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Cancer is a major health burden worldwide, and despite continuous advances in medical therapies, resistance to standard drugs and adverse effects still represent an important cause of therapeutic failure. There is a growing evidence that gut bacteria can affect the response to chemo- and immunotherapeutic drugs by modulating either efficacy or toxicity. Moreover, intratumor bacteria have been shown to modulate chemotherapy response. At the same time, anticancer treatments themselves significantly affect the microbiota composition, thus disrupting homeostasis and exacerbating discomfort to the patient. Here, we review the existing knowledge concerning the role of the microbiota in mediating chemo- and immunotherapy efficacy and toxicity and the ability of these therapeutic options to trigger dysbiotic condition contributing to the severity of side effects. In addition, we discuss the use of probiotics, prebiotics, synbiotics, postbiotics, and antibiotics as emerging strategies for manipulating the microbiota in order to improve therapeutic outcome or at least ensure patients a better quality of life all along of anticancer treatments.

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.

Background and aimsPancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-related death. We aimed to evaluate whether gemcitabine treatment shapes the gut microbiota in a model of PDAC xenografted mice.Materials and methodsPancreatic cancer xenograft mice were subjected to gemcitabine injection once per week for 3 weeks to assess the tumor volume as compared to control mice injected with normal saline solution. The composition of fecal microbiota, the activation of NF-kB pathway in cancer tissues and the serum metabolomics were further analyzed.ResultsGemcitabine considerably decreases the proportion of Gram- positive Firmicutes (from about 39 to 17%) and the Gram- negative Bacteroidetes (from 38 to 17%) which are the two dominant phyla in the gut of tumor-bearing control mice. This downshift was replaced by an increase of Proteobacteria (Escherichia coli and Aeromonas hydrophila) from 15 up to 32% and Verrucomicrobia (Akkermansia muciniphila) from 5 to 33% in the gut of drug-receiving mice. An overall increase in inflammation-associated bacteria was observed upon gemcitabine. Consistently, activation of the NF-kB canonical pathway was found in cancer tissues from gemcitabine-treated mice. Serum metabolomics revealed a significant decrease of the purine compounds inosine and xanthine, and a decreasing trend for their metabolically-related molecule hypoxanthine.DiscussionUnderstanding chemotherapy side effects may explain the lack of activity or the chemoresistant processes and it may help to set up strategies to improve the effectiveness of therapy.

Background: Pancreatic cancer (PC) and colorectal cancer (CRC) are among the most lethal malignancies, with growing evidence pointing to the gut microbiota’s role in their progression. This study aimed to explore the anticancer potential of two microbiota-derived postbiotics, N-acetylcysteine (NAC) and tetrahydro β-carboline carboxylic acid (THC), in targeting some hallmark traits of PC and CRC, both as standalone agents and in combination with standard chemotherapeutics (gemcitabine for PC and 5-fluorouracil (5-FU) for CRC). Methods: Cell viability assays and IC50 determination was assessed using either the Muse™ Count & Viability Kit or the Sulforhodamine B assay; cell death was determined by Annexin V/Propidium Iodide and cell cycle assessed by Propidium Iodide was analyzed by flow cytometry. Results: Here, we found that NAC selectively reduced the viability of PC cells BxPC-3 without triggering apoptosis, while effectively inducing apoptosis in PC cells Panc-1 and in CRC cell lines. THC exhibited stronger anticancer activity, inhibiting proliferation and promoting apoptosis in all tested PC and CRC cells, even at lower concentrations. Combination treatments yielded promising enhancement effects. NAC enhanced the cytotoxicity of gemcitabine in Panc-1 cells through increased apoptosis. NAC, when combined with 5-FU, also increased apoptosis of CRC cells. THC further potentiated gemcitabine’s impact on Panc-1 cells by increasing apoptosis and by inducing cell cycle changes in BxPC-3. In the CRC model, THC co-treatment with 5-FU reduced cell viability and increased apoptosis in all cells. Conclusions: These findings provide preliminary in vitro evidence supporting the potential of integrating microbiota-derived postbiotics with conventional chemotherapy both in PC and CRC.

Seasonality is a key determinant in shaping the composition and function of the human gut microbiota, exerting its influence through multiple interconnected factors. These include seasonal variations in diet, environmental conditions (such as temperature, humidity, and sunlight exposure), behavioral patterns (physical activity, time spent outdoors), and the incidence of seasonal infections. These changes are most visible in certain populations where food availability follows a seasonal pattern. Increasing evidence suggests that gut microbiota composition undergoes seasonal variations, which may have significant implications for human health. In patients with non-communicable chronic diseases (NCDs), where microbiota dysbiosis plays a crucial role in disease progression, understanding the seasonal effects on gut microbiota is essential. These dynamic changes impact the gut microbiota immune system interaction and may contribute to the onset or exacerbation of various diseases, including chronic inflammatory, metabolic, and autoimmune disorders. Most clinical trials on probiotics do not consider seasonality as a confounding variable, which could impact the interpretation of results and therapeutic efficacy, potentially biasing estimates of intervention efficacy or associations with disease. This review examines the current evidence on gut microbiota seasonality, discusses its potential bias, and outlines methodological considerations for future clinical trials.

