Abstract

Particulate matter pollution is a significant respiratory tract irritant which impacts sleep through multiple mechanisms including cough and neuroinflammation. Epidemiological studies consistently point to better overall health and sleep quality in populations that regularly consume fish. A previous study of whole salmon oil, OmeGo, showed a faster recovery from mild to moderate COVID-19. This study aimed to further explore the respiratory and overall inflammation-resolving benefits of the oil. One hundred and twenty-seven healthy adult participants, experiencing sleep disturbed by pollution-induced coughing, were randomized to OmeGo at 2g or 4g per day for 8 weeks. Outcome measures included change in cough severity and sleep quality, measured by Visual Analogue Scale (VAS) score and by wearable device hypnograms, as well as change in gene expression of relevant cytokines, measured via nasal swab samples. Both doses showed a progressive and significant improvement in sleep quality, cough burden and in markers of inflammation. Whilst both daily doses provided similar health benefits there was the suggestion of a slightly greater impact from the 4g/d dose on differential gene expression, although no statistically significant differences in sleep and cough metrics were noted. The positive health impact from an oil containing a broad array of unsaturated fatty acids appears consistent with those seen from regularly eating fish.

Keywords

Particulate Matter Pollution; Sleep; Cough; Inflammation-Resolution; Hypnograms

Introduction

Modern, time-poor lifestyles pose significant challenges to maintaining optimal health, particularly regarding the key health drivers of diet, daily activity levels and adequate sleep, both quantity and quality [1-3]. Inadequate exercise and the consumption of energy-rich, rather than nutrient-rich diets, are associated with poorer sleep metrics and a greater risk of ill-health [4]. Sleep can be further compromised by the nighttime use of computer and smart-phone screens as well as the effects of Particulate Matter (PM) pollution [5,6]. Whilst the exposure to artificial blue light is becoming increasingly documented as a factor contributing to poorer sleep quality, the impact of PM exposure on sleep remains less well understood. A similar impact on sleep is seen with regular cigarette smoking [7]. Several possible causes have been implicated including irritation to the respiratory mucosa with nasal, throat and lung effects including coughing, a change in body water distribution and lowgrade systemic inflammation [8-10].

Longitudinal studies suggest both occupational and environmental exposure to PM pollution results in lung irritation and sporadic coughing and conversely a decrease in exposure to PM results in a declining incidence of cough [11-13]. Chronic inhalation of noxious particles results in oxidative stress within epithelial cells and the release of inflammatory mediators. This causes irritation of the respiratory mucosa and symptoms including intermittent coughing, post-nasal drip and dry throat [8,14]. However, while cough serves as a protective mechanism, its activation in response to exposure to pollution, alongside natural allergens, fails to clear the irritants from the lungs. Instead, it negatively impacts quality of life, especially when sleep is disrupted [15].

Research into smoking provides data analogous to the health effects of pollution. Smoking is known to increase the risk of sleep disruption, and similarly, a link has been established between reduced air quality due to increased Particulate Matter (PM) pollution and reduced sleep quality and quantity [7,10]. This negative impact on sleep has been documented in large population-based studies [6,16]. Notably these were otherwise healthy individuals, and the net effect of PM pollution manifested as increased daytime sleepiness and sleep disordered breathing during the night. Furthermore, heightened airway sensitivity to pollution and pollen can also trigger a nonproductive cough, dry throat, and nasal irritation, including postnasal drip, further disrupting sleep [8,14]. Once airways become sensitised, even low-level exposure to chemical stimuli can provoke coughing episodes [14].

The health-promoting fatty acids present in the oil fraction of fresh fish provide well-documented anti-inflammatory and antioxidant benefits that are important for the maintenance of good health [17]. Both observational and epidemiological studies indicate that regular fish consumption yields wide-ranging benefits for human health, including better cardiovascular, metabolic and respiratory function [18,19]. However, contemporary dietary habits have led to a decline in fish consumption and an associated increase in allergies.

