Search Results (164)

Deciphering the spatiotemporal distribution of bacteria during breast cancer progression may provide critical insights for developing bacterial-based therapeutic strategies. Using a murine breast cancer model, we longitudinally profiled the microbiota in breast tumor tissue, mammary gland, spleen, and cecal contents at 3-, 5-, and 7- weeks post-tumor implantation through 16S rRNA gene sequencing. Breast tumor progression was associated with lung metastasis and splenomegaly, accompanied by distinct tissue-specific microbial dynamics. While alpha diversity remained stable in tumors, mammary tissue, and cecal contents, it significantly increased in the spleen (p < 0.05). Longitudinal analysis revealed a progressive rise in Firmicutes and a decline in Proteobacteria abundance within tumors, mammary tissue, and cecum, whereas the spleen microbiota displayed unique phylum-level compositional shifts. Tissue- and time-dependent microbial signatures were identified at phylum, genus, and species levels during breast tumor progression. Strikingly, the spleen microbiota integrated nearly all genera enriched in other sites, suggesting its potential role as a microbial reservoir. Gut-associated genera (Lactobacillus, Desulfovibrio, Helicobacter) colonized both cecal contents and the spleen, with Lactobacillus consistently detected across all tissues, suggesting microbial translocation. The spleen exhibited uniquely elevated diversity and compositional shifts, potentially driving splenomegaly. These results delineated the trajectory of microbiota translocation and colonization, and demonstrated tissue-specific microbial redistribution during breast tumorigenesis, offering valuable implications for advancing microbiome-targeted cancer therapies. Full article

Background/Objectives: Breast cancer (BC) is the leading cause of cancer incidence and mortality among women and the recent identification of a resident mammary microbiota has highlighted its potential role in breast carcinogenesis. Given that environmental and socioeconomic factors influence both BC prevalence and tumor-associated bacterial composition, this study aimed to evaluate the compositional and functional features of the mammary microbiota in cancerous (oncobiome) and adjacent healthy BC tissues from patients living in urban and rural areas. Methods: Microbiota composition in both the oncobiome and adjacent healthy BC tissues was analyzed using 16S rRNA sequencing. Results: Significant variations in breast oncobiome composition were observed among BC patients from urban and rural areas. A statistically significant β dispersion among breast oncobiome of patients from urban or rural areas was highlighted. Specifically, the genera Selenomonas, Centipeda, Leptotrichia, Neisseria and Porphyromonas were found exclusively in BC tissues of patients from rural areas. Additionally, bacteria from the Neisseriaceae, Porphyromonadaceae, and Selenomonadaceae families, as well as the Selenomonas genus, were significantly enriched in the oncobiome of rural BC patients. Furthermore, the results of the PICRUSt2 (phylogenetic investigation of communities by reconstruction of unobserved states) revealed a significant increase in phospholipid biosynthesis pathways in breast oncobiome of patients from rural areas compared to those from urban areas. Conclusions: This study provides evidence of distinct compositional and functional differences in the breast oncobiome between BC patients from rural and urban areas. These findings suggest that environmental factors influence local microbiome composition, potentially contributing to BC development and/or progression. Full article

Background: Breast cancer (BC) is the second most common cancer among women in the United States. It has been estimated that one in eight women will be diagnosed with breast cancer in her lifetime. Various BC risk factors, such as age, physical inactivity, and smoking, play a substantial role in BC occurrence and development. Early life dietary intervention with plant-based bioactive compounds has been studied for its potential role in BC prevention. Sulforaphane (SFN), an isothiocyanate, is an antioxidant and anti-inflammatory agent extracted from broccoli sprouts (BSp) and other plants. Dietary supplementation of SFN suppresses tumor growth by inducing protective epigenetic changes and inhibiting cancer cell proliferation. Inulin, as a dietary fiber, has been studied for alleviating GI discomfort and weight loss by promoting the growth of beneficial bacteria in the gut. Objective: Early-life combinatorial treatment with both phytochemical SFN and potential prebiotic agent inulin at lower and safer dosages may confer more efficacious and beneficial effects in BC prevention. Methods: Transgenic mice representing estrogen receptor-negative BC were fed 26% (w/w) BSp and 2% (w/v) inulin supplemented in food and water, respectively. Results: The combinatorial treatment inhibited tumor growth, increased tumor onset latency, and synergistically reduced tumor weight. Gut microbial composition was analyzed between groups, where Ruminococcus, Muribaculaceae, and Faecalibaculum significantly increased, while Blautia, Turicibacter, and Clostridium sensu stricto 1 significantly decreased in the combinatorial group compared with the control group. Furthermore, combinatorial treatment induced a protective epigenetic effect by inhibiting histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Intermediates in the AKT/PI3K/MTOR pathway were significantly suppressed by the combinatorial treatment, including PI3K p85, p-AKT, p-PI3K p55, MTOR, and NF-κB. Cell cycle arrest and programmed cell death were induced by the combinatorial treatment via elevating the expression of cleaved-caspase 3 and 7 and inhibiting the expressions of CDK2 and CDK4, respectively. Orally administering F. rodentium attenuated tumor growth and induced apoptosis in a syngeneic triple-negative breast cancer (TNBC) mouse model. Conclusions: Overall, the findings suggest that early-life dietary combinatorial treatment contributed to BC prevention and may be a potential epigenetic therapy that serves as an adjunct to other traditional neoadjuvant therapies. Full article

