bi L., Zhu J., Huang X., Cui B., Zhang F.

Background Increasing evidence has indicated that gut microbiota is closely associated with radiation-induced bowel injury. We aimed to evaluate the safety and efficacy of fecal microbiota transplantation (FMT) in patients with chronic radiation enteritis (CRE). Methods A pilot study of FMT for CRE was performed. The primary outcomes were safety and response to FMT which was defined as a ≥1-grade reduction in Radiation Therapy Oncology Group (RTOG/EORTC) late toxicity grade from baseline, by 8 weeks post-FMT. The secondary outcomes included a decrease in the severity of four common symptoms (diarrhea, rectal hemorrhage, abdominal/rectal pain and fecal incontinence) in CRE and changes in Karnofsky Performance Status (KPS) score. Microbial analyses were performed by 16S rRNA sequencing. Results Five female patients underwent FMT from January to November 2018 with a median age of 58 (range 45–81) years. The median baseline RTOG/EORTC grade was 2 (range 2–4). Three patients responded to FMT and experienced improvement in diarrhea, rectal hemorrhage, abdominal/rectal pain and fecal incontinence as well as a decrease in KPS score. No FMT-related death and infectious complications occurred. One mild FMT-related AE was observed during a follow-up ranged from 8 to 18 months. 16S rRNA sequencing indicated that FMT altered the composition of gut microbiota of patients. Conclusion The present case series first demonstrated that FMT might be safe and effective to improve intestinal symptoms and mucosal injury in patients with CRE for a period of time. Trial registration ID: NCT03516461.

Obata Y., Castaño Á., Boeing S., Bon-Frauches A.C., Fung C., Fallesen T., de Agüero M.G., Yilmaz B., Lopes R., Huseynova A., Horswell S., Maradana M.R., Boesmans W., Vanden Berghe P., Murray A.J., et. al.

Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders1. Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility2–5, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health. In a mouse model, aryl hydrocarbon receptor signalling in enteric neurons is revealed as a mechanism that helps to maintain gut homeostasis by integrating the luminal environment with the physiology of intestinal neural circuits.

Soleimani A., Rahmani F., Ferns G.A., Ryzhikov M., Avan A., Hassanian S.M.

• Over-activation of the NF-κB pathway is a feature of CRC. • Suppression of the NF-κB signaling pathway is a potential therapeutic approach in the treatment of CRC. • This review summarizes the regulatory role of NF-κB signaling pathway in the pathogenesis of CRC. The NF-κB signaling pathway is a key regulator of CRC cell proliferation, apoptosis, angiogenesis, inflammation, metastasis, and drug resistance. Over-activation of the NF-κB pathway is a feature of colorectal cancer (CRC). While new combinatorial treatments have improved overall patient outcome; quality of life, cost of care, and patient survival rate have seen little improvement. Suppression of the NF-κB signaling pathway using biological or specific pharmacological inhibitors is a potential therapeutic approach in the treatment of colon cancer. This review summarizes the regulatory role of NF-κB signaling pathway in the pathogenesis of CRC for a better understanding and hence a better management of the disease.

Pradhan D., Mallappa R.H., Grover S.

Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. Among the different microbial types, lactobacilli have been explored most extensively as potential therapeutics in human health. Lactobacilli belong to the human normal microbiota of the gastro-intestinal and urogenital tracts and have been traditionally used as starter cultures in the preparation of fermented foods. They are considered extremely safe as compared to pharmacological agents since there have been very rare reports of any adverse effects. However, the safety of probiotics is of paramount importance as new strains are continuously evolving and being commercialized. The introduction of a new probiotic strain demands that it is at least as safe as its conventional counterparts. The newly emerging strains of probiotic lactobacilli with specific health claims may not necessarily have a documented history of safe use, hence, their safety is a matter of great concern from public health perspective. Moreover, it is now well recognized that the specific health claims associated with probiotics are highly strain specific, therefore, their safety needs to be assessed very comprehensively at strain level on case to case basis. Hence, an attempt have been made in this review to focus, at the preclinical level, on the various in vitro and in vivo tests using appropriate animal models, for assessing the safety and toxicity of probiotic organisms with a special emphasis on lactobacilli.