OmeGo is a whole fish oil with low levels of oxidation and retaining all the fatty acids found in whole fatty fish. Previous in-vitro work demonstrated that this full spectrum oil significantly reduced eosinophilic effector function when compared to oils containing only omega-3 or omega-3 and astaxanthin [20]. Beyond this modulation of type 2 (allergic) inflammation [21], the fatty acids also demonstrated modulation of type 1 inflammation [22]. Furthermore, the oil also contains astaxanthin, a powerful, natural antioxidant. A study of OmeGo in healthy participants demonstrated a significantly greater reduction (3-5-fold) in oxidised LDL cholesterol compared to conventional omega-3 oil or algae oil [23]. Based on these broad inflammation-resolving health benefits, a study in adults suffering from mild COVID-19 was undertaken. Participants were randomised to Best Standard of Care (BSC) with or without supplementation with OmeGo capsules. Gene expression analyses from nasal swabs, taken throughout the duration of the study, showed that the participants who received OmeGo capsules (at 4g daily for 28 days) experienced a more rapid resolution of inflammatory cytokines released from alveolar macrophages, including TNFα (tumour necrosis factor alpha), IL-6 (interleulin-6) and GM-CSF (granulocyte-monocyte colony stimulatory factor) [24].

Collectively, this preclinical and clinical work suggests that OmeGo could help reduce lung irritation observed in response to PM exposure and thereby help reduce sleep disruption. The omega fatty acids contained in the whole fish oil are also likely to improve sleep metrics given that the pineal gland utilizes them in the production of serotonin and melatonin [25,26]. This study was, therefore, undertaken to assess whether the array fatty acids in OmeGo salmon oil could improve sleep metrics both through their inflammation-resolving effects and their nutritional benefits.

Materials and Methods

This decentralized trial was conducted using Alethios, a clinical research software platform designed to enable remote and digitized clinical research, rather than requiring specific trial research sites. This approach was selected to facilitate efficient recruitment timelines with participant demographics likely to be more representative of the general population than might be obtained in a traditional study. Alethios provides a fully digital infrastructure that facilitates study design, participant recruitment, data collection, and study monitoring without requiring in-person visits. The platform supports multiple device integrations, including commercially available wearables, sensors, and Electronic Patient-Reported Outcome (ePRO) tools. Additionally, it includes built-in capabilities for managing intervention and study device distribution for at-home testing.

Alethios has been used in various clinical studies across different therapeutic areas, including sleep research, behavioral health, and nutraceutical studies. By leveraging Alethios, this study ensured efficient participant engagement, real-time data monitoring, and adherence to Good Clinical Practice (GCP) guidelines. This approach enhanced study accessibility and reduced logistical barriers associated with traditional site-based trials.

The study was conducted in accordance with ethical principles originating from the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable regulatory requirements. Registration of participant data was carried out in accordance with national personal data laws. The study protocol, including the participant information and informed consent form, were approved by the regional IRB (Sterling IRB, approval number 11960-CCurrie protocol #001) before initiating participant enrolment. The study was registered on clinicaltrials.gov, NCT06768970.

The study was designed as a pilot study and, therefore, there was no control arm, rather participants were randomised to 8 weeks of OmeGo salmon oil (Hofseth BioCare, Norway, batch number SO20009H) at either 2g daily (equating to 2 capsules) or 4g daily (equal to 4 capsules). These dosages were based on data from a study of OmeGo in milder forms of COVID-19, which demonstrated reductions in the gene expression of a broad range of inflammatory cytokines and chemokines that would also be expected to be raised after PM exposure [24]. The latter was assessed by analyzing nasal swab samples as part of this study to evaluate changes in gene expression of inflammatory markers, including TNFα, IL-5, IL-6, IL-8 and GM-CSF. For healthy subjects, OmeGo is typically taken at 2g per day. Hence this dose level was also selected to assess whether it provided a sufficient amount of fish fat omegas to help improve or resolve inflammation resulting from PM pollution and support better sleep.