Breast cancer (BC) is globally becoming a great challenge, being both the most diagnosed cancer and the leading cause of death in women. In addition to cancer cells, many bacteria co-inhabit BC, which differ in type and number from the resident microbiota found in healthy breast tissue. While many reports have demonstrated the ability of different bacteria to dysregulate BC’s metabolites, the reciprocal effect of these metabolites on the bacterial microbiota has not yet been investigated. Herein, we assess the effect of conditioned media (CM) from a triple-negative BC cell line (MDA-MB-231) on the metabolic profile of Pseudomonas aeruginosa (P. aeruginosa), an important breast resident Gram-negative bacteria that influence oncogenesis. Optical density and scanning electron microscopes were used to assess the impact of MDA-MB-231-CM (BC-CM) on P. aeruginosa growth and morphological changes, respectively. In addition, liquid chromatography–high-resolution mass spectrometry was used to identify metabolic changes in P. aeruginosa and their secretomes in response to the BC-CM. The BC-CM significantly suppressed the growth of P. aeruginosa in the log phase and induced concentration-dependent cytopathological changes in their cell walls. The metabolites of P. aeruginosa were dysregulated considerably depending on the time of exposure to the BC-CM. When treated with the BC-CM, P. aeruginosa induced the purine alkaloid spliceostatin (FR901464), a prominent antitumor metabolite. The BC-CM also promoted other P. aeruginosa metabolites such as amino acids, phosphoribosyl-AMP, 2-aminoacetophenone, pyochelin I, guanosine monophosphate, riboflavin, and terpenoids, which are capable of interfering with oncogenesis. Nine of the significantly identified metabolites from the 0–3 h comparison and four of those identified from the 0–6 h comparison have potential roles in influencing cancer cell behavior. Our findings demonstrate the ability of triple-negative BC-CM not only to alter the growth and morphology of P. aeruginosa but also to modulate their metabolic profile. A better understanding of the influence of BC on certain resident breast microbiomes, such as P. aeruginosa, may open a new therapeutic intervention opportunity for the treatment of cancer. Full article

Breast milk is vital for infant survival, protecting against infections and strengthening the immune system. In addition to nutrients, breast milk contains beneficial microorganisms, antimicrobial peptides and proteins (APPs), including lactoferrin and lysozyme, and peptides such as defensins and cathelicidins that destroy harmful bacteria and regulate the neonatal immune response. Breast milk also promotes the growth of beneficial gut bacteria (Bacteroidaceae and Bifidobacteriaceae) while reducing harmful pathogens, fostering a healthy gut microbiome, and supporting long-term infant health. Traditionally, research on antimicrobial proteins and milk microbiota has been conducted in isolation. However, at the molecular level, these components do not function independently; they interact synergistically, influencing immunomodulation, inflammation, and the composition of the gut microbiome. Therefore, this review aims to provide an overview of the discovery and identification of APPs in breast milk, the dynamic relationship between the breast milk microbiota, and the potentiation of artificial feeding with supplemented formulas when breastfeeding is impossible, benefits on newborn immune systems, and even the benefits to breast tissue. Full article

Breast cancer treatment, including surgery, chemotherapy, radiotherapy, and endocrine therapy, can affect the microbiome and microenvironment of the human body. The present study examined how the microbiome changes before and after treatment in patients with breast cancer and explored variations in the expression of putative proteins linked to these shifts. Forty-five patients enrolled in this study, and blood samples were collected and sequenced to analyze microbiome composition. Using these sequences, we estimated and compared the putative protein expression levels. In addition, complete blood count results were analyzed to evaluate treatment-induced alterations. The findings indicate that treatment leads to microbiome modifications associated with changes in the human microenvironment. Moreover, key putative proteins involved in these processes were identified. This study provides valuable insights into how breast cancer treatment affects the microbiome and helps elucidate the potential role of microbial protein expression in patient outcomes. Full article

