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. 2025 Sep 18;13(9):e70935. doi: 10.1002/fsn3.70935

Euglena gracilis Suppresses Cold Symptoms in Healthy Individuals: A Double‐Blind, Randomized, Placebo‐Controlled Trial

Ayaka Nakashima 1,✉, Kengo Suzuki 1, Masafumi Nagata 2, Tsuyoshi Takara 3
PMCID: PMC12445114  PMID: 40979570

ABSTRACT

The immune system functions to eliminate pathogens, such as viruses, and regulate physiological responses and pathways. General immunity is affected by various factors, including fatigue, stress, and aging. A weakened immune system reduces the ability of the body to eliminate pathogens, thereby increasing the risk of infections, including the common cold. Euglena gracilis is a microalga rich in various nutrients, including β‐1,3‐glucan paramylon, which aids in maintaining and regulating immune function. In the present study, we aimed to investigate the effects of E. gracilis administration on cold symptoms in healthy individuals. Euglena gracilis was administered orally in capsule form (once daily, in the morning) continuously for 8 weeks to healthy adult Japanese men and women. Evaluation of the effects of E. gracilis administration on alleviating cold symptoms revealed significantly fewer cumulative days with cold‐like symptoms over 8 weeks in the E. gracilis group than those in the placebo group. Participants in the E. gracilis group also demonstrated significantly fewer severe cold‐like symptoms, such as nasal congestion, sore throat, fatigue, and myalgia, than the placebo group in the second half of the trial (weeks 5–8). In conclusion, this study demonstrated that the continuous intake of E. gracilis could suppress cold‐like symptoms. Moreover, the consumption of the test food under the conditions used in this study was deemed safe.

Keywords: common cold, Euglena gracilis, immune system, microalgae, paramylon, virus

In this double‐blind, randomized, placebo‐controlled trial, 8 weeks of Euglena gracilis supplementation significantly reduced the cumulative number and severity of cold‐like symptoms in healthy Japanese adults. These effects are likely attributed to the immunomodulatory action of paramylon, a β‐glucan contained in E. gracilis .

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1. Introduction

Viruses trigger the symptoms associated with the common cold (common cold syndrome) by infecting the pharyngeal mucosa and replicating within the mucosal tissue. These symptoms, such as runny nose, sneezing, nasal congestion, and sore throat, are commonly observed in the general population, including individuals who are otherwise considered healthy. However, these symptoms can lead to significant economic and psychological consequences, as individuals may be required to miss work or school (Bramley et al. 2002).

Euglena gracilis is a unicellular microorganism classified as a microalga. E. gracilis , which exhibits both plant and animal properties, contains a myriad of nutrients, including vitamins, minerals, amino acids, and fatty acids. Since the introduction of large‐scale cultivation technology for E. gracilis in 2005 for dietary purposes, it has been widely used as a dietary and nutritional supplement (Suzuki 2017). Based on established production data, the nutritional composition of E. gracilis per gram includes moisture (≥ 33 mg, by heat drying), protein (≥ 256 mg, by combustion), lipid (≥ 93 mg, by diethyl ether extraction), ash (≥ 31 mg, by direct ashing), and carbohydrate (≥ 433 mg, calculated by difference).

Paramylon, an insoluble β‐glucan, typically accounts for approximately 70%–80% of the carbohydrate content (Shimada et al. 2016; Nakashima et al. 2017; Yasuda et al. 2020; Dai et al. 2022). A notable nutrient and the principal component of Euglena, β‐1,3‐glucan paramylon is a storage polysaccharide known for its effects in alleviating atopic dermatitis and providing hepatoprotection (Sugiyama et al. 2009, 2010). In a mouse model, the intake of paramylon powder alleviated the symptoms associated with influenza infections (Nakashima et al. 2017). In healthy individuals, the consumption of E. gracilis EOD‐1, which is rich in paramylon, for 4 weeks markedly increased the concentration and secretion rate of salivary secretory IgA (sIgA) (Ishibashi et al. 2019). These data indicate that paramylon plays a key role in immune function.

Dectin‐1 is the main receptor for β‐glucans and is expressed on intestinal immune cells, including dendritic cells (DCs) and macrophages. Upon recognition by Dectin‐1, paramylon is internalized by cells, activating the tyrosine kinase SYK and the transcription factor NF‐κB, thereby promoting cytokine secretion (Nakashima et al. 2018; Ujita et al. 2009). Paramylon may also act directly on DCs, which are antigen‐presenting cells, in the intestine (Yasuda et al. 2020). These findings suggest that paramylon exerts its immunological effects through Dectin‐1.

The autonomic nervous system and immune functions are closely interconnected. Specifically, immune function is enhanced under parasympathetic dominance, aiding in defense against infections (Piccirillo et al. 2004). However, factors such as fatigue, stress, and lack of sleep can disrupt this balance, diminishing immune function. Furthermore, consumption of 1000 mg of E. gracilis has been shown to regulate autonomic balance, reduce irritability and tension, and enhance sleep quality (Nakashima et al. 2020), indirectly supporting immune function maintenance. Several studies have indicated the potential of E. gracilis containing paramylon to alleviate cold symptoms (Evans et al. 2019; Kawano et al. 2023); however, large‐scale investigations involving Japanese populations have yet to be conducted.

We hypothesized that Euglena intake suppresses cold symptoms by modulating the immune balance. Therefore, in the present study, we aimed to investigate the effects of E. gracilis consumption on cold symptoms in a population of healthy Japanese men and women.

2. Materials and Methods

2.1. Materials

Euglena gracilis powder was obtained from Euglena Co. Ltd. (Tokyo, Japan). The Euglena used in this study was derived from the Euglena gracilis Z strain. The placebo capsules contained the same combination of agents without E. gracilis powder.

2.2. Intake Study

2.2.1. Target Demographics

The study involved 213 healthy Japanese adults, including 68 men and 145 women, aged between 21 and 82 years. After the participants received a sufficient explanation of the objective and content of the study, both verbally and in writing, they provided written informed consent to participate. The present study was conducted in accordance with the tenets of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. The rights of the participants were upheld throughout the study. The study was approved by the Institutional Review Board of Takara Clinic (approval no. 2112‐00395: 2112‐00395‐0022‐1C‐TC, approval date: 12/24/2021). This trial is registered at UMIN ID: 000046464.

2.2.2. Trial Methods

This study was designed as a double‐blind, randomized, placebo‐controlled trial. The participants were selected through screening based on the severity of their typical cold symptoms and fatigue levels.

An independent staff member not involved in the trial randomly assigned the participants to two groups using a computer‐generated random number table. The assignment was conducted considering age, sex, typical cold symptoms, specific IgE levels for cedar and cypress pollen, and fatigue levels to minimize variability between the groups. Blinding was applied to all individuals involved in the trial, including participants, intervention implementers, and evaluators. The allocation table remained blinded until the analysis population was finalized. Access to the allocation table was restricted to the principal investigator, and no other organizations or individuals were able to view it until the allocation manager provided it after the completion of the trial.

