Ana Isabel Alvarez-Mercado

Background: In 2022, there were an estimated 20 million new cancer cases and 9.7 million deaths. The number of new cancer cases is expected to rise to over 35 million by 2050, marking a 75% increase from 2022 levels. Twenty to eighty-six percent of cancer patients suffer from taste disorders (TD), which are associated with an increased risk of malnutrition. Cachectic syndrome is linked to the presence and growth of tumors and leads to systemic inflammation. Synsepalum dulcificum is a plant whose berries contain miraculin, a glycoprotein that transforms sour tastes into sweet and can ameliorate TD. Objectives: To evaluate the effect of the regular intake of dried miracle berries (DMBs), a novel food containing miraculin, on biomarkers of inflammation and cachexia in malnourished patients with cancer and TD receiving systemic antineoplastic therapy. Methods: we conducted a triple-blind, randomized, placebo-controlled pilot clinical trial. Thirty-one patients with cancer of various etiologies who received chemotherapy were enrolled in this pilot study and divided into three groups. The first group received a tablet containing 150 mg of DMB (standard dose), the high-dose group received a tablet of 300 mg of DMB, and the third group received a tablet with 300 mg of the placebo for three months before each main meal. The plasma levels of several molecules associated with inflammation and cancer cachexia were measured using the X-MAP Luminex multiplexing platform. Results: We found decreased plasma levels of IFN-γ in the standard-dose group. In addition, our results suggest a downtrend of IL-1β levels in the three groups after three months of intervention (p = 0.093). Moreover, the three groups showed a reduction in tumor-derived molecule proteolysis-inducing factor/dermcidin (p = 0.021). It is important to highlight the positive correlation between IL-6 and IL-10 in the standard group, which suggests a better balance between proinflammatory and anti-inflammatory cytokines. Regardless of DMB consumption, soluble TNF receptor type II tended to decrease with treatment in patients who responded well to the antineoplastic treatment (p = 0.011). We did not find significant correlations between cytokines and sensory variables or dietary and nutritional status. Conclusions: Our results suggest that the regular consumption of a standard dose of DMB along with a systemic antineoplastic treatment could contribute to reducing inflammation and cachexia biomarkers in malnourished patients with cancer exhibiting TD. In this sense, nutritional support is crucial in the treatment of cancer cachexia. In our view, it should be considered a coadjuvant of therapeutics. Future studies on the molecular signaling pathways and specific mechanisms of action of bioactive compounds within food supplements, such as miraculin, will allow them to be used to target pathogenic mechanisms of cancer cachexia and malnutrition: NCT05486260.

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.

Background/Objectives: Dysgeusia contributes to malnutrition and worsens the quality of life of patients with cancer. Despite the different strategies, there is no effective treatment for patients suffering from taste disorders provided by the pharmaceutical industry. Therefore, we developed a novel strategy for reducing side effects in cancer patients by providing a novel food supplement with the taste-modifying glycoprotein miraculin, which is approved by the European Union, as an adjuvant to medical–nutritional therapy. Methods: A pilot randomized, parallel, triple-blind, and placebo-controlled intervention clinical trial was carried out in which 31 malnourished patients with cancer and dysgeusia receiving antineoplastic treatment were randomized into three arms—standard dose of dried miracle berries (DMBs) (150 mg DMB/tablet), high dose of DMBs (300 mg DMB/tablet), or placebo (300 mg freeze-dried strawberry)—for three months. Patients consumed a DMB or placebo tablet before each main meal (breakfast, lunch, and dinner). Using stool samples from patients with cancer, we analyzed the intestinal microbiome via nanopore methodology. Results: We detected differences in the relative abundances of genera Phocaeicola and Escherichia depending on the treatment. Nevertheless, only the Solibaculum genus was more abundant in the standard-dose DMB group after 3 months. At the species level, Bacteroides sp. PHL 2737 presented a relatively low abundance in both DMB groups, whereas Vescimonas coprocola presented a relatively high abundance in both treatment groups after 3 months. Furthermore, a standard dose of DMB was positively associated with TNF-α levels and Lachnoclostridium and Mediterraneibacter abundances, and a high dose of DMB was negatively associated with TNF-α levels and the relative abundance of Phocaeicola. Following the administration of a high dose of DMB, a positive correlation was observed between erythrocyte polyunsaturated fatty acids and the presence of Lachnoclostridium and Roseburia. Additionally, a positive association was identified between Phocaeicola and the acetic acid concentration of feces. There was a negative association between the relative abundance of Phocaeicola and taste perception in the high-dose DMB group. Conclusions: The combination of DMB intake with nutritional treatment and individualized dietary guidance results in positive changes in the intestinal microbiome of patients with cancer and dysgeusia. Changes observed in the intestinal microbiome might contribute to maintaining an appropriate immune response in cancer patients. As the current pilot study included a limited number of participants, further clinical trials on a larger group of patients are needed to draw robust findings.