Background: The anti-tumor response of the immune system is pivotal for treating triple-negative breast cancer (TNBC), particularly as targeted therapies are limited. However, the impact of immune-modulating factors such as the application of granulocyte-stimulating factors (G-CSFs) or infections, including febrile neutropenia, prophylactic or therapeutical application of oral antibiotics (OABs), and the need for intravenous antibiotics (IABs), on survival outcomes remains unclear. Methods: 1583 patients with early-stage TNBC enrolled in the SUCCESS A or C study underwent primary surgery, adjuvant chemotherapy, and radiotherapy if indicated. All patients had Eastern Cooperative Oncology Group (ECOG) status ≤ 2. The effects of G-CSF, OAB, and IAB application on overall survival (OS), invasive disease-free survival (iDFS), breast cancer-specific survival (BCSS), and distant disease-free survival (DDFS) were assessed. Results: Only IAB treatment was significantly associated with decreased survival in univariable analyses (OS: p = 0.003; iDFS: p = 0.036; BCSS: p = 0.011; DDFS: p = 0.044), while G-CSF and OAB administration were not. Adjusted multivariable Cox regressions including febrile neutropenia and dose reduction/shift, ECOG, age of patients, and other clinicopathological parameters confirmed a significant negative effect of IABs on OS (p = 0.020), BCSS (p = 0.018), and DDFS (p = 0.044). Conclusions: In summary, IABs during adjuvant chemotherapy seems to be a risk factor for inferior OS, BCSS, and DDFS in TNBC patients, possibly by affecting microbiome-related immune response modulation. Hence, preventive measures to avoid the need for IABs should be considered in these patients. Full article

Recent clinical trials have suggested that solid cancers with mismatch repair (MMR) deficiency are highly responsive to immunotherapy, regardless of cancer types. Previous MMR-related studies on breast cancer have predominantly focused on germline variants. However, the somatic MMR alterations have not been comprehensively characterized in breast cancer. In this study, we integrated genomic, transcriptomic, and clinical data from over 3000 breast cancer cases across six public cohorts. Our findings revealed that 1.2% of breast cancers harbored oncogenic somatic MMR alterations, with triple-negative breast cancer (TNBC) demonstrating the highest mutation rate at 3.1%. Additionally, somatic MMR alterations were significantly associated with microsatellite instability-high (MSI-H) and MMR-related mutational signatures, indicating that somatic MMR alterations led to impaired function of the MMR system. Biallelic inactivation of MMR genes resulted in a more pronounced loss of MMR function compared to monoallelic inactivation. Importantly, these MMR alterations significantly increased the tumor mutational burden (TMB) and neoantigen load in breast cancer, regardless of MSI-H status. These findings indicate that the frequency of MMR alterations is highest in TNBC and that MMR alterations in breast cancer can lead to MMR functional deficiencies, suggesting that some patients harboring such alterations may benefit from immunotherapy. Full article

Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of female death. Altered interactions between the host and the gut microbiota appear to play an influential role in carcinogenesis. Several studies have shown different signatures of the gut microbiota in patients with breast cancer compared to healthy women. Currently, there is disagreement regarding the different DNA isolation and sequencing methodologies for studies on the human microbiota, given that they can influence the interpretation of the results obtained. The goal of this work was to compare (1) three different DNA extraction strategies to minimize the impact of human DNA, and (2) two sequencing strategies (16S rRNA and shotgun) to identify discrepancies in microbiome results. We made use of breast tissue and fecal samples from both healthy women and breast cancer patients who participated in the MICROMA study (reference NCT03885648). DNA was isolated by means of mechanical lysis, trypsin, or saponin. The amount of eukaryotic DNA isolated using the trypsin and saponin methods was lower compared to the mechanical lysis method (mechanical lysis, 89.11 ± 2.32%; trypsin method, 82.63 ± 1.23%; saponin method, 80.53 ± 4.09%). In samples with a predominance of prokaryotic cells, such as feces, 16S rRNA sequencing was the most advantageous approach. For other tissues, which are expected to have a more complex microbial composition, the need for an in-depth evaluation of the multifactorial interaction between the various components of the microbiota makes shotgun sequencing the most appropriate method. As for the three extraction methods evaluated, when sequencing samples other than stool, the trypsin method is the most convenient. For fecal samples, where contamination by host DNA is low, no prior treatment is necessary. Full article