Participants were advised against consuming alcohol and exercising excessively from the day before testing until the end of the testing. Additionally, they were instructed to abstain from food and drinks, including the test food, for 6 h before blood collection. However, water intake was permitted. Baseline measurements were recorded during clinic visits prior to intake testing (0 week), which included visual analog scale (VAS) administration, blood collection, and physical measurements such as height, body weight, and body mass index. Cold symptoms during the 5 days before pre‐intake testing were recorded with dietary recall. Following these baseline measurements (0 week), the participants consumed capsules containing 1000 mg of E. gracilis powder or placebo powder (starch) once daily for 8 weeks and recorded their cold symptoms in a diary. Participants typically took the capsules in the morning; if they forgot, they took them later in the day. After 8 weeks of intake, the participants returned to the clinic for the same measurements conducted at baseline. Participants were enrolled in the study between January 31 and May 1, 2022, and completed the study between March 28 and June 26, 2022, at a clinic in Tokyo, Japan.

2.2.3. Survey of Cold Symptoms

During the trial period, participants rated general malaise, chills, feverishness, fatigue, sneezing, runny nose, nasal congestion, sore throat, coughing, arthralgia, myalgia, and headache daily in a diary on the following five‐point scale: (1) Normal; (2) Slight; (3) Mild; (4) Moderate; and (5) Severe. The diaries were mailed weekly by post. The final diary was submitted directly to the clinic during final testing. Responses of 3–5 were assessed as the presence of symptoms. “Cold symptoms” were defined as the presence of one or more of the following symptoms: general malaise, chills, fever, fatigue, sneezing, runny nose, nasal congestion, sore throat, coughing, arthralgia, or myalgia. Cumulative days with cold symptoms, the most consecutive days, and symptom severity were also recorded. These figures were calculated from the first day of intake to the end of week 8; the first day to the end of week 4 (Days 1–28) was defined as the first half, whereas the beginning of week 5 to the end of week 8 (Days 29–56) was defined as the second half.

2.2.4. VAS

As immune function is associated with the autonomic nervous system and stress, related parameters that may reflect these factors were further evaluated as supplementary measures. A 100 mm VAS was used to quantify the following on Day 0 (baseline) and Day 56: physical fatigue, mental fatigue, stress, mood, energy, anxiety, tension, depression, relaxedness, irritability, satisfaction with sleep, wake‐up quality, falling asleep, satisfaction with defecation, and refreshment upon defecation. Each VAS question had “0” as an endpoint representing affirmative status and “100” as an endpoint representing negative status. Participants were instructed to mark a point on the line representing their current mood. Responses to the VAS questions were measured as the distance (mm) from the zero endpoint.

2.3. Statistical Analysis

The primary outcome was the cumulative days with cold symptoms throughout the trial period; all other outcomes were considered secondary outcomes. Cumulative days, the highest number of consecutive days, and symptom severity are presented as means and standard deviations (SD) and were compared between groups using Welch's t‐test. The proportions of individuals with and without symptoms and responses to each question throughout the trial period and during the first and second halves of the trial period were compared between the groups using the chi‐square test, given that these data were categorical. All statistical analyses were performed using two‐sided tests, with the level of statistical significance defined as p < 0.05. SPSS Statistics version 23 (SPSS Inc., San Diego, CA, USA) was used for statistical analysis. Given that this trial focused on analyzing the primary outcome, the multiplicity of secondary outcomes was not considered.

The VAS was compared between groups using analysis of covariance (ANCOVA), with Δ defined as the difference between groups in estimated marginal means, the baseline as a covariate, and the group as a factor. Within‐group comparisons were performed using paired t‐tests.

3. Results

3.1. Participants

Of the 356 individuals who consented to participate in the trial, 220 met the eligibility criteria and were included in the study (Figure 1) and were assigned to the Euglena or placebo groups, with 110 participants in each group. Although all participants received the intervention, seven (three in the placebo group and four in the Euglena group) dropped out during the trial. Therefore, data were analyzed for 213 participants (placebo: 107, Euglena: 106).

FIGURE 1.

FIGURE 1

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Participant flowchart.

Baseline parameters did not differ significantly between the placebo and Euglena groups (Table 1; Tables S1 and S2). Additionally, no differences were observed between the groups in specific IgE class levels for cedar or cypress pollen or cold symptoms 5 days before pre‐intake testing (Table S3).

TABLE 1.

Baseline data of the participants.

Item Unit Placebo group Euglena group
Sex — n 107 106
Male 35 (32.7%) 33 (31.1%)
Female 72 (67.3%) 73 (68.9%)
p value (vs. placebo) a — 0.883
Age Years n 107 106
Mean (SD) 46.5 (12.1) 46.3 (11.8)
Med 48.0 46.0
Min–Max 21–82 21–80
p value (vs. placebo) b — 0.901
Height cm n 107 106
Mean (SD) 163.6 (8.2) 162.3 (8.4)
Med 163.00 162.00
Min–Max 147.0–184.0 142.5–181.0
p (vs. placebo) b — 0.247
Body weight kg n 107 106
Mean (SD) 60.3 (12.1) 58.4 (12.5)
Med 59.10 54.50
Min–Max 40.6–107.4 30.5–90.9
p value (vs. placebo) b — 0.265
BMI kg/m2 n 107 106
Mean (SD) 22.4 (3.4) 22.0 (3.7)
Med 21.60 21.10
Min–Max 16.3–35.1 13.0–37.9
p value (vs. placebo) b — 0.471
Systolic blood pressure mmHg n 107 106
Mean (SD) 116.6 (13.4) 115.8 (12.3)
Med 114.00 116.00
Min–Max 93–148 88–148
p value (vs. placebo) b — 0.653
Diastolic blood pressure mmHg n 107 106
Mean (SD) 75.8 (11.0) 75.5 (9.7)
Med 75.0 74.0
Min–Max 52–105 54–96
p value (vs. placebo) b — 0.831
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Abbreviations: BMI, body mass index; Max, maximum; Med, median; Min, minimum; SD, standard deviation.

a

Between‐group comparison with chi‐square test.

b

Between‐group comparison with Welch's t‐test; n, number of participants.

3.2. Safety Assessment

No adverse drug reactions were reported during the trial period. Although some participants experienced adverse events, these were determined to be unrelated to the test capsules in all groups (Table S4). The two groups did not exhibit significant differences in the proportion of participants whose urine and peripheral blood test values were within the normal range during screening or baseline testing and subsequently deviated from the normal range after the intervention (Table S5). The investigator verified the safety assessment criteria for each participant, confirming that no medically concerning changes were associated with the test capsules.

3.3. Efficacy Assessment

3.3.1. Measurement of Cold Symptoms

The number of cumulative days with cold symptoms throughout the trial (primary outcome) was 21.3 ± 19.2 days in the placebo group compared to 15.9 ± 17.5 days in the Euglena group (p = 0.032; Table 2). Similarly, as a secondary outcome, the cumulative number of days with cold symptoms in the second half (weeks 5–8) was significantly lower in the Euglena group than that in the placebo group (placebo: 11.0 ± 10.4 days, Euglena: 7.7 ± 9.3 days, p = 0.015). Regarding the cumulative number of days for each cold symptom, the number of days where fatigue was experienced during the second half of the trial was significantly reduced in the Euglena group compared to that in the placebo group (6.8 ± 8.8 days vs. 4.5 ± 7.5 days, p = 0.042). In terms of symptom severity, the Euglena group showed significantly lower severity of feverishness over the entire trial period (1.1 ± 0.3 vs. 1.0 ± 0.2, p = 0.040; Table 3), as well as fatigue (1.8 ± 0.9 vs. 1.5 ± 0.7, p = 0.007), nasal congestion (1.3 ± 0.6 vs. 1.1 ± 0.4, p = 0.029), sore throat (1.2 ± 0.5 vs. 1.1 ± 0.3, p = 0.023), and myalgia (1.2 ± 0.5 vs. 1.1 ± 0.4, p = 0.036), in the second half than the placebo group.