Zhao S., Yu Y., Xin Y., Lu H., Li X., Wang S., Ma F., Gao H.

Sha T., Tang Y., Hu X., Zhou H., Rao L.

AbstractGut microbiota play a key role in cancer immunotherapy and regulating gut microbiota provides new strategies with great potential for cancer therapeutics. Several gut microbiota‐based strategies, such as antibiotic treatment and fecal microbiota transplantation, have gained certain achievements in enhancing cancer immunotherapy, while the potential risk of biosafety and the destruction of commensal microbiota limit their further applications. Nanomaterials with excellent capabilities in delivering drugs and modulating bacteria may provide specific solutions for these limitations, and have shown promising potential in manipulating the gut microbiota to boost cancer immunotherapy. In this perspective, we reviewed the breakthroughs of nanomaterials in modulating the gut microbiota and their metabolites to enhance cancer immunotherapy, and further discussed the challenges and opportunities in this emerging field. It is anticipated that this perspective will offer new insights on the rational design of nanomaterials to regulate the gut microbiota for enhanced cancer immunotherapy, fostering clinical translation and ultimately benefiting patients.

Li X., Wu M., Wu Y., Xin Y., Gao L., Elsabahy M., Wang X., Zhang J., Qu X., Gao H.

Pezeshki B., Abdulabbas H.T., Alturki A.D., Mansouri P., Zarenezhad E., Nasiri-Ghiri M., Ghasemian A.

Research into the role of probiotics—often referred to as “living supplements”—in cancer therapy is still in its early stages, and uncertainties regarding their effectiveness remain. Relevantly, chemopreventive and therapeutic effects of probiotics have been determined. There is also substantial evidence supporting their potential in cancer treatment such as immunotherapy. Probiotics employ various mechanisms to inhibit cancer initiation and progression. These include colonizing and protecting the gastrointestinal tract (GIT), producing metabolites, inducing apoptosis and autophagy, exerting anti-inflammatory properties, preventing metastasis, enhancing the effectiveness of immune checkpoint inhibitors (ICIs), promoting cancer-specific T cell infiltration, arresting the cell cycle, and exhibiting direct or indirect synergistic effects with anticancer drugs. Additionally, probiotics have been shown to activate tumor suppressor genes and inhibit pro-inflammatory transcription factors. They also increase reactive oxygen species production within cancer cells. Synergistic interactions between probiotics and various anticancer drugs, such as cisplatin, cyclophosphamide, 5-fluorouracil, trastuzumab, nivolumab, ipilimumab, apatinib, gemcitabine, tamoxifen, sorafenib, celecoxib and irinotecan have been observed. The combination of probiotics with anticancer drugs holds promise in overcoming drug resistance, reducing recurrence, minimizing side effects, and lowering treatment costs. In addition, fecal microbiota transplantation (FMT) and prebiotics supplementation has increased cytotoxic T cells within tumors. However, probiotics may leave some adverse effects such as risk of infection and gastrointestinal effects, antagonistic effects with drugs, and different responses among patients. These findings highlight insights for considering specific strains and engineered probiotic applications, preferred doses and timing of treatment, and personalized therapies to enhance the efficacy of cancer therapy. Accordingly, targeted interventions and guidelines establishment needs extensive randomized controlled trials as probiotic-based cancer therapy has not been approved by Food and Drug Administration (FDA).

Oncina-Cánovas A., Torres-Collado L., García-de-la-Hera M., Compañ-Gabucio L.M., González-Palacios S., Signes-Pastor A.J., Vioque J.