The human milk (HM) microbiome is variable and depends on maternal, perinatal, and cultural–environmental factors. The diversity of the HM microbiome is crucial in the development of the child. The aim of the study was to assess the prevalence of bacteria (using culture-based methods) of Polish women with normal BMI, giving birth on time through vaginal delivery. Methods: The research material consisted of human milk and swabs from the areola and nipple, before and after breastfeeding, derived from Polish women (n = 86). Classic culture methods were used to obtain multiple bacteria. Species identification of the grown colonies was performed using MALDI TOF MS (Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry). Results: 120 species of bacteria were isolated, mainly from the genus Streptococcus and Staphylococcus. Species specific only to human milk were identified (belonging to the following genera: Microbacterium, Shewanella, Psychrobacter, Aeromonas, Serratia, Buttiauxella, Lactobacillus, Bifidobacterium) as well as species specific only to areola and nipple swabs after breastfeeding (Acinetobacter lactucae, Moraxella catarrhalis, Corynebacterium pseudodiphtheriticum, Corynebacterium propinquim). It was confirmed that most species were present in all tested materials collected from one patient. Conclusions: The analysis carried out showed the presence of bacteria in the human milk of Polish women, including strains of lactic acid bacteria. The human milk microbiota may significantly influence the formation of the infant’s intestinal microbiota, including some key genera, i.e., Lactobacillus, Bifidobacterium, and Limosilactobacillus, which were also isolated from the tested samples. The data presented here provide new data on culturable bacterial species isolated from breast milk from Polish women giving birth via vaginal delivery and potential routes of transmission from the neonate’s oral cavity. Full article

Breast milk is rich in bioactive components, especially human milk oligosaccharides (HMOs), which are crucial for establishing gut microbiota. The 2′-FL (2-Fucosyllactose), one of the most abundant oligosaccharides in breast milk, functions as a selective prebiotic. Objective: To examine the effect of adding 2′-FL (2-Fucosyllactose) to an infant formula containing prebiotic galacto-oligosaccharides (GOSs) and fructo-oligosaccharides (FOSs) on the gut microbiome of healthy formula-fed infants. Methods: This study enrolled infants from three groups: an HMO experimental group (n = 29), a GOS/FOS control group (n = 30), and an exclusively breastfed (breast milk [BM]) reference group (n = 28). Fecal samples from the three groups in the first and fourth months of life were analyzed. The V3 and V4 regions of the 16S rRNA gene were amplified and sequenced on the Illumina MiSeq. ANOVA, Kruskal–Wallis, richness indices (Chao1, Shannon), UniFrac distances, and the Adonis tests were used to perform statistical analyses on the relative abundance of phyla and genera, as well as the alpha and beta-diversity of the gut microbiota. Results: After intervention, Actinobacteriota emerged as the predominant phylum in both the HMO (60.4%) and BM (46.6%) groups. Bifidobacterium and Escherichia-Shigella were identified as the two most abundant bacterial genera in both groups. Nevertheless, the statistical analysis showed that the relative abundance of Bifidobacterium in the HMO formula-fed group after intervention was similar to that in the BM group (p > 0.05). Infants in the HMO and GOS/FOS groups showed higher relative abundance of [Ruminococcus]_gnavus_group bacteria compared to those in the BM group. Groups fed with infant formula demonstrated higher alpha-diversity of gut microbiota compared to breastfed infants (p < 0.05), at the time of admission as well as after the intervention. Beta-diversity was significantly different among the three groups, according to type of feeding. Infants fed a 2′-FL-supplemented infant formula exhibited growth comparable to that of breastfed infants throughout the intervention period, demonstrating that the formula was both safe and well tolerated. Conclusions: Adding 2′-FL to an infant formula containing 4 g/L of GOS + FOS resulted in a stronger bifidogenic effect compared to the formula without 2′-FL. Full article