Inclusion and Exclusion Criteria

Eligible participants were aged 18 to 70 years residing in urban locations and experiencing sleep that was not fully refreshing, likely in part a result of PM exposure. Other key inclusion criteria included were sleep disturbed by coughing resulting in daytime tiredness, a cough burden over the previous twenty-four hours of ≥40mm on visual analogue scale, ownership of a wearable device that collects and records time spent in different sleep stages. This “bring-your-owndevice” study included devices from the following device families: Garmin, Fitbit, Oura, Whoop, Google Fit and Apple watches, and access to and use of any mobile or web-based device manufactured after 2008.

The use of Angiotensin Converting Enzyme (ACE) inhibitors and prescription or over-the-counter sleep aids were prohibited. Smokers, and those who had quit within the preceding 12 months, were ineligible as were pregnant or lactating women and those with allergies to fish. Regarding lifestyle considerations, participants were advised to maintain the same dietary habits, caffeine and alcohol intake and general activities of daily living. Shift work, involving night shifts, and pre-existing use of fish oil supplementation were also exclusion criteria. Finally, subjects with chronic-degenerative diseases were also excluded.

Intervention

OmeGo capsules contain a whole, fish oil liberated from fresh Norwegian Atlantic salmon using enzymatic hydrolysis. The supplements contain the same range of fatty acids as found in salmon and are manufactured according to Good Manufacturing Practices for food facilities, complying with the Hazard Analysis and Critical Control Points (HACCP) principles. The fatty acid composition includes around 16% omega-3s (including EPA, DHA, DPA, and AHA), low levels of omega-5, 16% omega-6, 2.8% omega-7, 43% omega-9 and 2.6% omega-11. The balance is comprised of minor fatty acid fractions with low levels of saturated fatty acids. The product is intended for human consumption, including food supplements, and has US FDA New Dietary Ingredient (NDI) status. The salmon oil is produced by Hofseth Biocare ASA (Ålesund, Norway) and encapsulated by Pharmatec ASA (Rolvsøy, Norway). The same production batch (SO20009H) was used for all participants throughout the 8-week duration of treatment.

The 4g daily dose was selected as this was the dose used in the prior COVID-19 study. OmeGo has US FDA NDI (New Dietary Ingredient) status with a maximum daily serving size set at 29g per day for chronic administration. The fatty acids within OmeGo are in the natural triglyceride form and therefore are easily absorbed and rarely cause fish burps.

Endpoints and Assessments

Prior to initiating OmeGo dosing, a run-in period of up to 14 days was undertaken to establish baseline sleep metrics via wearable devices and the Epworth Sleepiness Scale was used to assess daytime sleepiness. Any participant with a score of ≥16 was advised to seek medical attention before entering the study to ensure they were free from undiagnosed medical conditions.

The co-primary endpoints were (1) the mean change in self-scored cough severity, from baseline to week eight, on Visual Analogue Scale (VAS) (with 0mm representing “no cough” and 100mm representing the “worst possible cough”) and (2) the change in awakening events after sleep onset and Total Sleep Time (TST) from baseline (via a 2-week run-in period) to week eight, as recorded on wearable device hypnograms. Statistical significance was set at 5% (p=0.05). Key secondary endpoints were the change in self-assessed sleep quality by VAS score (with 0mm representing the “worst possible sleep” and 100mm representing the “best possible sleep”), sleep efficiency (defined as time asleep divided by total time in bed), time in R.E.M and deep sleep, and time in light sleep.

Voluntary nasal swabs were collected from thirty-two participants to assess the change in gene expression of relevant cytokines and chemokines. An exploratory analysis of the relationship between Air Quality Index (AQI) in the participants’ neighborhood and severity of cough and response to OmeGo capsules was planned but is not reported in this paper. Residential zip code was captured at the beginning of the study and verified during the study. This analysis will be presented in a future publication.

