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The Regular Consumption of a Food Supplement Containing Miraculin Can Contribute to Reducing Biomarkers of Inflammation and Cachexia in Malnourished Patients with Cancer and Taste Disorders: The CLINMIR Pilot Study

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Abstract

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.
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The Regular Consumption of a Food Supplement Containing Miraculin Can
Contribute to Reducing Biomarkers of Inflammation and Cachexia in
Malnourished Patients with Cancer and Taste Disorders: The CLINMIR Pilot Study
Running Title: DMB and inflammatory biomarkers in cancer
Ana Isabel Álvarez-Mercado* 1,2,3, Bricia López Plaza 4,5, Julio Plaza-Diaz 2,6,7, Lucía Arcos
Castellanos 4,5, Francisco Javier Ruiz-Ojeda 2,3,6,8, Marco Brandimonte-Hernández 3,6, Jaime
Feliú-Batlle 9,10,11, Thomas Hummel12 , Samara Palma Milla# 4,13, Ángel Gil# 2,3,6,8.
1 Department of Pharmacology, University of Granada, 18071 Granada, Spain;
alvarezmercado@ugr.es
2 Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario
Universitario de Granada, 18014 Granada, Spain
3 Institute of Nutrition and Food Technology “José Mataix”, Centre of Biomedical
Research, University of Granada, Avda. del Conocimiento s/n, Armilla, 18016
Granada, Spain.
4 Food, Nutrition and Health Platform, Hospital La Paz Institute for Health
Research (IdiPAZ), 28046 Madrid, Spain; bricia.plaza@idipaz.es;
lucia.arcos.castellanos@idipaz.es
5 Medicine Department, Faculty of Medicine, Complutense University of Madrid,
Plaza de Ramón y Cajal, s/n, 28040 Madrid, Spain
6 Department of Biochemistry and Molecular Biology II, University of Granada,
18071 Granada, Spain; jrplaza@ugr.es; agil@ugr.es
7 Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1,
Canada
8 CIBEROBN (CIBER Physiopathology of Obesity and Nutrition), Instituto de
Salud Carlos III, 28029 Madrid, Spain
9 Oncology Department, Hospital La Paz Institute for Health Research—IdiPAZ,
Hospital Universitario La Paz, 28029 Madrid, Spain;
jaime.feliu@salud.madrid.org
10 CIBERONC (CIBER Cancer), Instituto de Salud Carlos III, 28029 Madrid, Spain
11 Medicine Department, Faculty of Medicine, Autonomous University of Madrid,
Arzobispo Morcillo 4, 28029 Madrid, Spain
12 Smell & Taste Clinic, Department of Otorhinolaryngology, Technische
Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany;
thomas.hummel@tu-dresden.de
13 Nutrition Department, Hospital University La Paz, 28046 Madrid, Spain;
samara.palma@salud.madrid.org
* Correspondence: Ana Isabel Álvarez-Mercado, E-mail: alvarezmercado@ugr.es
# Equal contribution
Abstract
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.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprintthis version posted June 24, 2024. ; https://doi.org/10.1101/2024.06.23.24309349doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
2
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.
Keywords
Cachexia; cancer; DMB; miraculin; dysgeusia; inflammation; neoplasia; nutritional status;
taste disorders
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1 BACKGROUND
Cancer is one of the leading causes of death worldwide, accounting for almost 10 million deaths
in 2020 (1 in 6 deaths) (1,2). The most common treatments for cancer are surgery, chemotherapy,
and radiation. Other treatment options include targeted therapy, immunotherapy, laser therapy,
or hormonal therapy (2). Chemotherapy and radiotherapy can cause taste and smell disorders by
altering the structure of the pores of the palate with consequent thinning of the epithelium of the
papilla (3), affecting taste nerves and salivary glands and destroying taste cells, including the
eradication of proliferative progenitors (4). Those disorders alter the pleasure produced by taste
and smell through the formation of conditioned aversions. In this regard, the term dysgeusia refers
to quantitative or qualitative taste dysfunction, including taste distortions with bitter, metallic, salty,
or unpleasant tastes (5,6). As a result, since food is perceived as unpleasant, a lower intake of
food can contribute to weight loss and malnutrition in patients with cancer. Indeed, foods
consumed can cause nausea, which negatively impacts the quality of life and nutritional status
(5,7).