Milk is the principal nutrient of newborn humans and a diagnostic feature of the order Mammalia. Its release is elicited as a reflex by infant sucking under the control of the hormone oxytocin. While it is recognized that breast milk optimally promotes infant longitudinal growth and development, this review explores facts and controversies regarding the extent to which the milks of several dairy animals and infant formula milk (IF) approximate special properties and bioactivities of breast milk. It also provides evidence that early exposure to undernutrition during the very rapid fetal and early infancy growth predominantly and permanently stunts longitudinal growth trajectory in both animals and humans and is often followed in later life by obesity and metabolic dysfunction, and sometimes also by precocious timing of sexual maturation. There is a knowledge gap as to whether there may be additional critical periods of nutritional vulnerability in human development, which is characterized by a relatively prolonged period of slow childhood growth bracketed by the rapid fetal–neonatal and pubertal growth spurts. It is also unclear whether any quantitative differences in caloric intake and supply during neonatal period may influence developmental fatness programming. A further knowledge gap exists regarding the role of infant microbiome composition and development in the possible epigenetic programming of longitudinal growth or fatness in later life. Extending the research of early developmental programming to the entire period of human growth from conception to the end of puberty, examining infant caloric intake and supply as possible factors modulating the epigenetic programming in favor of obesity, and examining the role of infant gut microbiome in developing infant’s capacity to process nutrients may provide a better understanding of the interaction between critical nutritional influences in the control of human longitudinal growth and later-life obesity. Full article

The breast tissue microbiome has been increasingly recognized as a potential contributor to breast cancer development and progression. However, inconsistencies in microbial composition across studies have hindered the identification of definitive microbial signatures. We conducted a systematic review and meta-analysis of 11 studies using 16S rRNA sequencing to characterize the bacterial microbiome in 1260 fresh breast tissue samples, including normal, mastitis-affected, benign, cancer-adjacent, and cancerous tissues. Studies published until 31 December 2023 were included if they analyzed human breast tissue using Illumina short-read 16S rRNA sequencing with sufficient metadata, while non-human samples, non-breast tissues, non-English articles, and those lacking metadata or using alternative sequencing methods were excluded. We also incorporated microbiome data from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort to enhance our analyses. Our meta-analysis identified Proteobacteria, Firmicutes, Actinobacteriota, and Bacteroidota as the dominant phyla in breast tissue, with Staphylococcus and Corynebacterium frequently detected across studies. While microbial diversity was similar between cancer and cancer-adjacent tissues, they both exhibited a lower diversity compared to normal and mastitis-affected tissues. Variability in bacterial genera was observed across primer sets and studies, emphasizing the need for standardized methodologies in microbiome research. An analysis of TCGA-BRCA data confirmed the dominance of Staphylococcus and Corynebacterium, which was associated with breast cancer proliferation-related gene expression programs. Notably, high Staphylococcus abundance was associated with a 4.1-fold increased mortality risk. These findings underscore the potential clinical relevance of the breast microbiome in tumor progression and emphasize the importance of methodological consistency. Future studies to establish causal relationships, elucidate underlying mechanisms, and assess microbiome-targeted interventions are warranted. Full article

Most brain development occurs in the “first 1000 days”, a critical period from conception to a child’s second birthday. Critical brain processes that occur during this time include synaptogenesis, myelination, neural pruning, and the formation of functioning neuronal circuits. Perturbations during the first 1000 days likely contribute to later-life neurodegenerative disease, including sporadic amyotrophic lateral sclerosis (ALS). Neurodevelopment is determined by many events, including the maturation and colonization of the infant microbiome and its metabolites, specifically neurotransmitters, immune modulators, vitamins, and short-chain fatty acids. Successful microbiome maturation and gut–brain axis function depend on maternal factors (stress and exposure to toxins during pregnancy), mode of delivery, quality of the postnatal environment, diet after weaning from breast milk, and nutritional deficiencies. While the neonatal microbiome is highly plastic, it remains prone to dysbiosis which, once established, may persist into adulthood, thereby inducing the development of chronic inflammation and abnormal excitatory/inhibitory balance, resulting in neural excitation. Both are recognized as key pathophysiological processes in the development of ALS. Full article

Breastfeeding supplies nutrition, immunity, and hormonal cues to infants. Feeding expressed breast milk may result in de-phased milk production and feeding times, which distort the real-time circadian cues carried by breast milk. We hypothesized that providing expressed breast milk alters the microbiotas of both breast milk and the infant’s gut. To test this hypothesis, we analyzed the microbiota of serial breast milk and infant fecal samples obtained from 14 mother–infant dyads who were lactating, half of which were providing expressed breast milk. Infant fecal microbiota showed lower α-diversity than breast milk microbiota. Bacterial amplicon sequence variant sharing occurred between breast milk and infant feces with no feeding group differences. However, the age-dependent gain in breast milk α-diversity was only significant in the expressed breast milk group and not in the direct breastfeeding group, suggesting that decreased contact with the infant’s mouth influences the milk microbiota. Trending lower connectivity was also noted with breast milk microbes in the direct breastfeeding group, consistent with regular perturbations of the developing baby’s oral microbiota by latching on the breast. The results of this preliminary study urge further research to independently confirm the effects of providing expressed breast milk and their health significance. Full article