RT-qPCR Gene Expression Profiling from Nasal Samples

Gene expression profiles for 11 select genes were quantified using TaqMan probe-based real-time quantitative polymerase chain reaction (RT-qPCR) assays (Thermo Fisher Scientific, Waltham, MA, USA). The genes were: TNFα, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, CRP, GM-CSF, BMP2 and TGFβ with respective TaqMan Assay IDs of Hs00174128_m1, Hs01548712_g1, Hs00174131_m1, Hs00174103_m1, Hs00961622_m1, Hs00265044_m1, Hs00174379_ m1, Hs00154459_m1, Hs00174122_m1, Hs00154192_m1 and Hs00234244_m1.

Sample Collection and Handling: Nasal swab samples were collected at Baseline, Week 4, and Week 8 from 32 participants. Samples were obtained by insertion into both nasal cavities (midturbinate region). The swab was rotated three full turns to ensure adequate mucosal contact. After collection, swabs were handled according to established protocols to preserve RNA integrity.

Randomisation

Participants were assigned to study groups using a simple randomization approach. Randomization occurred after the participant completed eConsent. Simple randomization in an even allocation ratio was implemented by the Alethios platform and monitored by the study statistician.

The study targeted the recruitment of fifty participants per arm (100 in total) and assumed a 25% drop-out (10 participants per arm). The design provided sufficient power to detect a decrease in cough severity of 35% at the 95% significance level with an assumed baseline mean VAS score of 50 [27]. This would equate to an absolute reduction in cough VAS of 17.5mm. The co-primaries awakening events and Total Sleep Time (TST) were expected to show modest improvements as these were healthy participants whose sleep was interrupted by coughing. To illustrate, six and a half hours of uninterrupted sleep would typically yield sixty to eighty minutes of REM sleep and a similar amount of deep sleep, which could be significantly reduced by frequent sleep disruption [28]. A moderate reduction in awakenings of 10-15 minutes could therefore significantly improve sleep quality and thereby reduce daytime tiredness.

Statistical Analysis

Descriptive baseline statistics were presented using means and Standard Deviation (SD) for continuous variables and numbers and percentages for categorical variables. Outcomes were analyzed by calculating averages over study arm and study day, and trends over time and differences between study arms assessed by fitting linear regression models on the calculated means. Analyses were conducted using StataNow 18.5.

Cough and sleep VAS scores data collection and aggregation: Visual Analog Scale (VAS) scores for cough severity and sleep quality, ranging from 0 (no symptoms) to 100 (severe symptoms), were collected daily. To reduce individual variability and enhance the interpretability of group-level trends, mean VAS scores were aggregated by treatment arm (Arm 1 and Arm 2) at Baseline, Week 4, and Week 8.

Statistical methodology cough and sleep VAS scores: Paired and two-sample t-tests were used to evaluate within-group and betweengroup differences in mean VAS scores over time. Within-Group Analysis: Paired t-tests compared mean VAS scores at Baseline and Week 8 within each treatment arm. Between-Group Analysis: twosample t-tests assessed differences in mean VAS score changes between treatment arms. Statistical significance was established at p<0.05. Analyses were conducted using IBM SPSS Statistics (Version 30.0).

Linear regression was employed to examine the relationship between time and VAS scores. Time was modeled as the independent variable, with cough severity and sleep quality as dependent variables. Regression coefficients (slopes) represented the rate of change, and model fit was assessed using the coefficient of determination (R²). Standard error estimates were calculated to evaluate the precision of predictions.

Data visualization cough and sleep VAS scores: Aggregated mean VAS scores were visualized using line charts with separate trend lines for each treatment arm and outcome (cough severity and sleep quality). Error bars (±SD) represented variability. Scatter plots with linear trend lines were used to highlight individual-level relationships between time and VAS scores, annotated with regression coefficients and p-values to indicate the significance of observed trends.