Background/Objectives: Dysgeusia contributes to the derangement of nutritional status in patients with cancer as well as worsening the quality of life. There has been a lack of effective treatments for taste disorders provided by the pharmaceutical industry. Methods: This was a pilot randomized, parallel, triple-blind, and placebo-controlled intervention clinical trial in which 31 malnourished patients with cancer and dysgeusia receiving antineoplastic treatment were randomized into three arms [standard dose of DMB (150 mg DMB/tablet), high dose of DMB (300 mg DMB/tablet) or placebo (300 mg freeze-dried strawberry)] for three months. Patients consumed a DMB or placebo tablet before each main meal. Using the nanopore methodology, we analyzed the oral microbiome of patients with cancer using saliva samples. Results: All patients with cancer and dysgeusia had dysbiosis in terms of lower bacterial diversity and richness. DMB consumption was associated with changes in oral microbiome composition. Neither selected bacteria nor taste perception, type of diet, and cytokine levels were associated with mucositis. Likewise, alcohol and tobacco consumption as well as general and digestive toxicity due to systemic therapy were not associated with specific changes of the oral microbiome, according to logistic binary regression. The standard dose of DMB resulted in a lower abundance of Veillonella compared with the high DMB dose and placebo at 3 months after intervention with DMB. In particular, some species such as Streptococcus parasanguinis, Veillonella parvula, and Streptococcus mutans were less abundant in the DMB standard-dose group. Additionally, the consumption of a standard dose of DMB revealed a negative association between the concentrations of TNF-α and the abundance of species such as Streptococcus thermophilus, Streptococcus pneumoniae, Streptococcus dysgalactiae and Streptococcus agalactiae. Conclusions: Accordingly, regular DMB consumption could modify the oral microbiome in patients with cancer and dysgeusia, which may contribute to maintaining an appropriate immune response. However, as the present pilot study involved a small number of participants, further studies are necessary to draw robust conclusions from the data.