TABLE 2.

Cumulative days of cold symptoms overall and for individual symptoms.

Item Period Unit Placebo group Euglena group Between‐group comparisons
n Mean SD Med Min Max n Mean SD Med Min Max Δ SE 95% CI− 95% CI+ p
Cumulative days with cold symptoms Overall a Days 107 21.3 19.2 18.0 0.0 56.0 106 15.9 17.5 8.0 0.0 56.0 −5.4 2.5 −10.4 −0.5 0.032*
1st half Days 107 10.3 9.9 7.0 0.0 28.0 106 8.2 9.3 4.0 0.0 28.0 −2.1 1.3 −4.7 0.5 0.110
2nd half Days 107 11.0 10.4 8.0 0.0 28.0 106 7.7 9.3 3.0 0.0 28.0 −3.3 1.4 −6.0 −0.7 0.015*
Cumulative days with general malaise Overall Days 107 6.0 10.3 1.0 0.0 54.0 106 5.6 11.6 0.0 0.0 56.0 −0.4 1.5 −3.4 2.6 0.783
1st half Days 107 2.8 4.8 0.0 0.0 26.0 106 3.2 6.4 0.0 0.0 28.0 0.4 0.8 −1.2 1.9 0.630
2nd half Days 107 3.2 6.0 0.0 0.0 28.0 106 2.4 5.8 0.0 0.0 28.0 −0.8 0.8 −2.4 0.8 0.332
Cumulative days with chills Overall Days 107 1.1 3.6 0.0 0.0 30.0 106 1.0 2.7 0.0 0.0 20.0 −0.2 0.4 −1.0 0.7 0.683
1st half Days 107 0.7 2.7 0.0 0.0 26.0 106 0.7 2.4 0.0 0.0 20.0 0.1 0.4 −0.6 0.7 0.879
2nd half Days 107 0.5 1.3 0.0 0.0 7.0 106 0.3 0.8 0.0 0.0 6.0 −0.2 0.2 −0.5 0.1 0.130
Cumulative days with feverishness Overall Days 107 0.9 2.2 0.0 0.0 16.0 106 0.9 3.0 0.0 0.0 28.0 0.0 0.4 −0.7 0.7 0.997
1st half Days 107 0.3 0.9 0.0 0.0 4.0 106 0.5 2.0 0.0 0.0 18.0 0.2 0.2 −0.3 0.6 0.440
2nd half Days 107 0.5 1.6 0.0 0.0 12.0 106 0.4 1.3 0.0 0.0 10.0 −0.2 0.2 −0.6 0.2 0.401
Cumulative days with fatigue Overall Days 107 12.8 15.9 6.0 0.0 55.0 106 9.8 14.7 3.0 0.0 56.0 −3.0 2.1 −7.1 1.1 0.153
1st half Days 107 6.0 7.8 2.0 0.0 27.0 106 5.3 7.7 2.0 0.0 28.0 −0.7 1.1 −2.8 1.4 0.497
2nd half Days 107 6.8 8.8 2.0 0.0 28.0 106 4.5 7.5 1.0 0.0 28.0 −2.3 1.1 −4.5 −0.1 0.042*
Cumulative days with sneezing Overall Days 107 4.3 9.0 0.0 0.0 43.0 106 3.5 8.8 0.0 0.0 52.0 −0.8 1.2 −3.2 1.6 0.494
1st half Days 107 1.9 4.8 0.0 0.0 23.0 106 1.4 4.1 0.0 0.0 25.0 −0.5 0.6 −1.7 0.8 0.461
2nd half Days 107 2.4 5.4 0.0 0.0 24.0 106 2.0 5.7 0.0 0.0 27.0 −0.4 0.8 −1.9 1.1 0.614
Cumulative days with a runny nose Overall Days 107 6.5 12.5 0.0 0.0 55.0 106 5.0 11.6 0.0 0.0 56.0 −1.5 1.7 −4.7 1.8 0.370
1st half Days 107 2.9 6.4 0.0 0.0 27.0 106 2.4 6.0 0.0 0.0 28.0 −0.5 0.9 −2.2 1.2 0.564
2nd half Days 107 3.6 7.4 0.0 0.0 28.0 106 2.7 6.5 0.0 0.0 28.0 −1.0 1.0 −2.9 0.9 0.300
Cumulative days with nasal congestion Overall Days 107 3.0 7.9 0.0 0.0 40.0 106 1.8 6.4 0.0 0.0 49.0 −1.1 1.0 −3.1 0.8 0.259
1st half Days 107 1.2 3.4 0.0 0.0 18.0 106 1.0 3.4 0.0 0.0 25.0 −0.2 0.5 −1.1 0.7 0.659
2nd half Days 107 1.8 5.1 0.0 0.0 27.0 106 0.9 3.8 0.0 0.0 26.0 −0.9 0.6 −2.1 0.3 0.144
Cumulative days with sore throat Overall Days 107 2.3 7.2 0.0 0.0 56.0 106 1.9 6.3 0.0 0.0 48.0 −0.5 0.9 −2.3 1.3 0.607
1st half Days 107 1.2 4.1 0.0 0.0 28.0 106 1.2 4.1 0.0 0.0 24.0 0.0 0.6 −1.1 1.1 0.957
2nd half Days 107 1.1 3.6 0.0 0.0 28.0 106 0.6 2.6 0.0 0.0 24.0 −0.5 0.4 −1.4 0.4 0.245
Cumulative days with coughing Overall Days 107 2.5 8.4 0.0 0.0 56.0 106 1.4 4.4 0.0 0.0 34.0 −1.1 0.9 −2.9 0.7 0.226
1st half Days 107 1.2 4.4 0.0 0.0 28.0 106 0.7 2.2 0.0 0.0 13.0 −0.5 0.5 −1.4 0.4 0.299
2nd half Days 107 1.3 4.3 0.0 0.0 28.0 106 0.7 2.6 0.0 0.0 21.0 −0.6 0.5 −1.6 0.3 0.202
Cumulative days with arthralgia Overall Days 107 1.9 5.0 0.0 0.0 36.0 106 2.0 7.6 0.0 0.0 55.0 0.0 0.9 −1.7 1.8 0.992
1st half Days 107 1.0 3.5 0.0 0.0 24.0 106 1.0 4.1 0.0 0.0 28.0 0.0 0.5 −1.0 1.1 0.943
2nd half Days 107 0.9 2.4 0.0 0.0 14.0 106 0.9 3.6 0.0 0.0 27.0 0.0 0.4 −0.9 0.8 0.945
Cumulative days with myalgia Overall Days 107 2.9 7.4 0.0 0.0 51.0 106 1.8 6.0 0.0 0.0 41.0 −1.1 0.9 −2.9 0.7 0.235
1st half Days 107 1.3 3.7 0.0 0.0 23.0 106 1.1 3.3 0.0 0.0 21.0 −0.2 0.5 −1.2 0.7 0.616
2nd half Days 107 1.6 4.1 0.0 0.0 28.0 106 0.7 2.9 0.0 0.0 20.0 −0.9 0.5 −1.8 0.1 0.079
Cumulative days with a headache Overall Days 107 3.1 5.8 0.0 0.0 37.0 106 2.7 6.8 0.0 0.0 54.0 −0.4 0.9 −2.1 1.3 0.656
1st half Days 107 1.5 3.4 0.0 0.0 20.0 106 1.4 3.4 0.0 0.0 26.0 −0.1 0.5 −1.0 0.8 0.862
2nd half Days 107 1.6 3.2 0.0 0.0 17.0 106 1.3 3.8 0.0 0.0 28.0 −0.3 0.5 −1.3 0.6 0.527
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Note: Between‐group comparisons were conducted with Welch's t‐test. *p < 0.05; **p < 0.01.