Statistical and differential gene expression analysis: Gene expression data were analyzed as Log2-transformed fold-change (Log2FC) values, defined as the natural logarithm of the ratio of expression levels in the treatment condition to those in the reference condition. A positive Log2FC indicates upregulation, while a negative Log2FC suggests down regulation in response to experimental conditions. Temporal changes for all genes in Arm 1 and Arm 2 were evaluated using a dual approach: applying a Log2FC threshold (≥ ± 0.585, corresponding to a 1.5-fold change) to classify biologically significant upregulation and down regulation, and testing statistical significance with repeated-measures ANOVA (RM-ANOVA). Genes meeting both criteria were considered differentially expressed and likely to reflect biologically relevant changes.

Log2 transformation was applied to normalize the distribution of gene expression data. RM-ANOVA was employed to analyze temporal changes within study arms and assess interaction effects between time points (Baseline, Week 4, and Week 8) and group allocation. The assumption of sphericity was tested using Mauchly’s test, and the Greenhouse-Geisser correction was applied when violations were detected. Pair wise comparisons (Baseline vs. Week 4, Baseline vs. Week 8, and Week 4 vs Week 8) were performed using a General Linear Model (GLM) with Tukey’s adjustment for multiple comparisons, ensuring robust detection of significant differences.

Data visualization gene expression analysis: Data visualization included bar plots with error bars (±SD) to illustrate group-level trends and scatter plots with linear trend lines to depict individual-level patterns. All statistical analyses and visualizations were conducted using IBM SPSS Statistics version 30.0. P-values <0.05 were considered statistically significant, and results are reported as means ± SD unless otherwise stated.

Results

Participants Characteristics, Study Implementation and Supplement Tolerance

A total of 131 participants were randomized and 127 participants completed the study and were included in the final analysis (2g/day: n = 60; 4.0g/day: n = 67). As such, four discontinued three from the 2g/day group and one from the 4g/d group. The reasons for discontinuations from the lower dose group were as follows: two were a result of logistical issues and one because of mild indigestion and fish burps and constipation. These symptoms were completely resolved after a short period of ceasing OmeGo. A re-challenge was offered however the participant decided to withdraw. A further participant reported an episode of mild indigestion which was resolved by taking the capsules with food. The participant who withdrew from the 4g/d group did so during on boarding and did not provide a reason. One other participant in the 4g/d group reported occasional burping but no other GI-related symptoms. There were no severe adverse events and the overall incidence of adverse events was comparable between groups. Adherence to supplementation was high, with 77% of the assigned doses taken over the 8-week trial period.

Baseline demographic characteristics were generally balanced across groups apart from sex with 56% of the 2g/d group comprised of women and 82% in the 4g/d group (Table 1). Participants were composed of female, 70.1%, and male, 29.9% with a mean age of 41 years and 43.4 years, respectively. Importantly, baseline cough severity on VAS score was similar in both groups at 35.3mm in the 2g/d group and 33.76mm in the 4g/d group. There was a good mix of ethnicity generally representative of the background population with Caucasian ethnicity the most frequent followed by African-American, Indian, Mixed, Latino or Hispanic and Other.

	OmeGo 2g/d	n	OmeGo 4g/d	n
Age	41.9 years	60	41.6 years	67
Female	57%	34	82%	55
Male	43%	26	18%	12
Ethnicity
African-American	15%	9	16.42%	11
Asian	10%	6	20.90%	14
Caucasian	58.33%	35	43.28%	29
Latino or Hispanic	3.33%	2	8.96%	6
Mixed	10%	6	10.45%	7
Other	3.33%	2	0	0
Baseline Cough Severity (VAS Scale)	35.3	60	33.76	67

Table 1: Baseline characteristics of participants by supplementation group.

Baseline Characteristics of Participants by Supplementation Group. For ethnicity classification, anyone reporting more than one ethnicity was registered as “Mixed” and anyone identifying their ethnicity as “other” and with no more than one ethnicity was registered as “Other”.

Cough Severity: Visual Analogue Scale (VAS) Scores

Cough severity, measured daily using the Visual Analogue Scale (VAS), significantly decreased in both supplementation groups over the 8-week intervention period (Figure 1). In the 2.0g/day group, mean VAS scores (in mm) decreased from 34.63 (± 25.20) to 15.11 (± 18.02), with a mean change of -19.52 (± 27.38; p < 0.0001). Similarly, the 4.0g/day group showed a reduction from 33.34 (± 22.55) to 18.47 (± 18.08), with a mean change of -14.87mm (± 24.86; p < 0.001).