Dysgeusia contributes to nutritional derangement and worsens the quality of life of patients with cancer. Despite the different strategies, there is no effective treatment for patients suffering from taste disorders provided by the pharmaceutical industry. We developed a novel strategy for reducing side effects in cancer patients by providing a novel food supplement with the tastemodifying glycoprotein miraculin, which is approved by the European Union, as an adjuvant to medical-nutritional therapy. A pilot randomized, parallel, triple-blind, and placebo-controlled intervention clinical trial was carried out in which 31 malnourished patients with cancer and dysgeusia receiving antineoplastic treatment, and were randomized into three arms: standard dose of DMB (150 mg DMB/tablet), high dose of DMB (300 mg DMB/tablet) or placebo (300 mg freeze-dried strawberry) for three months. Patients consumed a DMB or placebo tablet before each main meal (breakfast, lunch and dinner). Using stool samples from patients with cancer, we analyzed the intestinal microbiome via nanopore methodology. We detected differences in the relative abundances of genera Phocaeicola and Escherichia depending on the treatment. Nevertheless, only the Solibaculum genus was more abundant in the standard-dose DMB group after 3 months. At the species level, Bacteroides sp. PHL 2737 presented a relatively low abundance in both DMB groups, and Vescimonas coprocola presented a relatively high abundance in both treatment groups after 3 months. Furthermore, a standard dose of DMB was positively associated with TNF-α levels and Lachnoclostridium and Mediterraneibacter abundances, whereas a high dose of DMB was negatively associated with TNF-α levels and the relative abundance of Phocaeicola . After a high dose of DMB, erythrocyte polyunsaturated fatty acids were positively correlated with Lachnoclostridium and Roseburia , and there was a positive association between Phocaeicola and the acetic acid concentration of feces. The intake of DMB together with nutritional treatment and individualized dietary advice results in positive changes in the intestinal microbiome of patients with cancer and dysgeusia There was a negative association between the relative abundance of Phocaeicola and taste perception in the DMB high dose group. Changes observed in the intestinal microbiota might contribute to maintaining an appropriate immune response of cancer patients. Since the present pilot study involved only a few participants, further research is needed to draw robust conclusions.

Dysgeusia contributes to the derangement of nutritional status in patients with cancer, as well as worsening the quality of life. The pharmaceutical industry has failed to provide effective treatments for patients suffering from taste disorders. The present study provided a novel strategy to reduce side effects in patients with cancer through the administration of a novel food supplement approved by the European Union, Dried Miracle Berries (DMB), containing the taste-modifying glycoprotein miraculin, as an adjuvant to medical-nutritional treatment. This was done in a pilot randomized, parallel, triple-blind, and placebo-controlled intervention clinical trial in which 31 malnourished patients with cancer and dysgeusia receiving antineoplastic treatment were randomized into three arms [standard dose of DMB (150 mg DMB/tablet), high dose of DMB (300 mg DMB/tablet) or placebo (300 mg freeze-dried strawberry)] for three months. Patients consumed a DMB or placebo tablet before each main meal. Using the Nanopore methodology, we analyzed the oral microbiome of patients with cancer using saliva samples. All patients with cancer and dysgeusia had dysbiosis in terms of lower bacterial diversity and richness. DMB consumption was associated with changes in oral microbiome composition. Neither selected bacteria, nor taste perception, type of diet, and cytokine levels were associated with mucositis. Likewise, alcohol and tobacco consumption as well as general and digestive toxicity due to systemic therapy was not associated to specific changes of the oral microbiota. The standard dose of DMB resulted in a greater relative abundance of Enterococcus and a lower abundance of Veillonella compared with the high DMB dose and placebo. In particular, some species such as Granulicatella elegans , Granulicatella adiacens , Streptococcus mutans , and Gemella morbillorum showed higher relative abundances in the DMB standard-dose group; in contrast, Streptococcus parasanguinis , Veillonella parvula , Streptococcus australis , and Streptococcus cristatus were less abundant. Additionally, the consumption of a standard dose of DMB revealed a negative association between the concentrations of TNF-α and the abundance of species such as Streptococcus thermophilus , Streptococcus pneumoniae , Streptococcus dysgalactiae and Streptococcus agalactiae. Accordingly, regular DMB consumption changed the oral microbiome in patients with cancer and dysgeusia, which may contribute to maintaining an appropriate immune response without changing taste perception. However, as the present pilot study involved a small number of participants, further studies are necessary draw robust conclusions from the data. Highlights: Patients with cancer and dysgeusia exhibit a dysbiotic state in terms of bacterial diversity and richness. The regular consumption of a standard dose of Dried Miracle Berries (DMB), rich in miraculin, before each main meal for three months as an adjuvant to medical-nutritional treatment, improves the oral microbiome composition in malnourished patients with cancer and dysgeusia. Several species i.e., Granulicatella elegans , Granulicatella adiacens , Streptococcus mutans , and Gemella morbillorum , show higher relative abundances in the DMB standard-dose group; in contrast, Streptococcus parasanguinis , Veillonella parvula , Streptococcus australis , and Streptococcus cristatus are less abundant DMB consumption is negatively associated with some species of Streptococcus and TNF-α concentrations in malnourished patients with cancer and dysgeusia. Neither of the highly represented bacteria are associated with the presence or absence of mucositis, digestive toxicity, or tobacco use and alcohol consumption or a change in taste perception at the end of the intervention.