Abbreviations: Δ, difference between groups (Euglena group vs. placebo group); 95% CI−, lower bound of 95% confidence interval; 95% CI+, upper bound of 95% confidence interval; Max, maximum; Med, median; Min, minimum; n, number of participants; SD, standard deviation; SE, standard error of the difference between groups.

a

Primary outcome.

TABLE 3.

Severity of cold symptoms overall and for individual symptoms.

Item Period Unit Placebo group Euglena group Between‐group comparisons
n Mean SD Med Min Max n Mean SD Med Min Max Δ SE 95% CI− 95% CI+ p
Severity of general malaise Overall — 107 1.4 0.6 1.0 1.0 4.0 106 1.4 0.6 1.0 1.0 3.0 0.0 0.1 −0.2 0.2 0.821
1st half — 107 1.4 0.6 1.0 1.0 4.0 106 1.4 0.7 1.0 1.0 4.0 0.0 0.1 −0.2 0.2 0.800
2nd half — 107 1.4 0.7 1.0 1.0 4.5 106 1.3 0.6 1.0 1.0 3.0 −0.1 0.1 −0.2 0.1 0.409
Severity of chills Overall — 107 1.1 0.4 1.0 1.0 3.0 106 1.1 0.3 1.0 1.0 2.0 −0.1 0.0 −0.1 0.0 0.173
1st half — 107 1.2 0.4 1.0 1.0 3.0 106 1.1 0.4 1.0 1.0 3.0 0.0 0.1 −0.1 0.1 0.672
2nd half — 107 1.1 0.3 1.0 1.0 2.0 106 1.1 0.2 1.0 1.0 2.0 −0.1 0.0 −0.1 0.0 0.166
Severity of feverishness Overall — 107 1.1 0.3 1.0 1.0 2.0 106 1.0 0.2 1.0 1.0 2.5 −0.1 0.0 −0.2 0.0 0.040*
1st half — 107 1.1 0.3 1.0 1.0 2.0 106 1.1 0.3 1.0 1.0 3.0 −0.1 0.0 −0.1 0.0 0.189
2nd half — 107 1.1 0.3 1.0 1.0 2.0 106 1.0 0.2 1.0 1.0 2.0 −0.1 0.0 −0.1 0.0 0.081
Severity of fatigue Overall — 107 1.7 0.9 2.0 1.0 4.0 106 1.5 0.8 1.0 1.0 4.0 −0.2 0.1 −0.4 0.0 0.095
1st half — 107 1.7 0.8 1.5 1.0 4.0 106 1.6 0.8 1.0 1.0 4.0 −0.1 0.1 −0.3 0.1 0.303
2nd half — 107 1.8 0.9 2.0 1.0 5.0 106 1.5 0.7 1.0 1.0 4.0 −0.3 0.1 −0.5 −0.1 0.007**
Severity of sneezing Overall — 107 1.3 0.5 1.0 1.0 3.0 106 1.2 0.5 1.0 1.0 3.0 −0.1 0.1 −0.2 0.1 0.386
1st half — 107 1.3 0.6 1.0 1.0 3.5 106 1.2 0.5 1.0 1.0 3.5 0.0 0.1 −0.2 0.1 0.504
2nd half — 107 1.3 0.6 1.0 1.0 3.5 106 1.3 0.6 1.0 1.0 3.5 0.0 0.1 −0.2 0.1 0.585
Severity of runny nose Overall — 107 1.4 0.7 1.0 1.0 4.0 106 1.3 0.6 1.0 1.0 5.0 −0.1 0.1 −0.3 0.1 0.202
1st half — 107 1.4 0.7 1.0 1.0 4.0 106 1.3 0.7 1.0 1.0 4.0 −0.1 0.1 −0.3 0.1 0.444
2nd half — 107 1.4 0.7 1.0 1.0 4.0 106 1.3 0.7 1.0 1.0 5.0 −0.1 0.1 −0.3 0.0 0.131
Severity of nasal congestion Overall — 107 1.2 0.5 1.0 1.0 3.0 106 1.1 0.4 1.0 1.0 3.0 −0.1 0.1 −0.2 0.0 0.098
1st half — 107 1.2 0.5 1.0 1.0 4.0 106 1.2 0.4 1.0 1.0 3.0 −0.1 0.1 −0.2 0.1 0.386
2nd half — 107 1.3 0.6 1.0 1.0 3.0 106 1.1 0.4 1.0 1.0 4.0 −0.1 0.1 −0.3 0.0 0.029*
Severity of sore throat Overall — 107 1.2 0.4 1.0 1.0 3.0 106 1.1 0.4 1.0 1.0 3.0 −0.1 0.1 −0.2 0.0 0.157
1st half — 107 1.2 0.5 1.0 1.0 4.0 106 1.2 0.4 1.0 1.0 3.0 0.0 0.1 −0.2 0.1 0.618
2nd half — 107 1.2 0.5 1.0 1.0 4.0 106 1.1 0.3 1.0 1.0 3.0 −0.1 0.1 −0.2 0.0 0.023*
Severity of coughing Overall — 107 1.2 0.5 1.0 1.0 4.0 106 1.1 0.3 1.0 1.0 3.0 −0.1 0.1 −0.2 0.0 0.075
1st half — 107 1.2 0.5 1.0 1.0 4.0 106 1.1 0.3 1.0 1.0 2.0 −0.1 0.1 −0.2 0.0 0.152
2nd half — 107 1.2 0.5 1.0 1.0 4.0 106 1.1 0.3 1.0 1.0 3.0 −0.1 0.1 −0.2 0.0 0.059
Severity of arthralgia Overall — 107 1.2 0.4 1.0 1.0 3.0 106 1.1 0.4 1.0 1.0 4.0 −0.1 0.1 −0.2 0.1 0.359
1st half — 107 1.2 0.4 1.0 1.0 3.0 106 1.2 0.5 1.0 1.0 4.0 0.0 0.1 −0.2 0.1 0.508
2nd half — 107 1.2 0.4 1.0 1.0 2.5 106 1.1 0.4 1.0 1.0 4.0 −0.1 0.1 −0.2 0.0 0.073
Severity of myalgia Overall — 107 1.2 0.5 1.0 1.0 4.0 106 1.1 0.4 1.0 1.0 3.0 −0.1 0.1 −0.2 0.0 0.070
1st half — 107 1.2 0.5 1.0 1.0 3.0 106 1.1 0.4 1.0 1.0 3.0 −0.1 0.1 −0.2 0.1 0.284
2nd half — 107 1.2 0.5 1.0 1.0 4.0 106 1.1 0.4 1.0 1.0 3.0 −0.1 0.1 −0.3 0.0 0.036*
Severity of headache Overall — 107 1.2 0.4 1.0 1.0 3.0 106 1.1 0.4 1.0 1.0 3.0 −0.1 0.1 −0.2 0.1 0.362
1st half — 107 1.2 0.4 1.0 1.0 3.0 106 1.2 0.4 1.0 1.0 3.0 0.0 0.1 −0.1 0.1 0.696
2nd half — 107 1.2 0.5 1.0 1.0 3.0 106 1.1 0.4 1.0 1.0 3.0 −0.1 0.1 −0.2 0.0 0.161
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Note: *p < 0.05; **p < 0.01.