Background Bacterial toxins are emerging as promising hallmarks of colorectal cancer (CRC) pathogenesis. In particular, Cytotoxic Necrotizing Factor 1 (CNF1) from E. coli deserves special consideration due to the significantly higher prevalence of this toxin gene in CRC patients with respect to healthy subjects, and to the numerous tumor-promoting effects that have been ascribed to the toxin in vitro. Despite this evidence, a definitive causal link between CNF1 and CRC was missing. Here we investigated whether CNF1 plays an active role in CRC onset by analyzing pro-carcinogenic key effects specifically induced by the toxin in vitro and in vivo. Methods Viability assays, confocal microscopy of γH2AX and 53BP1 molecules and cytogenetic analysis were carried out to assess CNF1-induced genotoxicity on non-neoplastic intestinal epithelial cells. Caco-2 monolayers and 3D Caco-2 spheroids were used to evaluate permeability alterations specifically induced by CNF1, either in the presence or in the absence of inflammation. In vivo, an inflammatory bowel disease (IBD) model was exploited to evaluate the carcinogenic potential of CNF1. Immunohistochemistry and immunofluorescence stainings of formalin-fixed paraffin-embedded (FFPE) colon tissue were carried out as well as fecal microbiota composition analysis by 16 S rRNA gene sequencing. Results CNF1 induces the release of reactive oxidizing species and chromosomal instability in non-neoplastic intestinal epithelial cells. In addition, CNF1 modifies intestinal permeability by directly altering tight junctions’ distribution in 2D Caco-2 monolayers, and by hindering the differentiation of 3D Caco-2 spheroids with an irregular arrangement of these junctions. In vivo, repeated intrarectal administration of CNF1 induces the formation of dysplastic aberrant crypt foci (ACF), and produces the formation of colorectal adenomas in an IBD model. These effects are accompanied by the increased neutrophilic infiltration in colonic tissue, by a mixed pro-inflammatory and anti-inflammatory cytokine milieu, and by the pro-tumoral modulation of the fecal microbiota. Conclusions Taken together, our results support the hypothesis that the CNF1 toxin from E. coli plays an active role in colorectal carcinogenesis. Altogether, these findings not only add new knowledge to the contribution of bacterial toxins to CRC, but also pave the way to the implementation of current screening programs and preventive strategies.

Rheumatoid arthritis (RA) is an autoimmune disorder in which gut and oral microbiota play a crucial role. Diet is a modifiable factor that can influence both microbiota composition and arthritis outcome; previous studies have suggested associations between dietary habits and RA, with contrasting results. We investigate the protective effect of the Mediterranean diet (MD) on disease activity and the gut microbiota profile in RA patients. Sixty consecutive RA patients were enrolled upon filling a validated 14-item questionnaire for the assessment of adherence to the Mediterranean diet (Prevention with Mediterranean Diet-PREDIMED). Then, 16S analysis was employed to explore the gut microbiota within the two cohorts of patients. Patients with high adherence to MD (20) had a significantly lower C-reactive protein (p < 0.037) and disease activity (p < 0.034) than the 40 patients with low/moderate adherence to MD. An inverse association between MD and disease activity was confirmed by multivariate analysis after adjustments for all the different demographic, clinical and serologic variables. A healthier gut microbiota composition was observed in the high adherence group, with a significant decrease in Lactobacillaceae and an almost complete absence of Prevotella copri with respect to the low/moderate adherence group. In conclusion, our findings support the protective role of MD on disease activity and microbiota composition in RA patients, and suggest the feasibility of shifting the habitual diet to modulate the gut microbiota and promote the benefits associated with MD.