In severe cases, malnutrition can progress to cachexia, which is also a common condition in many
patients with cancer (8); this complex metabolic disorder is characterized by a pronounced loss
of muscle and fat mass, systemic inflammation, weakness and fatigue (9). Certain cancers also
induce systemic reprogramming of the host's energy metabolism. This leads to alterations in
glucose, lipid and protein turnover. These metabolic imbalances are promoted by tumor-secreted
and tumor-induced factors that promote cachexia (9).
Chronic systemic inflammation is also a critical component of cachexia. Inflammatory cytokines,
particularly TNF-α, IL-6 and interferon-γ, are major drivers of many symptoms of the disease and
are thought to be responsible for the metabolic changes associated with tissue loss in cancer
wasting (10,11). In contrast, the cytokine IL-15, which is essential for the development,
proliferation, and activation of immune cells, can also enhance the antitumor activity of immune
cells and has been shown to possess significant antitumor potential (12). Interleukin-10 (IL-10), a
multifunctional cytokine with multiple properties, has been extensively studied in various
immunology and cancer biology fields. IL-10 is a pleiotropic cytokine that promotes cytotoxicity
although high levels of IL-10 can inhibit antitumor responses (13). On the other hand, when
present systemically, ciliary neurotrophic factor (CNTF) is involved in the induction of cachexia,
induces the catabolism of stored fat, skeletal muscle protein, and liver glycogen, and decreases
the circulating concentrations of several intermediary metabolites (5). Moreover, tumor-derived
molecules such as proteolysis-inducing factor/dermcidin (PIF) have also been proposed as
mediators of cancer cachexia. PIF induces protein degradation in skeletal muscle via the
ubiquitin-proteasome proteolytic pathway (11). Notably, cancer cachexia is a strong independent
cause of mortality in cancer patients (9) and those suffering from cancer cachexia are generally
less tolerant to chemotherapies and radiotherapies, limiting their treatment options (14).
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Unfortunately, cancer patients are involved in a vicious cycle in which illness provokes decreased
food intake, malabsorption and/or increased loss of nutrients, leading to an increase in
susceptibility to chemotherapy-induced toxicity. Ultimately, these complications, together with
reduced mobility, fatigue, poor response to therapy and other complications, can further
compromise nutritional status and the cachectic state becomes self-perpetuating (15).
Overall, products developed to prevent or alleviate cachexia should meet both the nutritional and
sensory needs of cancer patients, promote the enjoyment of food, counteract malnutrition,
stabilize weight and improve quality of life (7). In this sense, Synsepalum dulcificum (Daniell) is a
plant whose berries contain miraculin, a glycoprotein that transforms sour flavors into sweet ones
and limits bitter and metallic off-flavors, making food more palatable. In December 2021, the
European Commission authorized the dried fruits of S. dulcificum (also known as DMB), which
naturally contain the taste-modifying protein miraculin as a novel food (16). Recently, our group
reported that regular consumption of DMB before each main meal for three months improved
taste acuity and salty taste, leading to greater dietary intake (energy intake, fat quantity and
quality), and ameliorated nutritional status (fat-free mass) and erythrocyte polyunsaturated fatty
acid (PUFA) status (16). Indeed, an improvement in nutritional status could have a positive impact
on inflammatory and cachexia states. In the present work, we aimed to evaluate the effect of
regular consumption of DMB on several biomarkers of inflammation and cachexia in
malnourished patients with cancer suffering from taste disorders and receiving systemic
antineoplastic therapy.
2 METHODS
2.1 Study Design and Patients
The pilot CLINMIR study was designed to evaluate the efficacy and safety of the DMB food
supplement on sensory function, nutritional status, dietary intake, quality of life and the fatty acid
profile of erythrocytes in adult malnourished cancer patients with taste disorders undergoing
active antineoplastic therapy (17). The complete protocol as well as the results of the major
characteristics of patients and main outcomes, as well as the DMB composition, have been
reported elsewhere (16,17).
The clinical trial protocol was approved by the Scientific Research and Ethics Committee of the
Hospital University La Paz (HULP), Madrid (Spain) in version 1 in June 2022 and protocolled by
the HULP Code 6164. This clinical trial was registered at http://clinicaltrials.gov (Clinical Trial
NCT05486260). Briefly, a triple-blind, randomized, placebo-controlled intervention clinical trial
with three arms was conducted. Thirty-one malnourished patients with cancer of various
etiologies receiving systemic therapy and presenting taste disorders were included. Malnutrition
diagnosis was assessed using the Global Leadership Initiative on Malnutrition (GLIM) criteria and
morphofunctional assessment of disease-related malnutrition (18,19). Sensory disturbances were
assessed by electrogustometry (20). The inclusion criteria included adult patients with cancer and
systemic antineoplastic treatment for at least three months who had a weight loss 5%. All of
them were capable of oral intake of food and drinks. The exclusion criteria were patients with
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cancer participating in another clinical trial, with enteral or parenteral nutrition, major
gastrointestinal, metabolic, neurological and mental diseases, eating disorders, and severe
digestive toxicity due to treatment with chemo-radiotherapy, as well as the willingness to consume
the DMB food supplement (17).