Figure 1: Change in Subjective Cough Burden.

Mean VAS scores (in mm) for cough severity over the 8-week intervention period for participants in the 2.0g/day (blue) and 4.0g/ day (red) OmeGo supplementation groups. Trend lines represent regression models showing significant reductions in VAS scores over time (2g/day: p < 0.0001, R² = 0.750; 4g/day: p < 0.001, R² = 0.721). Individual points represent mean VAS scores at each time point and regression trend lines illustrate overall improvements.

Sleep Quality: Visual Analogue Scale (VAS) Scores

Consistent with the progressive improvement in coughing, there was a steady upward trajectory over time, in subjective sleep quality, evaluated using VAS scores and both supplementation groups showed statistically significant improvements over the 8-week intervention period (Figure 2). For the 2g/day group, mean VAS scores (in mm) increased from 42.42 (± 19.62) at baseline to 56.53 (± 27.96) at week 8, a mean change of +14.12 (± 30.52; p = 0.0007). In the 4g/day group, the mean VAS scores rose from 43.78 (± 18.48) at baseline to 61.49 (± 26.14) at week 8, corresponding to a mean change of +17.72 (± 30.69; p<0.0001). Although the improvement was numerically greater in the 4.0g/day group, the between-group difference (-3.60 ± 5.44) was not statistically significant (p=0.5094), nor clinically relevant. Consequently, the lower dose appears to provide a comparable benefit to the higher dose, making it a more convenient option for achieving similar outcomes.

Figure 2: Change in Subjective Sleep Quality.

Mean VAS scores (in mm) for subjective sleep quality in the 2g/ day (blue) and 4g/day (pink) OmeGo supplementation groups over the 8-week intervention period. Data was averaged across participants at each time point to minimize individual variability and highlight group-level trends. Both groups showed statistically significant improvement, with no significant difference between doses Individual points represent the mean VAS scores at each time point, and regression trend lines illustrate overall improvements.

Sleep Architecture Metrics Collected by Wearable Device Hypnograms

Objective sleep parameters, measured by wearable device, were the co-primary sleep endpoints of change in awakenings per night and change in Total Sleep Time (TST). Data was available from one hundred and seventeen participants and whilst positive data was noted in terms of reduced awakening events (Figure 3) no change was seen with TST (data not presented).

Figure 3: Change in the mean number of nightly wake-up events.

The secondary outcome measures were time in bed, time spent in different sleep phases (light sleep, deep sleep and REM sleep) and sleep efficiency. The wearable devices were less reliable in data collection for the different sleep phases than for awakening events with thirty percent of the data points missing for the sleep phases.

Change in wake-up events: The mean number of wake-up events experienced by the participants progressively declined over the course of the trial (Figure 4). The decline was statistically significant for Arm 2 (p=0.021) and represents around a 10% decline in wakening events. Arm 1 showed a slight downward trend in reduced awakenings which was not statistically significant (p=0.417) (Figure 3).

Figure 4: Change in Mean Sleep Efficiency.

The 4g/d group showed a statistically significant decline in awakenings (p=0.021), while the 2g/d groups showed a non-significant downward trend (p=0.417). Individual points represent mean scores at specific time intervals, while trend lines illustrate the overall reductions for each group.

Sleep efficiency: Sleep efficiency was defined as time asleep divided by time spent in bed. Both groups showed a progressive, and statistically significant improvement in sleep efficiency over the course of the study and the improvement was more marked in Arm 1 (p<0.001) than in Arm 2 (p=0.032) (Figure 4).

The change in the 2g/day (blue line and dots) and 4g/day (red line and dots) groups indicates a progressive increase in sleep efficiency with both arms reaching statistical significance (Arm 1, 2g/d p<0.001 and Arm 2, 4g/d p=0.032). Individual points represent mean scores at specific time intervals, while trend lines illustrate the overall reduction in VAS scores for each group.