Major depressive disorder (MDD) is a common severe psychiatric illness, exhibiting sub-optimal response to existing pharmacological treatments. Although its etiopathogenesis is still not completely understood, recent findings suggest that an altered composition of the gut microbiota might play a role. Here we aimed to explore potential differences in the composition of the gut microbiota between patients with MDD and healthy controls (HC) and to identify possible signatures of treatment response by analyzing two groups of MDD patients characterized as treatment-resistant (TR) or responders (R) to antidepressants. Stool samples were collected from 34 MDD patients (8 TR, 19 R and 7 untreated) and 20 HC. Microbiota was characterized using the 16S metagenomic approach. A penalized logistic regression analysis algorithm was applied to identify bacterial populations that best discriminate the diagnostic groups. Statistically significant differences were identified for the families of Paenibacillaceae and Flavobacteriaceaea, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis among others. The phyla Proteobacteria, Tenericutes and the family Peptostreptococcaceae were more abundant in TR, whereas the phylum Actinobacteria was enriched in R patients. Moreover, a number of bacteria only characterized the microbiota of TR patients, and many others were only detected in R. Our results confirm that dysbiosis is a hallmark of MDD and suggest that microbiota of TR patients significantly differs from responders to antidepressants. This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD, suggesting a role in response to antidepressants.

Recent studies suggest a role for the gut microbiota in the onset, progression, and prognosis of prostate cancer (PCa), one of the most common neoplasms in males. PCa screening relies on PSA testing, whose usefulness remains controversial due to its low specificity. This study was aimed at investigating the differences in the gut microbiota of PCa patients and healthy controls (HCs) and finding correlations between gut microbes and the clinical laboratory parameter assessed in the evaluation of PCa, to identify bacteria which could be used as diagnostic and prognostic biomarkers. Fecal samples collected from 18 PCa patients and 18 HCs were used to isolate bacterial DNA. 16S rRNA gene sequencing provided the gut microbial profiles of the enrolled subjects, whose functional impact was also predicted. A recursive partitioning tree method allowed us to identify a bacterial signature discriminating PCa from HC. A correlation analysis was performed between gut bacteria and the clinical laboratory parameters assessed in the evaluation of PCa. Differential bacterial patterns emerged between PCa patients and HCs, together with significant differences in beta-diversity, alpha-diversity, and richness. The functional prediction of the microbial profiles revealed several metabolic processes differentially regulated, including an enrichment in the Krebs cycle and in steroid hormone synthesis in PCa patients. A bacterial signature based on the abundance of Lactobacillus and Collinsella was found to discriminate between the two groups. Significant correlations were found between gut bacteria and the clinical laboratory parameters generally assessed in the evaluation of PCa. These results indicate that gut microbiota profiles may, in the future, represent potential biomarkers associated with prostate cancer risk or progression; however, further prospective studies and clinical validation are needed before considering their use as diagnostic or prognostic tools.

Background Colorectal cancer (CRC) harboring BRAF V600E mutation exhibits low response to conventional therapy and poorest prognosis. Due to the emerging correlation between gut microbiota and CRC carcinogenesis, we investigated in serrated BRAF V600E cases the existence of a peculiar fecal microbial fingerprint and specific bacterial markers, which might represent a tool for the development of more effective clinical strategies. Methods By injecting human CRC stem-like cells isolated from BRAF V600E patients in immunocompromised mice, we described a new xenogeneic model of this subtype of CRC. By performing bacterial 16S rRNA sequencing, the fecal microbiota profile was then investigated either in CRC-carrying mice or in a cohort of human CRC subjects. The microbial communities’ functional profile was also predicted. Data were compared with Mann-Whitney U, Welch’s t-test for unequal variances and Kruskal-Wallis test with Benjamini–Hochberg false discovery rate (FDR) correction, extracted as potential BRAF class biomarkers and selected as model features. The obtained mean test prediction scores were subjected to Receiver Operating characteristic (ROC) analysis. To discriminate the BRAF status, a Random Forest classifier (RF) was employed. Results A specific microbial signature distinctive for BRAF status emerged, being the BRAF -mutated cases closer to healthy controls than BRAF wild-type counterpart. In agreement, a considerable score of correlation was also pointed out between bacteria abundance from BRAF -mutated cases and the level of markers distinctive of BRAF V600E pathway, including those involved in inflammation, innate immune response and epithelial-mesenchymal transition. We provide evidence that two candidate bacterial markers, Prevotella enoeca and Ruthenibacterium lactatiformans , more abundant in BRAF V600E and BRAF wild-type subjects respectively, emerged as single factors with the best performance in distinguishing BRAF status (AUROC = 0.72 and 0.74, respectively, 95% confidence interval). Furthermore, the combination of the 10 differentially represented microorganisms between the two groups improved performance in discriminating serrated CRC driven by BRAF mutation from BRAF wild-type CRC cases (AUROC = 0.85, 95% confidence interval, 0.69–1.01). Conclusion Overall, our results suggest that BRAF V600E mutation itself drives a distinctive gut microbiota signature and provide predictive CRC-associated bacterial biomarkers able to discriminate BRAF status in CRC patients and, thus, useful to devise non-invasive patient-selective diagnostic strategies and patient-tailored optimized therapies.