The patients were randomly assigned into three groups and received one tablet of 150 mg of
DMB (standard dose), 300 mg of DMB (high dose) or a placebo for three months before each
main meal. The progression of cancer was assessed by a specialized oncologist using Computer
Assisted Tomography (CAT). Likewise, dietary intake, nutritional status, quality of life, physical
activity and potential adverse events were monitored by specialized nutritionists and
endocrinologists at the University Hospital La Paz, Madrid, Spain (17).
2.2 Blood Samples
Blood samples were collected in the morning (approx. 8:00 am) by trained personnel at the
Hospital University La Paz Extraction Unit (Madrid, Spain) coinciding with blood tests before
chemotherapy to avoid more punctures and hospital visits than necessary. Blood samples were
obtained at the baseline, at mid-time and the end of the intervention in tubes containing EDTA
and were centrifuged immediately at 1000 x g for 10 min. Plasma was isolated and stored at −80
°C until analysis.
2.3 Determination of plasma cytokines and tumor cachexia factors
Based on previous reports, (21–24) relevant molecules previously described to be associated
with inflammatory processes and cancer cachexia were selected for plasma analysis. Specifically,
tumor necrosis factor-alpha (TNFα), interleukin (IL) 6 (IL-6), IL-1β, IL-4, IL-10, IL-15, interferon-
gamma (IFN-γ), IL-15, soluble IL-6 receptor (sIL-6R), soluble TNF receptor type I (sTNFR-I) and
soluble TNF receptor type II (sTNFR-II) were analyzed by the X-MAP Luminex multiplex
enzimoinmmunoassay platform using specific antibodies as previously described (25). Human
ciliary neurotrophic factor (CNTF) and human proteolysis-inducing factor/dermcidin (PIF) were
analyzed by enzyme-linked immunosorbent assay (ELISA) following the kit instructions provided
by the manufacturers. Specific bead panels and ELISA Kits used with their corresponding
variation coefficients are detailed in Table 1.
2.4 Statistical analysis
For each variable, the results were tested to ascertain whether they followed a normal distribution
using the Shapiro-Will test. The results are expressed as the mean ± SEM. General linear mixed
models of variance (GLM-ANOVA) were used to evaluate the effects of time, treatment, and time
per treatment, assuming homogeneity of regression slopes. The analysis of differences in
percentages was carried out through χ2 or Fisher's F analysis.
To assess whether the plasma cytokine levels are independently associated with the response to
the oncologic treatment, either as a reduction in cancer or a maintenance or worsening of the
condition, a binary logistic regression was performed using the statistical package SPSS 25.0,
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with Wald backward option, and a statistical significance level of p<0.05 (IBM SPSS Inc, Chicago,
IL) (26). Additionally, based on Pearson's correlations, we examined the relationships between
inflammatory variables in plasma and taste acuity, body mass index, free-fat mass, energy intake,
quality of life score, as well as albumin and prealbumin in patients with cancer. Studio’s corrplot
function (27) was used to express associations by correcting multiple tests with the false discovery
rate (FDR) procedure (28). Plots show only significant and corrected associations. Red and purple
lines indicate the correlation values, with negative correlations highlighted in red (-1) and positive
correlations highlighted in purple (+1). Figure 2. All results were analyzed using the R Project for
Statistical Computing (https://www.r-project.org/) (29) and a p-value < 0.05 was considered to
indicate statistical significance.
3 Results
Firstly, we tested if plasma levels of cytokines and tumor factors were related to the success of
the antineoplastic treatment, regardless of DMB consumption, by using a logistic regression
analysis. We found that only levels of sTNFR-II tended to decrease with the reduction of tumor
mass as measured by CAT (P=0.098).