Abbreviations: Δ, difference between groups (Euglena group versus placebo group); 95% CI−, lower bound of 95% confidence interval; 95% CI+, upper bound of 95% confidence interval; Max, maximum; Med, median; Min, minimum; n, number of participants; SD, standard deviation SE, standard error of the difference between groups.

The significant difference observed in the severity of many individual symptoms in the second half of the trial period suggests that E. gracilis may be effective when administered continuously for at least 4 weeks. However, the most consecutive days did not differ significantly between the groups for any symptom (Table S6).

The proportion of days with cold symptoms was significantly lower in the Euglena group than that in the placebo group throughout the study period (38.0% vs. 28.3%, p < 0.001) and in the first (36.9% vs. 29.3%, p < 0.001) and second (39.2% vs. 27.3%, p < 0.001) halves of the trial (Table 4). Additionally, for individual symptoms such as general malaise, chills, fatigue, sneezing, runny nose, nasal congestion, sore throat, coughing, and muscle pain, the Euglena group exhibited a significantly lower proportion of symptomatic days than the placebo group. Additionally, a greater number of significant differences were observed in the later phase than that in the earlier one, suggesting the effectiveness of continuous intake for at least 4 weeks.

TABLE 4.

Proportions of cumulative days with cold and individual symptoms.

Item Period Placebo group Euglena group Between‐group comparisons
Total participant days Applicable days Percentage of applicable days (%) Total participant days Applicable days Percentage of applicable days (%) Δ (%) 95% CI− 95% CI+ χ2 p
Cumulative days with cold symptoms Overall 5992 2279 38.0 5936 1682 28.3 −9.7 −11.4 −8.0 126.456 0.000***
1st half 2996 1105 36.9 2968 871 29.3 −7.5 −9.9 −5.1 38.221 0.000***
2nd half 2996 1174 39.2 2968 811 27.3 −11.9 −14.3 −9.5 94.457 0.000***
Cumulative days with general malaise Overall 5992 639 10.7 5936 589 9.9 −0.7 −1.8 0.3 1.776 0.185
1st half 2996 299 10.0 2968 336 11.3 1.3 −0.2 2.9 2.817 0.102
2nd half 2996 340 11.3 2968 253 8.5 −2.8 −4.3 −1.3 13.281 0.000***
Cumulative days with chills Overall 5992 122 2.0 5936 102 1.7 −0.3 −0.8 0.2 1.634 0.225
1st half 2996 70 2.3 2968 75 2.5 0.2 −0.6 1.0 0.228 0.674
2nd half 2996 52 1.7 2968 27 0.9 −0.8 −1.4 −0.2 7.782 0.006**
Cumulative days with feverishness Overall 5992 93 1.6 5936 92 1.5 0.0 −0.4 0.4 0.000 1.000
1st half 2996 37 1.2 2968 54 1.8 0.6 0.0 1.2 3.389 0.072
2nd half 2996 56 1.9 2968 38 1.3 −0.6 −1.2 0.0 3.332 0.077
Cumulative days with fatigue Overall 5992 1368 22.8 5936 1036 17.5 −5.4 −6.8 −3.9 53.587 0.000***
1st half 2996 645 21.5 2968 562 18.9 −2.6 −4.6 −0.6 6.212 0.013*
2nd half 2996 723 24.1 2968 474 16.0 −8.2 −10.2 −6.1 61.913 0.000***
Cumulative days with sneezing Overall 5992 460 7.7 5936 367 6.2 −1.5 −2.4 −0.6 10.319 0.001**
1st half 2996 203 6.8 2968 153 5.2 −1.6 −2.8 −0.4 6.977 0.009**
2nd half 2996 257 8.6 2968 214 7.2 −1.4 −2.7 0.0 3.835 0.055
Cumulative days with a runny nose Overall 5992 699 11.7 5936 535 9.0 −2.7 −3.7 −1.6 22.624 0.000***
1st half 2996 309 10.3 2968 254 8.6 −1.8 −3.2 −0.3 5.377 0.021*
2nd half 2996 390 13.0 2968 281 9.5 −3.5 −5.2 −1.9 18.815 0.000***
Cumulative days with nasal congestion Overall 5992 317 5.3 5936 196 3.3 −2.0 −2.7 −1.3 28.648 0.000***
1st half 2996 125 4.2 2968 102 3.4 −0.7 −1.7 0.2 2.203 0.155
2nd half 2996 192 6.4 2968 94 3.2 −3.2 −4.3 −2.2 34.313 0.000***
Cumulative days with sore throat Overall 5992 250 4.2 5936 197 3.3 −0.9 −1.5 −0.2 6.022 0.016*
1st half 2996 130 4.3 2968 132 4.4 0.1 −0.9 1.1 0.042 0.850
2nd half 2996 120 4.0 2968 65 2.2 −1.8 −2.7 −0.9 16.346 0.000***
Cumulative days with coughing Overall 5992 268 4.5 5936 147 2.5 −2.0 −2.7 −1.3 35.384 0.000***
1st half 2996 131 4.4 2968 77 2.6 −1.8 −2.7 −0.8 14.006 0.000***
2nd half 2996 137 4.6 2968 70 2.4 −2.2 −3.1 −1.3 21.819 0.000***
Cumulative days with arthralgia Overall 5992 208 3.5 5936 207 3.5 0.0 −0.6 0.7 0.002 1.000
1st half 2996 107 3.6 2968 110 3.7 0.1 −0.8 1.1 0.077 0.783
2nd half 2996 101 3.4 2968 97 3.3 −0.1 −1.0 0.8 0.049 0.829
Cumulative days with myalgia Overall 5992 313 5.2 5936 193 3.3 −2.0 −2.7 −1.2 28.555 0.000***
1st half 2996 141 4.7 2968 114 3.8 −0.9 −1.9 0.2 2.728 0.109
2nd half 2996 172 5.7 2968 79 2.7 −3.1 −4.1 −2.1 35.067 0.000***
Cumulative days with a headache Overall 5992 327 5.5 5936 283 4.8 −0.7 −1.5 0.1 2.924 0.088
1st half 2996 156 5.2 2968 146 4.9 −0.3 −1.4 0.8 0.257 0.637
2nd half 2996 171 5.7 2968 137 4.6 −1.1 −2.2 0.0 3.628 0.061
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Note: Between‐group comparisons were conducted using the chi‐square test. *p < 0.05, **p < 0.01, ***p < 0.001.

Abbreviations: Δ, difference in proportion of applicable days (Euglena group versus placebo group); 95% CI−, lower bound of 95% confidence interval; 95% CI+, upper bound of 95% confidence interval.

Regarding the severity of individual symptoms, the proportion of participants who responded “(1) Normal” to general malaise, chills, feverishness, fatigue, sneezing, runny nose, nasal congestion, sore throat, coughing, arthralgia, myalgia, and headache was significantly higher in the Euglena group than that in the placebo group (Table 5; Table S7). Additionally, for general malaise, fatigue, sneezing, nasal congestion, and sore throat, the proportion of participants who responded “(5) Severe” was significantly lower in the Euglena group than that in the placebo group.