Background/Objectives: This study explored the association between dairy products consumption (total and subgroups) and cancer of the esophagus, stomach, and pancreas within the PANESOES case–control study. Methods: Data from 1229 participants, including 774 incident cases of cancer and 455 controls matched by age, sex, and region, were analyzed. Dietary intake was assessed using a validated Food Frequency Questionnaire, categorizing dairy intake by total and subgroups (fermented dairy, sugary dairy desserts, and milk). Multinomial logistic regression was used to estimate relative risk ratios (RRRs), adjusting for confounders. Results: We found an inverse association between moderate dairy consumption (T2) and esophageal cancer (RRR T2 vs. T1 = 0.59 (95%CI: 0.37–0.96)). The highest tertile (T3) of fermented dairy was associated with a lower risk of esophageal (RRR T3 vs. T1 = 0.55 (0.33–0.90)) and stomach cancers (RRR T3 vs. T1 = 0.68 (0.47–0.97)). By contrast, the highest tertile of consumption of sugary dairy desserts was associated with a higher risk of stomach cancer (RRR T3 vs. T1 = 1.85 (1.30–2.64)). No association was found for milk. Conclusions: This study suggests that fermented dairy may reduce the risk of esophageal and stomach cancers, while sugary dairy desserts may increase the risk of stomach cancer.

Chen P., Yang C., Ren K., Xu M., Pan C., Ye X., Li L.

Hepatocellular carcinoma, a common malignancy of the digestive system, typically progresses through a sequence of hepatitis, liver fibrosis, cirrhosis and ultimately, tumor. The interaction between gut microbiota, the portal venous system and the biliary tract, referred to as the gut-liver axis, is crucial in understanding the mechanisms that contribute to the progression of hepatocellular carcinoma. Mechanisms implicated include gut dysbiosis, alterations in microbial metabolites and increased intestinal barrier permeability. Imbalances in gut microbiota, or dysbiosis, contributes to hepatocellular carcinoma by producing carcinogenic substances, disrupting the balance of the immune system, altering metabolic processes, and increasing intestinal barrier permeability. Concurrently, accumulating evidence suggests that gut microbiota has the ability to modulate antitumor immune responses and affect the efficacy of cancer immunotherapies. As a new and effective strategy, immunotherapy offers significant potential for managing advanced stages of hepatocellular carcinoma, with immune checkpoint inhibitors achieving significant advancements in improving patients’ survival. Probiotics play a vital role in promoting health and preventing diseases by modulating metabolic processes, inflammation and immune responses. Research indicates that they are instrumental in boosting antitumor immune responses through the modulation of gut microbiota. This review is to explore the relationship between gut microbiota and the emergence of hepatocellular carcinoma, assess the contributions of probiotics to immunotherapy and outline the latest research findings, providing a safer and more cost-effective potential strategy for the prevention and management of hepatocellular carcinoma.

Brusnic O., Onisor D., Boicean A., Hasegan A., Ichim C., Guzun A., Chicea R., Todor S.B., Vintila B.I., Anderco P., Porr C., Dura H., Fleaca S.R., Cristian A.N.

Colorectal cancer (CRC) constitutes a significant global health challenge, with recent studies underscoring the pivotal role of the gut microbiome in its pathogenesis and progression. Fecal microbiota transplantation (FMT) has emerged as a compelling therapeutic approach, offering the potential to modulate microbial composition and optimize treatment outcomes. Research suggests that specific bacterial strains are closely linked to CRC, influencing both its clinical management and therapeutic interventions. Moreover, the gut microbiome’s impact on immunotherapy responsiveness heralds new avenues for personalized medicine. Despite the promise of FMT, safety concerns, particularly in immunocompromised individuals, remain a critical issue. Clinical outcomes vary widely, influenced by genetic predispositions and the specific transplantation methodologies employed. Additionally, rigorous donor selection and screening protocols are paramount to minimize risks and maximize therapeutic efficacy. The current body of literature advocates for the establishment of standardized protocols and further clinical trials to substantiate FMT’s role in CRC management. As our understanding of the microbiome deepens, FMT is poised to become a cornerstone in CRC treatment, underscoring the imperative for continued research and clinical validation.

Yan W., Cao Y., Yin Q., Li Y.