Secondly, we analyzed changes in the circulating levels of several biomarkers of inflammation
and cachexia in patients who regularly consumed DMB (standard dose and high dose) or placebo
before and after three months of intervention (Table 2, Figure 1). The three groups showed a
decrease in the plasma levels of IL-6, IL-1β and TNF-α throughout the intervention. The
percentage change from baseline was greater in patients receiving the standard dose of DMB
than in those receiving a high dose of DMB or placebo. Similar results were observed for
circulating levels of the soluble receptor sIL-6R, while sTNFR-II increased only in the placebo
group. In addition, the circulating levels of the tumor-derived molecule PIF decreased significantly
(P=0.02) over time in the three groups, while a decrease in the CNTF concentration was observed
only in the group that received the standard dose of DMB. In contrast, IL-15 increased in the DMB
standard dose group but not in the other groups. The same pattern was found for the anti-
inflammatory cytokine, IL-10, which increased in the groups treated with DMB but not in the
placebo group.
Then, we determined the IL-6/ IL-10 ratio to establish the balance between pro- and anti-
inflammatory cytokines. At the beginning of the study, all three groups had similar values for this
parameter (0.4 ± 0.1, standard dose; 0.5 ± 0.2, high dose; 0.5 ± 0.1, placebo group). However,
after 3 months of intervention, the groups that ingested DMB showed the greatest reduction in
the ratio (0.2 ± 0.03, standard dose; 0.2 ± 0.1, high dose; 0.4 ± 0.1, placebo group) (Figure 2).
Finally, we tried to ascertain whether plasma cytokines (IL-1β, IL-4, IL-6, IL-10, IL-15, INF-γ and
TNF-α), as well as soluble TNF-α and IL-6 receptors (sTNFR-I, sTNFR-II, sIL-6R) and C-reactive
protein, were associated among them and with sensory variables, body mass index, free-fat
mass, energy intake, quality of life score, as well as albumin and prealbumin. We did not find
significant correlations between cytokines and sensory variables or dietary and nutritional status.
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprintthis version posted June 24, 2024. ; https://doi.org/10.1101/2024.06.23.24309349doi: medRxiv preprint
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However, plasma levels of C-reacve protein were positively associated with other inflammatory
parameters (IL-6, TNF-α, and sTNFR-II). Additionally, IL-6 and IL-10 levels were negatively
associated with plasma albumin.
4 Discussion
The main finding of the present study is that the regular consumption of a standard dose of DMB
ameliorates several biomarkers of inflammation and cachexia in malnourished patients with
cancer undergoing antineoplastic treatment and suffering taste disorders. Concerning the effects
of the antineoplastic treatment, only plasma levels of the oncogene product sTNFR-II tended to
decrease in patients who exhibited a reduction in tumor mass, regardless of DMB intervention.
Many cancer patients, particularly those with advanced disease, experience cancer cachexia, a
complex and multifactorial syndrome thought to be the result of the actions of both host and tumor-
derived factors and cytokines involved in a systemic inflammatory response to the tumor (15).
Cancer-associated malnutrition contributes to cachexia and can be associated with taste changes
and food aversion (30–32). Early intervention with oral nutritional supplementation has been
reported to be effective in reversing malnutrition, leading to a positive impact on outcomes in
some patients (15). Hence, the benefits derived from the reduction in the inflammatory state
observed in the present study in patients receiving the standard dose of DMB might be attributable
to improved nutritional status. This improvement is due to better taste perception and increased
dietary intake facilitated by DMB. Nevertheless, we were unable to detect significant correlations
between plasma cytokines and sensory variables, energy intake and nutritional status, which
could be due to the relatively low number of patients included in the study and the high variance
of those major outcome variables evaluated. DMB is a novel food rich in miraculin, a glycoprotein
that activates sweet receptors in a pH-dependent manner, as miraculin does not possess a sweet
taste on its own but relies on acidification of the oral cavity to elicit a change in taste perception
(33). This perception of the sour taste as sweet can persist for more than 1 hour, although the
intensity of the sweet taste decreases over time (34).
Recently, we reported that regular consumption of DMB improved energy intake, fat quantity and
quality, fat-free mass, and quality of life in malnourished cancer patients receiving antineoplastic
treatment (16). Considering these results, a logical approach is to discern whether this
improvement is reflected in the cachexia status. Indeed, improvements in cachexia parameters
after nutritional interventions have already been reported (31,35). For instance, the production of
proinflammatory cytokines such as IL-6, IL-1β and TNF-α is downregulated by the omega-3 PUFA
eicosapentaenoic acid (EPA) in healthy people and cancer patients (31). Arachidonic acid (AA)
and omega-3 PUFAs are essential for cell signaling, cell structure and membrane fluidity (36,37).