TABLE 5.

Proportions of responses regarding symptom severity.

Item Period Placebo group Euglena group Between‐group comparisons
Total participant days Applicable days Percentage of applicable days (%) Total participant days Applicable days Percentage of applicable days (%) Δ (%) 95% CI− 95% CI+ χ2 p
Percentage of severity 1 general malaise Overall 5992 3943 65.8 5936 4005 67.5 1.7 0.0 3.4 3.719 0.055
1st half 2996 1953 65.2 2968 1956 65.9 0.7 −1.7 3.1 0.338 0.567
2nd half 2996 1990 66.4 2968 2049 69.0 2.6 0.2 5.0 4.662 0.033*
Percentage of severity 5 general malaise Overall 5992 43 0.7 5936 18 0.3 −0.4 −0.7 −0.2 10.064 0.002**
1st half 2996 10 0.3 2968 7 0.2 −0.1 −0.4 0.2 0.503 0.629
2nd half 2996 33 1.1 2968 11 0.4 −0.7 −1.2 −0.3 10.875 0.001**
Percentage of severity 1 chills Overall 5992 5120 85.4 5936 5292 89.2 3.7 2.5 4.9 36.869 0.000***
1st half 2996 2523 84.2 2968 2573 86.7 2.5 0.7 4.3 7.369 0.007**
2nd half 2996 2597 86.7 2968 2719 91.6 4.9 3.3 6.5 37.391 0.000***
Percentage of severity 5 chills Overall 5992 0 0.0 5936 2 0.0 0.0 0.0 0.1 2.019 0.248
1st half 2996 0 0.0 2968 2 0.1 0.1 0.0 0.2 2.020 0.248
2nd half 2996 0 0.0 2968 0 0.0 0.0 N.A. N.A. N.A. N.A.
Percentage of severity 1 feverishness Overall 5992 5194 86.7 5936 5508 92.8 6.1 5.0 7.2 120.617 0.000***
1st half 2996 2587 86.3 2968 2734 92.1 5.8 4.2 7.3 51.559 0.000***
2nd half 2996 2607 87.0 2968 2774 93.5 6.4 4.9 8.0 70.276 0.000***
Percentage of severity 5 feverishness Overall 5992 2 0.0 5936 9 0.2 0.1 0.0 0.2 4.525 0.038*
1st half 2996 0 0.0 2968 6 0.2 0.2 0.0 0.4 6.063 0.015*
2nd half 2996 2 0.1 2968 3 0.1 0.0 −0.1 0.2 0.210 0.686
Percentage of severity 1 fatigue Overall 5992 2775 46.3 5936 3401 57.3 11.0 9.2 12.8 144.055 0.000***
1st half 2996 1408 47.0 2968 1621 54.6 7.6 5.1 10.2 34.637 0.000***
2nd half 2996 1367 45.6 2968 1780 60.0 14.3 11.8 16.9 123.110 0.000***
Percentage of severity 5 fatigue Overall 5992 80 1.3 5936 40 0.7 −0.7 −1.0 −0.3 13.092 0.000***
1st half 2996 26 0.9 2968 27 0.9 0.0 −0.4 0.5 0.030 0.891
2nd half 2996 54 1.8 2968 13 0.4 −1.4 −1.9 −0.8 24.987 0.000***
Percentage of severity 1 sneezing Overall 5992 4475 74.7 5936 4713 79.4 4.7 3.2 6.2 37.449 0.000***
1st half 2996 2264 75.6 2968 2379 80.2 4.6 2.5 6.7 18.197 0.000***
2nd half 2996 2211 73.8 2968 2334 78.6 4.8 2.7 7.0 19.266 0.000***
Percentage of severity 5 sneezing Overall 5992 28 0.5 5936 16 0.3 −0.2 −0.4 0.0 3.173 0.096
1st half 2996 10 0.3 2968 15 0.5 0.2 −0.2 0.5 1.052 0.324
2nd half 2996 18 0.6 2968 1 0.0 −0.6 −0.9 −0.3 15.100 0.000***
Percentage of severity 1 runny nose Overall 5992 4148 69.2 5936 4472 75.3 6.1 4.5 7.7 55.568 0.000***
1st half 2996 2078 69.4 2968 2254 75.9 6.6 4.3 8.8 32.520 0.000***
2nd half 2996 2070 69.1 2968 2218 74.7 5.6 3.4 7.9 23.459 0.000***
Percentage of severity 5 runny nose Overall 5992 28 0.5 5936 52 0.9 0.4 0.1 0.7 7.477 0.007**
1st half 2996 10 0.3 2968 26 0.9 0.5 0.1 0.9 7.306 0.007**
2nd half 2996 18 0.6 2968 26 0.9 0.3 −0.2 0.7 1.542 0.229
Percentage of severity 1 nasal congestion Overall 5992 4813 80.3 5936 5159 86.9 6.6 5.3 7.9 94.364 0.000***
1st half 2996 2444 81.6 2968 2552 86.0 4.4 2.5 6.3 21.311 0.000***
2nd half 2996 2369 79.1 2968 2607 87.8 8.8 6.9 10.7 82.869 0.000***
Percentage of severity 5 nasal congestion Overall 5992 15 0.3 5936 0 0.0 −0.3 −0.4 −0.1 14.879 0.000***
1st half 2996 9 0.3 2968 0 0.0 −0.3 −0.5 −0.1 8.929 0.004**
2nd half 2996 6 0.2 2968 0 0.0 −0.2 −0.4 0.0 5.950 0.031*
Percentage of severity 1 sore throat Overall 5992 4892 81.6 5936 5360 90.3 8.7 7.4 9.9 184.933 0.000***
1st half 2996 2439 81.4 2968 2623 88.4 7.0 5.1 8.8 56.385 0.000***
2nd half 2996 2453 81.9 2968 2737 92.2 10.3 8.6 12.0 141.180 0.000***
Percentage of severity 5 sore throat Overall 5992 12 0.2 5936 11 0.2 0.0 −0.2 0.1 0.035 1.000
1st half 2996 6 0.2 2968 11 0.4 0.2 −0.1 0.4 1.522 0.235
2nd half 2996 6 0.2 2968 0 0.0 −0.2 −0.4 0.0 5.950 0.031*
Percentage of severity 1 coughing Overall 5992 4957 82.7 5936 5272 88.8 6.1 4.8 7.3 90.452 0.000***
1st half 2996 2476 82.6 2968 2618 88.2 5.6 3.8 7.4 37.046 0.000***
2nd half 2996 2481 82.8 2968 2654 89.4 6.6 4.9 8.4 54.433 0.000***
Percentage of severity 5 coughing Overall 5992 4 0.1 5936 6 0.1 0.0 −0.1 0.1 0.419 0.547
1st half 2996 2 0.1 2968 6 0.2 0.1 −0.1 0.3 2.041 0.177
2nd half 2996 2 0.1 2968 0 0.0 −0.1 −0.2 0.0 1.982 0.500
Percentage of severity 1 arthralgia Overall 5992 4813 80.3 5936 5205 87.7 7.4 6.0 8.7 120.159 0.000***
1st half 2996 2447 81.7 2968 2573 86.7 5.0 3.2 6.9 28.155 0.000***
2nd half 2996 2366 79.0 2968 2632 88.7 9.7 7.8 11.6 103.506 0.000***
Percentage of severity 5 arthralgia Overall 5992 7 0.1 5936 3 0.1 −0.1 −0.2 0.0 1.564 0.344
1st half 2996 1 0.0 2968 0 0.0 0.0 −0.1 0.0 0.991 1.000
2nd half 2996 6 0.2 2968 3 0.1 −0.1 −0.3 0.1 0.974 0.508
Percentage of severity 1 myalgia Overall 5992 4731 79.0 5936 5166 87.0 8.1 6.7 9.4 137.560 0.000***
1st half 2996 2376 79.3 2968 2542 85.6 6.3 4.4 8.3 41.453 0.000***
2nd half 2996 2355 78.6 2968 2624 88.4 9.8 7.9 11.7 103.956 0.000***
Percentage of severity 5 myalgia Overall 5992 21 0.4 5936 10 0.2 −0.2 −0.4 0.0 3.811 0.070
1st half 2996 8 0.3 2968 5 0.2 −0.1 −0.3 0.1 0.666 0.581
2nd half 2996 13 0.4 2968 5 0.2 −0.3 −0.5 0.0 3.491 0.096
Percentage of severity 1 headache Overall 5992 4725 78.9 5936 5062 85.3 6.4 5.0 7.8 83.482 0.000***
1st half 2996 2380 79.4 2968 2489 83.9 4.4 2.5 6.4 19.450 0.000***
2nd half 2996 2345 78.3 2968 2573 86.7 8.4 6.5 10.4 73.094 0.000***
Percentage of severity 5 headache Overall 5992 15 0.3 5936 16 0.3 0.0 −0.2 0.2 0.042 0.859
1st half 2996 6 0.2 2968 3 0.1 −0.1 −0.3 0.1 0.974 0.508
2nd half 2996 9 0.3 2968 13 0.4 0.1 −0.2 0.4 0.768 0.402
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Note: Between‐group comparisons were conducted using the chi‐square test. (1) Normal; (2) Slight; (3) Mild; (4) Moderate; (5) Severe. *p < 0.05, **p < 0.01, ***p < 0.001.