Immunotherapy combats tumors by enhancing the body’s immune surveillance and clearance of tumor cells. Various nucleic acid drugs can be used in immunotherapy, such as DNA expressing cytokines, mRNA tumor vaccines, small interfering RNAs (siRNA) knocking down immunosuppressive molecules, and oligonucleotides that can be used as immune adjuvants. Nucleic acid drugs, which are prone to nuclease degradation in the circulation and find it difficult to enter the target cells, typically necessitate developing appropriate vectors for effective in vivo delivery. Biomimetic drug delivery systems, derived from viruses, bacteria, and cells, can protect the cargos from degradation and clearance, and deliver them to the target cells to ensure safety. Moreover, they can activate the immune system through their endogenous activities and active components, thereby improving the efficacy of antitumor immunotherapeutic nucleic acid drugs. In this review, biomimetic nucleic acid delivery systems for relieving a tumor immunosuppressive microenvironment are introduced. Their immune activation mechanisms, including upregulating the proinflammatory cytokines, serving as tumor vaccines, inhibiting immune checkpoints, and modulating intratumoral immune cells, are elaborated. The advantages and disadvantages, as well as possible directions for their clinical translation, are summarized at last.

Lu L., Li F., Gao Y., Kang S., Li J., Guo J.

AbstractRadiotherapy is a widely used cancer treatment that utilizes powerful radiation to destroy cancer cells and shrink tumors. While radiation can be beneficial, it can also harm the healthy tissues surrounding the tumor. Recent research indicates that the microbiota, the collection of microorganisms in our body, may play a role in influencing the effectiveness and side effects of radiation therapy. Studies have shown that specific species of bacteria living in the stomach can influence the immune system’s response to radiation, potentially increasing the effectiveness of treatment. Additionally, the microbiota may contribute to adverse effects like radiation-induced diarrhea. A potential strategy to enhance radiotherapy outcomes and capitalize on the microbiome involves using probiotics. Probiotics are living microorganisms that offer health benefits when consumed in sufficient quantities. Several studies have indicated that probiotics have the potential to alter the composition of the gut microbiota, resulting in an enhanced immune response to radiation therapy and consequently improving the efficacy of the treatment. It is important to note that radiation can disrupt the natural balance of gut bacteria, resulting in increased intestinal permeability and inflammatory conditions. These disruptions can lead to adverse effects such as diarrhea and damage to the intestinal lining. The emerging field of radiotherapy microbiome research offers a promising avenue for optimizing cancer treatment outcomes. This paper aims to provide an overview of the human microbiome and its role in augmenting radiation effectiveness while minimizing damage.

Liu L., Sun T., Liu H., Li J., Tian L.

Extensive research has established the benefits of incorporating low carbohydrate diets (LCDs) for managing obesity, diabetes, and metabolic syndrome (Mets). Recent findings indicate that LCDs could additionally impact cancer development and progression by creating an unfavorable metabolic micro-environment that promotes reprogrammed metabolism in cancer cells. This has led to LCDs being considered as a possible complementary treatment for cancer. Our review specifically examines the association between cancer risk, consumption of dietary carbohydrate, glycemic index (GI), and glycemic load (GL), with a focus on prostate, breast, and colorectal cancer. We also explore relevant mechanism underlying the potential anti-tumor effects of LCD diets, especially in gut microbiota modulation. However, findings in this area remain controversial, and further research is needed to evaluate their application in clinical practice. On the other hand, resistant starch (RS) has gained attention as a healthy and high-quality component of carbohydrate diets. It not only serves as a dietary fiber but also acts as a valuable source of prebiotics due to its ability to influence gut microbial composition, leading to improved metabolic control. This has positioned RS as a potential means for preventing and treating cancer. In this review, we also summarized the RS-gut microbiota-cancer risk axis to enhance our understanding of the health effects of RS consumption. From a clinical perspective, RS supplementation shows promise as a strategy for preventing diseases and managing cancer. It is evident that simply assessing the quantity of dietary carbohydrate intake may not be enough to determine cancer risk; the quality of carbohydrates should also be considered to draw definitive conclusions which will help clinician and nutritionist make a reasonable choice in management cancer.

Tariq F., Zaman M., Hameed H., Khan M.A., Mahmood A.