Both act as eicosanoid precursors, lipid-based signaling molecules that play a key role in innate
immune responses (38). AA and omega-3 PUFAs also produce a group of lipid-based pro-
resolving mediators crucial for inhibiting proinflammatory signals: lipoxins, derived from
arachidonic acid, and resolvins, protectins, and maresins, derived from omega-3 PUFAs. We have
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previously reported increased levels of selected PUFAs including linoleic acid, AA and omega-3
fatty acids (EPA and docosahexaenoic acid- DHA) following the habitual intake of a standard dose
of DMB (16). These findings indicate a better food intake pattern, reflected in a better status of
the PUFAs profile. Remarkably, this improvement can be attributed to supplementation with the
miraculin-based food supplement DMB given that it was extended for three months, which is
sufficient time for the complete renewal of the total pool of erythrocytes (39) and is in line with the
amelioration observed in the biomarkers of inflammation. Furthermore, other authors reported
that the effects of PIF, another cachectic biomarker, were also inhibited after EPA intake (40).
Other trials aimed to identify the physiologic and clinical results of anticachexia treatment in
patients with advanced cancer. MacCiò et al. treated gynecological cancer patients with megestrol
acetate plus L-carnitine, a COX-2 inhibitor (celecoxib), and antioxidants versus only megestrol
acetate alone; the combination treatment improved lean body mass, resting energy expenditure,
fatigue, and quality of life (41).
TNF-α, IL-6 and INF-γ have been implicated as mediators of the metabolic changes associated
with cancer cachexia (10,11). The present study revealed decreased levels of IL-6 and INF-γ with
the time course of intervention, mainly in patients who consumed DMB. Similar results were
observed for the circulating levels of the soluble receptors sIL-6R and sTNFR-II. When receptors
are bound by their respective cytokines, they initiate a series of intracellular signaling cascades.
Dysregulation of the expression and secretion of these cytokines and their receptors is closely
linked to the pathogenesis of inflammatory diseases and cancer (42). In this sense, sIL-6R can
stimulate a variety of cellular responses including proliferation, differentiation and activation of
inflammatory processes, which are key in the regulation of IL-6 responses. Elevated levels of sIL-
6R have been documented in numerous clinical conditions, suggesting that its production is
coordinated as part of a disease response (43). On the other hand, TNF-α binds to two distinct
receptors TNFR-I and TNFR-II. TNFR-I has an intracellular death domain and induces
inflammation, tissue degeneration, and programmed cell death. In contrast, TNFR-II lacks a death
domain and mediates primarily homeostatic effects, including cell survival, proliferation, and
tissue regeneration (42). In some pathologic states, the production and release of sTNFRs may
mediate the host response and determine the course and outcome of disease by interacting with
TNF-α and competing with cell surface receptors (44). In the tumor microenvironment, TNF-α via
its receptors TNFR-I and TNFR-II plays a dual role in suppressing or promoting cancer
proliferation and metastasis. TNFR-I can be expressed by nearly all cells, while TNFR-II can be
highly expressed by tumor cells. In malignant cells, TNFR-II promotes tumor cell proliferation and
is increasingly considered an oncogene because it is overexpressed in more than 20 types of
cancer (45).
Concerning anti-inflammatory cytokines, the group that received the standard dose of DMB had
the greatest increase in plasma IL-10. IL-10 acts as a double-edged sword in the immune system:
it is a potent anti-inflammatory and immunosuppressive cytokine but can also have
immunostimulatory properties (46).
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In line with these results, IL-15 levels showed a similar pattern to that of IL-10 (the greatest
increase was observed in the group that received a standard dose of DMB). IL-15 can enhance
the antitumor activity of the immune system. In addition, the results of clinical trials revealed that
IL-15 is an effective inhibitor of tumor growth and prevents metastasis (12). Taken together, these
results suggest an improvement in the inflammatory profile following the consumption of a
standard dose of DMB.
The correlations observed between markers of inflammation are within the range expected in
patients who suffer from a state of inflammation. Based on these data, it could be hypothesized
that there is a 'correct functioning' of the mechanisms involved in the course of the disease and
the body's responses, which could undoubtedly facilitate therapeutic approaches. Strikingly, these
correlations were observed only in the group receiving the standard dose of DMB.
Another aspect of our results that deserves attention is the positive correlation between IL-6 and
IL-10 in this group. This led us to question the balance of pro- and anti-inflammatory cytokines in
patients. Several studies have highlighted the importance of this balance. For example, it has
been reported that the ratio of IL-6 to IL-10 is strongly correlated with injury severity and the
intensity of the anti-inflammatory response after trauma (47). In addition, an imbalance in the
systemic inflammatory response, marked by an increased IL-6/IL-10 ratio, is one of the possible
factors contributing to the severity of primary open-angle glaucoma (48), gastric cancer (49) or
COVID-19 patients (50). Understanding the interplay between IL-6 and IL-10, which reflects the
balance between proinflammatory and anti-inflammatory cytokines, is critical for identifying
patients in a hyperinflammatory state and will allow rational determination of the best treatment
options for each patient (50).