Scope: This work is part of the clinical study NCT03885648 registered in ClinicalTrials.gov, aimed at studying the relationship among breast cancer, microbiota, and exposure to environmental pollutants. As a first step, we characterized and evaluated risk factors of the participants.Methods and results: A case–control study was designed with breast cancer (cases, n = 122) and healthy women (controls, n = 56) recruited in two hospitals of Andalusia (Southern Spain). Participants answered questionnaires of Mediterranean diet adherence and food frequency. Data were collected from medical histories and microbiota was analyzed on stool samples. Most cases (78.2%) were diagnosed as stages I and II. Cases had higher age, body mass index (BMI), glucose, cholesterol, and potassium values than controls. Cases exhibited higher adherence to the Mediterranean diet and their food consumption was closer to that dietary pattern. A hierarchical cluster analysis revealed that the Bacillota/Bacteroidota ratio was the most relevant variable in women with breast cancer, which was higher in this group compared with controls.Conclusion: Although cases exhibited higher adherence to the Mediterranean diet compared with controls, they presented features and microbiota alterations typical of the metabolic syndrome, probably due to their higher BMI and reflecting changes in their lifestyle around the time of diagnosis.

Background: Taste disorders are common in patients with cancer undergoing systemic therapy, persist during treatment and are associated with reduced food intake, increasing the risk of malnutrition. Cachectic syndrome, which is common in these patients and characterized by marked weight loss, anorexia, asthenia and anemia, is linked to the presence and growth of the tumor and leads to systemic inflammation. Synsepalum dulcificum is a plant whose berries contain miraculin, a glycoprotein that transforms sour tastes into sweet ones and could serve to ameliorate taste disorders in patients with cancer. Objective: To evaluate the effect of the regular intake of Dried Miracle Berries (DMB), a novel food containing miraculin, on several biomarkers of inflammation and cachexia in malnourished patients with cancer and taste disorders receiving systemic antineoplastic therapy. Materials and methods: Triple-blind, randomized, placebo-controlled clinical trial. Thirty-one patients with cancer of various etiologies receiving chemotherapy were enrolled in a pilot study and divided into three groups. The first group received a tablet containing 150 mg of DMB (standard dose); the high-dose group received a tablet of 300 mg of DMB, and the third group received a tablet with 300 mg of the placebo for three months before each main meal. Plasma levels of several molecules associated with inflammation and cancer cachexia were measured using the X-MAP Luminex multiplexing platform. Results: The three groups showed a decrease in the plasma levels of IL-6, IL-1β, TNF-α, and PIF throughout the intervention, although the percentage change from baseline was greater in patients receiving a standard dose of DMB. In contrast, the CNTF concentration only decreased in the DMB standard-dose group. This group also presented the greatest reduction in the IL-6/ IL-10 ratio, while IL-15 and IL-10 increased in the groups treated with DMB but not in the placebo. Regardless of DMB consumption, sTNFR-II tended to decrease with treatment in patients who responsed well to the antineoplastic treatment. We did not find significant correlations between cytokines and sensory variables or dietary and nutritional status. Conclusions: The regular consumption of a standard dose of the food supplement DMB containing miraculin along with a systemic antineoplastic treatment can contribute to reducing biomarkers of inflammation and cachexia in malnourished patients with cancer exhibiting taste disorders.