Abbreviations: Δ, difference in proportion of applicable days (Euglena group versus placebo group); 95% CI−, lower bound of 95% confidence interval; 95% CI+, upper bound of 95% confidence interval.

3.3.2. VAS Analysis

No significant changes were observed in VAS scores (Table S8). However, in the within‐group comparison of the placebo group, the values for wake‐up quality and satisfaction with defecation improved after 8 weeks of intake compared to baseline (Table S9). Comparisons within the Euglena group demonstrated that the values for tension and relaxation were significantly lower after 8 weeks of intake than those at baseline (Table S10), indicating improvements. Comparisons within the Euglena group also demonstrated that satisfaction with defecation and the feeling of refreshment upon defecation significantly improved after 8 weeks of intake compared to baseline (Table S10).

4. Discussion

The present study evaluated the effect of 8 weeks of continuous E. gracilis capsule intake on immune function in healthy adult Japanese men and women. Our findings demonstrated that the mean cumulative days with cold symptoms throughout the trial period (primary outcome) were significantly lower in the Euglena group than that in the placebo group. Although it is a secondary endpoint, the number of cumulative days with fatigue in the second half of the trial was also significantly lower in the Euglena group than that in the placebo group. Moreover, the Euglena group demonstrated significantly fewer cumulative days with general malaise, chills, fatigue, sneezing, runny nose, nasal congestion, sore throat, coughing, and myalgia than the placebo group. In terms of symptom severity, feverishness (overall), fatigue (second half), nasal congestion (second half), sore throat (second half), and myalgia (second half) were significantly milder in the Euglena group than in the placebo group. The proportion of responses ranked as severity 1 (“Normal” on the cold symptom survey) for general malaise, chills, feverishness, fatigue, sneezing, runny nose, nasal congestion, sore throat, coughing, arthralgia, myalgia, and headache was significantly higher in the Euglena group than in the placebo group. These findings suggest that the intake of E. gracilis can effectively mitigate cold symptoms.

Immune functions include eliminating pathogens and regulating physiological mechanisms (Kaufmann 2019). However, immune function can be diminished by various factors such as fatigue (Papacosta and Nassis 2011; Tirelli et al. 2013), stress (Seiler et al. 2020), and aging (Brauning et al. 2022), highlighting the importance of maintaining immunity. In the present study, some of the participants were selected based on relatively high levels of physical fatigue. In general, individuals experiencing chronic fatigue exhibit reduced immune function, primarily due to decreased expression and activity of natural killer (NK) cells (Cabanas et al. 2019; Nguyen et al. 2016, 2017). Weakened immunity prevents the body from effectively eliminating invading pathogens and viruses, thereby increasing the risk of developing and intensifying cold‐like symptoms.

Typically, mild cold symptoms include localized nasal and throat symptoms, whereas severe colds present with systemic symptoms, including fever and myalgia (Eccles 2005, 2009). Colds are triggered primarily by viral infections (Wine and Alper 2012), after which symptoms are elicited via two routes (Eccles 2009). In one route, local symptoms, such as sneezing, runny nose, nasal congestion, and coughing, are induced by bradykinin and prostaglandin synthesis in the nasal epithelium. In contrast, in the other route, systemic symptoms, such as fever, myalgia, and headache, occur when Toll‐like receptor (TLR) stimulation induces the release of cytokines from macrophages, neutrophils, and DCs (Eccles 2009). In this study, “cold symptoms” were defined as the presence of one or more of the following: general malaise, chills, feverishness, fatigue, sneezing, runny nose, nasal congestion, sore throat, coughing, arthralgia, and myalgia. Notably, in the present study, the manifestations of general malaise, chills, fatigue, sneezing, runny nose, nasal congestion, sore throat, arthralgia, and myalgia were suppressed by Euglena intake. This finding suggests that the regulation of the immune balance associated with Euglena intake affected both pathways of cold‐symptom induction, significantly shortening the period of symptom manifestation.

β‐glucans have been reported to alleviate symptoms of the common cold through the modulation of immune functions (Mah et al. 2020). Therefore, we speculated that the improvement in immune function observed in the present study might involve paramylon, a β‐glucan found in E. gracilis . Among the various β‐glucan receptors, including Dectin‐1, TLRs, and complement receptor 3 (CR3), paramylon has been reported to bind, at the very least, to Dectin‐1—a major β‐glucan receptor expressed on epithelial cells, macrophages, and DCs (Brown and Gordon 2001; Cohen‐Kedar et al. 2014; Nakashima et al. 2018). This binding triggers tyrosine kinase‐mediated signaling (Chan et al. 2009) and leads to the release of interleukin‐12 (IL‐12) (Komastu et al. 1998), IL‐10 (Ouyang and O'Garra 2019), IL‐6 (Tanaka et al. 2014), and other cytokines (Chan et al. 2009). These cytokines improve the activity of cells that contribute to immune function, such as NK, Th1, and B cells (Komastu et al. 1998; Ouyang and O'Garra 2019; Tanaka et al. 2014). Moreover, a study in which BALB/c mice were fed E. gracilis or paramylon and infected with an influenza virus revealed significantly increased survival rates and low viral titers in the lungs of mice fed E. gracilis and paramylon (Nakashima et al. 2017). Additionally, intraperitoneal injection of E. gracilis and paramylon stimulates DCs in Peyer's patches (Yasuda et al. 2020). A 12‐week intake of paramylon‐rich E. gracilis EOD‐1 in healthy adults aged 50–65 years maintained subjective health status and mitigated cold‐related symptoms, evidenced by decreased incidences of chills, fever, headache, cough, and sore throat. This intake also enhanced naïve T cell activation via increased CD28 expression and improved the antigen‐presenting function of monocytes by maintaining CD80 and CD38 expression, suggesting a strengthened immune defense (Kawano et al. 2023). Another study demonstrated that administering E. gracilis powder for 8 weeks in Korean adults (aged 20–70 years) significantly enhanced NK cell activity, demonstrating improved immune function (Park et al. 2023). Moreover, in a population predominantly comprising Western European individuals, with some Eastern European and South Asian representation (21–65 years), who engaged in intense daily endurance exercise and consumed β‐1,3‐glucan‐rich E. gracilis for 90 days, the incidence of upper respiratory tract infections and the number of sick days was markedly reduced (Evans et al. 2019). Considering the findings of these studies, the notable improvement in cold symptoms observed with E. gracilis intake in the present study may be, in part, attributed to the immunoregulatory action of paramylon. However, hot water extracts of Euglena also exhibit anti‐influenza virus activity in vitro, suggesting that the contribution of whole Euglena should also be considered (Nakashima, Horio, et al. 2021).