One of the earliest events of cachexia is adipose tissue loss, often preceding skeletal muscle loss
and predominantly driven by a combination of increased lipolysis and altered lipogenesis (9).
Therefore, we evaluated the effect of DMB intervention on the plasma levels of CNTF, a cytokine
that induces the catabolism of stored fat, skeletal muscle protein, and liver glycogen (5). CNTF
and PIF are tumor-derived molecules that also induce protein degradation in skeletal muscle
through the induction of the ubiquitin-proteasome proteolytic pathway (10). Remarkably, both
parameters were reduced only in the DMB standard-dose group, suggesting an amelioration of
cachexia in this group of patients. In contrast to the standard dose, the use of a high dose of DMB
caused patients to maintain an intensive sweet taste for a long time and, therefore had a negative
impact on dietary intake, which may explain why a dose greater than 150 mg is not as effective.
One of the major strengths of the present pilot study is that it was carefully designed as a
randomized triple-blind placebo-controlled intervention trial. In our view, although the number of
patients included did not allow us to detect major differences in the evaluated parameters, it is
undeniable that patients treated with the DMB supplement showed an improvement in their
cachectic state in general and their immune profile in particular compared with those in the
placebo group, especially at the standard dose of 150 mg (Figure 1). Consequently, this effect
should not be exclusively attributed exclusively to the antineoplastic treatment alone but rather to
the intervention with DMB. Thus, the success in the antineoplastic treatment was not correlated
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprintthis version posted June 24, 2024. ; https://doi.org/10.1101/2024.06.23.24309349doi: medRxiv preprint
10
to any of the cytokines, receptors and tumor factors determined, except for sTNFR-II, which is a
well-known protein highly expressed in tumor cells (51).
The major limitation of the present study is the number of subjects, although the relevance and
solidity of the results are of great importance and cannot be the result of chance alone. Other
studies have reported improvements in cachexia and inflammation in cancer patients after
nutritional interventions, especially with long-chain omega-3 PUFAs (31,52) However, improving
sensory alterations in cancer patients and promoting a better dining experience, which leads to
an improvement in nutritional status and thus a decrease in biochemical parameters of
inflammation and malnutrition, is a novel approach that has not been previously implemented.
This improvement also means an increase in the quality of life of patients and, as a result, a better
ability to cope with harsh treatment and side effects (16).
We are aware that systemic treatment of cancer patients has a key and unique role in the
amelioration of the disease. However, as all patients in our study received an antineoplastic
treatment, particularly chemotherapy, the intake of DMB should be considered responsible for at
least part of the observed benefits. DMB does not seem to have a direct role in tumorigenesis;
however, its indirect role in improving the nutritional status and particularly increasing the essential
and long-chain PUFA status could explain its effects on inflammation and cachexia. However, the
dried miracle berries are rich in several bioactive compounds, mainly polyphenols, triterpenoids
and amides and we cannot exclude a direct effect of DMB on cancer progression; in this sense,
DMB has been shown to exhibit antitumoral activities in vitro (53,54), although studies in humans
are lacking.
In conclusion, the regular consumption of a standard dose of the food supplement DMB containing
miraculin along with a systemic antineoplastic treatment can contribute to improving biomarkers
of inflammation and cachexia in malnourished patients with cancer and taste disorders.
DECLARATIONS
Data availability statement
The data used to support the findings of this study are available from the corresponding author
upon request.
Funding information
This study is funded by Medicinal Gardens S.L. through the Center for the Development of
Industrial Technology and Innovation (CDTI), “Cervera” Transfer R&D Projects. Ref. IDI-
20210622. (Ministry of Science, Innovation and Universities, Spain).
Conflict of interest statement
The authors declare no conflicts of interest.
Ethics approval and consent to participate
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprintthis version posted June 24, 2024. ; https://doi.org/10.1101/2024.06.23.24309349doi: medRxiv preprint
11
The study was conducted following the Declaration of Helsinki and approved by the Ethics
Committee of Hospital Universitario La Paz (protocol code 6164 and Jun 23rd, 2022 date of
approval).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Clinical Trial
NCT05486260
Acknowledgments
The authors would like to thank Medicinal Gardens S.L. (Baïa Food) for providing DMB®
orodispersible tablets (commercially known as TasteCare®) and for their support and technical
advice.