Breast cancer (BC) is one of the most diagnosed cancers in women. Based on histological characteristics, they are classified as non-invasive, or in situ (tumors located within the milk ducts or milk lobules) and invasive. BC may develop from in situ carcinomas over time. Determining prognosis and predicting response to treatment are essential tools to manage this disease and reduce its incidence and mortality, as well as to promote personalized therapy for patients. However, over half of the cases are not associated with known risk factors. In addition, some patients develop resistance to treatment and relapse. Therefore, it is necessary to identify new biomarkers and treatment strategies that improve existing therapies. In this regard, the role of the microbiome is being researched as it could play a role in carcinogenesis and the efficacy of BC therapies. This review aims to describe specific microbiome patterns associated with BC. For this, a literature search was carried out in PubMed database using the MeSH terms “Breast Neoplasms” and “Gastrointestinal Microbiome”, including 29 publications. Most of the studies have focused on characterizing the gut or breast tissue microbiome of the patients. Likewise, studies in animal models and in vitro that investigated the impact of gut microbiota (GM) on BC treatments and the effects of the microbiome on tumor cells were included. Based on the results of the included articles, BC could be associated with an imbalance in the GM. This imbalance varied depending on molecular type, stage and grade of cancer, menopause, menarche, body mass index, and physical activity. However, a specific microbial profile could not be identified as a biomarker. On the other hand, some studies suggest that the GM may influence the efficacy of BC therapies. In addition, some microorganisms and bacterial metabolites could improve the effects of therapies or influence tumor development.

Taste disorders (TDs) are common among systemically treated cancer patients and negatively impact their nutritional status and quality of life. The novel food approved by the European Commission (EFSA), dried miracle berries (DMB), contains the natural taste-modifying protein miraculin. DMB, also available as a supplement, has emerged as a possible alternative treatment for TDs. The present study aimed to evaluate the efficacy and safety of habitual DMB consumption in malnourished cancer patients undergoing active treatment. An exploratory clinical trial was carried out in which 31 cancer patients were randomized into three arms [standard dose of DMB (150 mg DMB/tablet), high dose of DMB (300 mg DMB/tablet) or placebo (300 mg freeze-dried strawberry)] for three months. Patients consumed a DMB tablet or placebo daily before each main meal (breakfast, lunch, and dinner). Throughout the five main visits, electrochemical taste perception, nutritional status, dietary intake, quality of life and the fatty acid profile of erythrocytes were evaluated. Patients consuming a standard dose of DMB exhibited improved taste acuity over time (% change right/left side: −52.8 ± 38.5/−58.7 ± 69.2%) and salty taste perception (2.29 ± 1.25 vs. high dose: 2.17 ± 1.84 vs. placebo: 1.57 ± 1.51 points, p < 0.05). They also had higher energy intake (p = 0.075) and covered better energy expenditure (107 ± 19%). The quality of life evaluated by symptom scales improved in patients receiving the standard dose of DMB (constipation, p = 0.048). The levels of arachidonic (13.1 ± 1.8; 14.0 ± 2.8, 12.0 ± 2.0%; p = 0.004) and docosahexaenoic (4.4 ± 1.7; 4.1 ± 1.0; 3.9 ± 1.6%; p = 0.014) acids in erythrocytes increased over time after DMB intake. The standard dose of DMB increased fat-free mass vs. placebo (47.4 ± 9.3 vs. 44.1 ± 4.7 kg, p = 0.007). Importantly, habitual patients with DMB did not experience any adverse events, and metabolic parameters remained stable and within normal ranges. In conclusion, habitual consumption of a standard 150 mg dose of DMB improves electrochemical food perception, nutritional status (energy intake, fat quantity and quality, fat-free mass), and quality of life in malnourished cancer patients receiving antineoplastic treatment. Additionally, DMB consumption appears to be safe, with no changes in major biochemical parameters associated with health status. Clinical trial registered (NCT05486260).