The intake of E. gracilis reportedly regulates the autonomic nervous system balance under workload, improves irritability and tension under workload, and enhances sleep quality (Nakashima et al. 2020). Therefore, in the present study, we assessed subjective symptoms, such as physical fatigue, mental fatigue, and tension, using the VAS. However, we observed no significant differences between the groups. Our findings showed no significant differences in well‐being indicators between the groups, which could be attributed to the fact that participants were not selected based on baseline impairments in these domains. Moreover, the limited frequency of VAS assessments (only at weeks 0, 4, and 8) could have contributed to the reduced sensitivity to detect transient changes during the intervention period. Nevertheless, comparisons within the Euglena group demonstrated that the values for tension and relaxation were significantly lower (i.e., improved) after 8 weeks of intake than those at baseline. This aligns with the findings of Nakashima et al. (2020), who reported that E. gracilis intake alleviates irritability and tension. In the present study, comparisons within the Euglena group also demonstrated that satisfaction with defecation and refreshment upon urination significantly improved after 8 weeks of intake compared to baseline. These findings are supported by a previous study reporting that 30 consecutive days of E. gracilis intake can significantly increase defecation frequency and volume by improving the gut microbiota in healthy participants aged 40–59 years (Nakashima, Sasaki, et al. 2021). Overall, our findings further support the ability of E. gracilis to improve defecation.

To the best of our knowledge, the present study, which is a clinical trial conducted in Japan, includes the largest number of participants and spans the widest age range among immune‐related clinical studies on Euglena intake conducted to date. The mechanism by which E. gracilis intake is hypothesized to improve immune function involves the binding of paramylon in E. gracilis to Dectin‐1, triggering the release of various cytokines, including IL‐12, IL‐10, and IL‐6, and stimulating cells, such as NK, T, and B cells. However, this study had some limitations. First, it lacked an assessment of immune cell activity and other indicators that could substantiate the hypothesized mechanism of action. Therefore, further research is required to clarify the speculative involvement of enhanced immune function and elucidate the underlying mechanisms. Second, as some data were collected through participant diaries, which rely on subjective self‐reporting, the potential for recall bias cannot be ruled out. Third, because the analyses of secondary outcomes were exploratory, no adjustments for multiple comparisons were performed. Future confirmatory studies should incorporate such adjustments to account for potential Type I errors. Future studies are also warranted to gain insights into definitive evidence which may further clarify the mechanism of action of Euglena by measuring the activity of immune‐related cells and evaluating their interactions with various β‐glucan receptors.

5. Conclusions

The present study demonstrated that E. gracilis intake significantly alleviated cold symptoms by regulating immune function. This clinical trial, conducted in Japan, involved the widest age range and the largest number of participants among immune‐related clinical studies on Euglena intake. The findings also support the safety and efficacy of E. gracilis as a functional food. However, further studies evaluating immune cell activity are needed to confirm its mode of action.

Author Contributions

Ayaka Nakashima: conceptualization (equal), formal analysis (equal), methodology (equal), resources (equal), writing – original draft (lead), writing – review and editing (equal). Kengo Suzuki: resources (equal), supervision (equal), writing – review and editing (equal). Masafumi Nagata: conceptualization (equal), writing – review and editing (supporting). Tsuyoshi Takara: conceptualization (equal), methodology (equal), supervision (equal), writing – review and editing (equal).

Ethics Statement

This study was conducted in accordance with the tenets of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. This study was approved by the Institutional Review Board of Takara Clinic (approval no. 2112‐00395: 2112‐00395‐0022‐1C‐TC, approval date: 12/22/2021).

Consent

Written informed consent was obtained from all participants involved in the study.

Conflicts of Interest

A.N. and K.S. are salaried employees of Euglena Co. Ltd., which produced some of the Euglena used in this study. All research funding for this study was provided by Euglena Co. Ltd. M.N. and T.T. were the medical advisors for this study and received honoraria from Euglena Co. Ltd. There are no other conflicts of interest.

Supporting information

Table S1: Baseline data of the participants (cedar‐specific IgE).

Table S2: Baseline data of the participants (cypress‐specific IgE).

Table S3: Cold symptoms during the 5 days before baseline testing.

Table S4: Summary of primary safety assessment items.

Table S5: Summary of secondary safety assessment items.

Table S6: The highest number of consecutive days of cold symptoms overall and for individual symptoms.

Table S7: Proportions of responses regarding symptom severity.

Table S8: Well‐being factors measured with VAS.

Table S9: Well‐being factors measured with VAS (comparisons within the placebo group).

Table S10: Well‐being factors measured with VAS (comparisons within the Euglena group).

FSN3-13-e70935-s001.docx (145.9KB, docx)

Acknowledgments

The authors appreciate the useful suggestions and technical support provided by ORTHOMEDICO Inc. and Yuto Watanabe.

Nakashima, A. , Suzuki K., Nagata M., and Takara T.. 2025. “ Euglena gracilis Suppresses Cold Symptoms in Healthy Individuals: A Double‐Blind, Randomized, Placebo‐Controlled Trial.” Food Science & Nutrition 13, no. 9: e70935. 10.1002/fsn3.70935.

Funding: The authors received no specific funding for this work.

Data Availability Statement

Data supporting the results of this study are included in the Supporting Information to this paper. If further data are required, they can be provided upon reasonable request to the authors.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1: Baseline data of the participants (cedar‐specific IgE).

Table S2: Baseline data of the participants (cypress‐specific IgE).

Table S3: Cold symptoms during the 5 days before baseline testing.

Table S4: Summary of primary safety assessment items.

Table S5: Summary of secondary safety assessment items.

Table S6: The highest number of consecutive days of cold symptoms overall and for individual symptoms.

Table S7: Proportions of responses regarding symptom severity.

Table S8: Well‐being factors measured with VAS.

Table S9: Well‐being factors measured with VAS (comparisons within the placebo group).

Table S10: Well‐being factors measured with VAS (comparisons within the Euglena group).

FSN3-13-e70935-s001.docx (145.9KB, docx)

Data Availability Statement

Data supporting the results of this study are included in the Supporting Information to this paper. If further data are required, they can be provided upon reasonable request to the authors.

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