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TABLE 1: Bead panels for enzyme-linked immunosorbent assay, analytes, and variation
coefficients for cytokines and cachexia tumor factors analyzed
Bead Panels or Enzyme-Linked
Immunosorbent Assay
Analytes
Assay
CV
HSTCMAG-28SK-06
(EMD Millipore Corporation, Missouri,
U.S.A.)
TNFα
12.64
IL-6
19.31
IL-1β
7.86
IFN-g
7.14
IL-4
16.89
IL-10
8.87
HCYTA-60K
(EMD Millipore Corporation, Missouri,
U.S.A.)
IL-15
9.35
HSCRMAG-32K-03
(EMD Millipore Corporation, Missouri,
U.S.A.)
sIL-6R
8.83
sTNFR-I
3.76
sTNFR-II
5.65
CSB-E04527h
(Cusabio, Wuhan, China).
CNTF
5.97
CSB-E13626h
(Cusabio, Wuhan, China)
PIF
8.54
Abbreviations: CNTF, Ciliary Neurotrophic Factor; IFN, Interferon; IL, Interleukin; PIF, Proteolysis
Inducing Factor/Dermcidin; sIL-6R soluble IL-6 receptor; sTNFR, soluble TNF receptor; TNF,
Tumor necrosis factor.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprintthis version posted June 24, 2024. ; https://doi.org/10.1101/2024.06.23.24309349doi: medRxiv preprint
16
Baseline 3 months Baseline 3 months Baseline 3 months Time (T) Treatment (t)
T x t
IL-6 4.7 ± 3.6 3.9 ± 5.1 5.0 ± 2.5 3.3 ± 3.1 5.9 ± 8.8 4.3 ± 5.0 0.134 0.984
0.889
IL-1 β 6.8 ± 4.5 4.7 ± 2.0 4.3 ± 1.1 4.2 ± 2.9 4.5 ± 1.6 3.8 ± 0.9 0.093 0.824
0.501
TNF-α 18.8 ± 4.8 16.3 ± 9.9 14.2 ± 5.6 9.3 ± 2.8 14.1 ± 3.5 13.1 ± 4.9 0.297 0.214
0.652
INF-γ39.7± 23.8 30.2±15.6 20.0 ± 9.6 19.6 ± 9.1 18.1 ± 4.7 18.8 ± 10.6 0.226 0.523 0.209
IL-15 11.7 ± 4.0 24.9 ± 33.0 42.1 ± 43.8 17.8 ± 16.6 10.4 ± 8.5 9.4 ± 2.5 0.205 0.808 0.389
IL-4 46.3±31.4 27.3±12.0 38.2 ± 30.0 37.2 ± 44.0 71.1 ± 91.5 51.9 ± 66.8 0.04 0.503 0.374
IL-10 10.9 ± 57.1 28.1 ± 48.4 12.8 ± 62.5 15.9 ± 53.1 17.1 ± 7.2 14.3 ± 16.0 0.47 0.908
0.554
CNTF 358.8 ± 299.7 300.0 ± 269.0 332.9 ± 258.3 413.3 ± 417.3 339.9 ± 379.3 378.3 ± 299.6 0.268 0.827 0.503
sIL-6R 11.0 ± 6.3 10.2 ± 3.9 9.7 ± 3 9.3 ± 3.6 8.6± 3.7 8.2 ± 4.4 0.049 0.386
0.852
sTNFRI 1.3 ± 0.8 1.3± 0.8 1.2 ± 0.8 0.9 ± 0.6 0.9 ± 0.1 1.2 ± 0.5 0.06 0.377
0.648
sTNFRII 7.5 ± 4.8 4.6 ± 1.8 6.8 ± 3.5 4.8 ± 2.4 5.0 ± 2.0 5.8 ± 3.8 0.042 0.151
0.119
PIF 15.3 ± 7.7 11.7 ± 5.8 15.2 ± 5.2 10.6 ± 3.7 15.2 ± 5.3 10.2 ± 4.2 0.02 0.427
0.323
Variables
Standard-dose DMB
n=10
High-dose DMB
n=11
Placebo
n=10
P-value
Abbreviations: CNTF, Ciliary Neurotrophic Factor; IFN, Interferon; IL, Interleukin; PIF, Proteolysis Inducing Factor/Dermcidin; sIL-6R soluble IL-6 receptor;
sTNFR, soluble TNF receptor; TNF, Tumor necrosis factor
TABLE 2 Plasma levels of several biomarkers of inflammation and cachexia in malnourished cancer patients after three months of intervention with DMB
or placebo.