Wan S., Wang K., Huang P., Guo X., Liu W., Li Y., Zhang J., Li Z., Song J., Yang W., Zhang X., Ding X., Leong D.T., Wang L.

AbstractPathogenic gut microbiota is responsible for a few debilitating gastrointestinal diseases. While the host immune cells do produce extracellular vesicles to counteract some deleterious effects of the microbiota, the extracellular vesicles are of insufficient doses and at unreliable exposure times. Here we use mechanical stimulation of hydrogel-embedded macrophage in a bioelectronic controller that on demand boost production of up to 20 times of therapeutic extracellular vesicles to ameliorate the microbes’ deleterious effects in vivo. Our miniaturized wireless bioelectronic system termed inducible mechanical activation for in-situ and sustainable generating extracellular vesicles (iMASSAGE), leverages on wireless electronics and responsive hydrogel to impose mechanical forces on macrophages to produce extracellular vesicles that rectify gut microbiome dysbiosis and ameliorate colitis. This in vivo controllable extracellular vesicles-produced system holds promise as platform to treat various other diseases.

Zhang Y., Cao T., Wang Y., Yang R., Han Y., Li S., Liu D., Yue Y., Cao Y., Li B., Wang S., Huo G.

Bifidobacterium longum is a common probiotic; both viable and heat-inactivated Bifidobacterium longum have many probiotic effects, such as anticancer effects. But some mechanisms of anticancer effects are still unclear, especially for heat-inactivated probiotics. In this study, we analyzed the effects of viable and heat-inactivated Bifidobacterium longum D42 on human colon cancer cells (HT-29). Cell proliferation, membrane permeability and apoptosis were detected by using the CCK-8 method, LDH method and Annexin V-FITC/PI kits. The ROS level and mitochondrial membrane potential were examined using the fluorescent probes DCFH-DA and JC-1. Real-time fluorescence quantitative PCR (RT-qPCR) and Western blot were used to detect the expression of mitochondrial apoptosis pathway genes and proteins. The results showed that viable and heat-inactivated Bifidobacterium longum D42 at concentrations of 1 × 106 CFU/mL significantly inhibited the proliferation of and increased the level of LDH release of HT-29 colon cancer cells. We found that they could increase the apoptosis rate of HT-29 cells. Moreover, they could also induce apoptosis by inducing cells to produce ROS and destroying the mitochondrial membrane potential of cells. Further studies found that they could increase the mRNA transcription and protein expression levels of the Caspase-3, Caspase-9 and Bax genes in cells, and reduce the mRNA transcription and protein expression levels of the Bcl-2 gene. In summary, our findings revealed that viable and heat-inactivated Bifidobacterium longum D42 have inhibitory effects on proliferation and promote the apoptosis of human colon cancer cells, and also have certain adjuvant drug therapeutic effects and have potential application value in the adjuvant treatment of colon cancer.

Filippou C., Themistocleous S.C., Marangos G., Panayiotou Y., Fyrilla M., Kousparou C.A., Pana Z., Tsioutis C., Johnson E.O., Yiallouris A.

This comprehensive review elucidates the profound relationship between the human microbiome and breast cancer management. Recent findings highlight the significance of microbial alterations in tissue, such as the gut and the breast, and their role in influencing the breast cancer risk, development, progression, and treatment outcomes. We delve into how the gut microbiome can modulate systemic inflammatory responses and estrogen levels, thereby impacting cancer initiation and therapeutic drug efficacy. Furthermore, we explore the unique microbial diversity within breast tissue, indicating potential imbalances brought about by cancer and highlighting specific microbes as promising therapeutic targets. Emphasizing a holistic One Health approach, this review underscores the importance of integrating insights from human, animal, and environmental health to gain a deeper understanding of the complex microbe–cancer interplay. As the field advances, the strategic manipulation of the microbiome and its metabolites presents innovative prospects for the enhancement of cancer diagnostics and therapeutics. However, rigorous clinical trials remain essential to confirm the potential of microbiota-based interventions in breast cancer management.

Liu Y., Chen J., Chen X., Liu H.