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LEGEND OF FIGURES
FIGURE 1. Mean change percentages of plasma levels for several biomarkers of inflammation
and cachexia in malnourished cancer patients after three months of intervention with DMB or
placebo. Abbreviations: CNTF, Ciliary Neurotrophic Factor; DBM, dried miracle berries; IFN,
Interferon; IL, Interleukin; PIF, Proteolysis Inducing Factor/Dermcidin; sIL-6R soluble IL-6
receptor; sTNFR-soluble TNF receptor, TNF-α, Tumor necrosis factor-α.
FIGURE 2. IL-6 to IL-10 ratio at the beginning of the study (baseline) and after three months of
intervention with DMB or placebo
FIGURE 3. Pearson correlation coefficients between plasma inflammatory variables and
nutritional status. (A) Standard dose of DMB; (B) High dose of DMB; (C) Placebo. Plots show
only significant and corrected associations. Red and purple lines indicate the correlation values,
with negative correlations highlighted in red (-1) and positive correlations highlighted in purple
(+1). IL, Interleukin; PCR, protein C reactive s; TNFR-soluble TNF receptor, TNF-α, Tumor
necrosis factor-α.
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... Participants were asked to return all packaging regardless of whether it was empty or partially consumed in order to assess compliance by comparing the number of tablets provided and returned. DMB was administered as an adjuvant medical-nutritional treatment [41,42,45]. ...
... Tumor necrosis factor-alpha (TNF-α) and human proteolysis-inducing factor/dermcidin (PIF) were determined and analyzed as previously described [41,42,45]. To avoid more punctures and hospital visits than necessary, blood samples were collected by trained personnel at the HULP Extraction Unit in the morning (approximately 8:00 am) during blood tests before chemotherapy. ...
... According to functional imaging studies, lingual electrical stimulation activates the same brain regions as chemical stimulation [52]. Patients who have cancer and taste distortion and who consume miraculinbased food supplements are expected to improve their taste perception by reducing their taste perception threshold (measured using decibel, dB) via electrical stimulation from baseline to one and three months after the intervention with DMB, as measured by electrical stimulation [41,45]. The threshold for an electric-induced taste stimulus was measured using an electrogustometer (SI-03 Model, Sensonics International, Haddon Heights, NJ, USA). ...
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Simple Summary Patients suffering from taste disorders have been unable to find treatments in the pharmaceutical industry. In this study, a novel strategy has been presented to reduce side effects in patients suffering from cancer by administering dried miracle berries (DMBs), which contain the taste-modifying glycoprotein miraculin, as an adjuvant to medical-nutritional therapy. During a three-month pilot randomized, parallel, triple-blind, and placebo-controlled clinical trial, malnourished patients with cancer and dysgeusia received either a standard dose of DMB, a high dose of DMB, or a placebo. We analyzed the oral microbiome of patients who consumed a DMB or placebo tablet before each main meal. Patients with cancer and dysgeusia who consumed DMB regularly displayed changes to their oral microbiome, which may have contributed to the maintenance of an appropriate immune response. Abstract 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.
... Plasma tumor necrosis factor-alpha (TNF-α) and human proteolysis-inducing factor (PIF) were analyzed as previously described [60]. The Biochemistry Laboratory at the Hospital La Paz, an ISO-certified laboratory, performed biochemical analyses using an Olympus AU5400 Automated Chemistry Analyzer (Olympus Corporation, Izasa, CA, USA) [49,51]. ...
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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.
... In this study, Shannon, Simpson and Chao1 indices were examined. Plasma tumor necrosis factor-alpha (TNF-α), and human proteolysis-inducing factor 515 (PIF) were analyzed as previously described [86]. For three days, including one holiday, daily food records were kept. ...
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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 re-ducing 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 adju-vant to medical-nutritional therapy. A pilot randomized, parallel, triple-blind, and place-bo-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 can-cer, we analyzed the intestinal microbiome via nanopore methodology. We detected differences in the relative abundances of genera Phocaeicola and Escherichia depending on the treatment. Nev-ertheless, 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 treat-ment 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 Pho-caeicola. After a high dose of DMB, erythrocyte polyunsaturated fatty acids were positively cor-related with Lachnoclostridium and Roseburia, and there was a positive association between Pho-caeicola 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 micro-biome of patients with cancer and dysgeusia There was a negative association between the rela-tive 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.
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