Sleep phases: light, deep and REM sleep: Rapid Eye Movement (REM) sleep showed a clear upward change over the duration of the study however this did not reach statistical significance (Figure 5). Both light and deep sleep showed minimal overall change over the eight weeks of supplementation. As noted previously, the wearable devices failed to record thirty percent of the individual sleep phase data points which limits the power to detect any significant changes as well as the robustness of the data. The data should therefore be considered as hypothesis-generating which needs further investigation in future studies.

Figure 5: Temporal trends in mean REM sleep duration.

Mean REM sleep duration (seconds) over time in participants receiving 2g/day (blue) and 4g/day (red) OmeGo supplementation. Individual points represent mean durations, and trend lines illustrate overall patterns.

Gene Expression Analysis from Nasal Swabs

Differential Gene Expression (DGE) analysis revealed pronounced suppression of inflammatory and immune-regulatory pathways following 8 weeks of OmeGo supplementation. By week 8 TNF, CXCL8 (IL-8), GM-CSF, IL-5 and IL-10 all showed biologically relevant reductions of greater than 1.5-fold from baseline and all changes, apart from IL-10, were statistically significant, ranging from p<0.05 to p<0.001 (depending on arm and particular gene expression). The change in DGE also showed a temporal effect with a clear pattern of a progressively increasing effect from week 4 to week 8.

Expression of TNF, CXCL8 (IL-8) and CSF2 (GM-CSF) showed a similar degree of decrease in expression. TNF decreased by 36% (1.56- fold / -0.654 log2 fold) at 2g/d and by 51% (2.05-fold / -1.032 log2 fold) with the 4g/d dose (p=0.04. & p<0.001 respectively). Similarly, CXCL8 declined 40%-44% (1.57-1.65-fold / -0.661 & -0.731 log2 fold) with the low and high dose (both p=0.04) and CSF2 declined by 42% and 52%, (1.72-2.07-fold / -0.784-1.046 log2 fold) respectively (p<0.01 & p<0.001). IL-5 showed a significant 1.57-fold reduction (-0.530 log2 fold) equaling a 36.3% decrease (p<0.01) by week 8 in the 4g/d arm but the change in the 2g/d arm was not significant. Similarly, whilst the expression of IL-10 was reduced by over 40% in both arms, with fold reductions of 1.59 (log2 fold change -0.675) and 1.78 (log2 fold change -0.840) in the 2g/day and 4g/day groups respectively, this did not quite reach significance.

The overall pattern therefore was of the 4g per day arm showing a slightly greater reduction in the expression of these cytokine-related genes (Figure 6 and Table 2).

Figure 6: Down regulation of Inflammatory and Immune-Related Genes Following OmeGo Supplementation.

Gene	Encoded protein/Cytokine	Cytokine function	Flod change (% change) 2g/d & 4g/d	p-value 2g/d / 4gd
TNF	Tumor Necrosis Factor-α	Pro-inflammatory cytokine	1.56 (-36%) & 2.05 (-51%)	p=0.04/p<0.001
CXCL8	Interleukin-8	Pro-inflammatory; neutro-phil recruitment	1.57 (-36%) & 1.65 (-39%)	p=0.04/p=0.04
CSF2	Granulocyte-Macrophage Colony-Stimulating Factor	Induced by TNFα; Pro-inflammatory; WBC Proliferaction	1.72 (-42%) & 2.07 (-51.6%)	p<0.01/p<0.001
IL5	Interleukin-5	Th2 Inflammation and allergy regulation. Activation and recruitment of eosinophils	1.44 (-31%) & 1.57 (-36%)	p=ns/p<0.001
IL10	Interleukin-10	Anti-inflammatory	1.59 (-37%) & 1.78 (-44%)	p=ns/p=ns

Table 2: Gene expression changes in inflammatory cytokines and immune-related genes following omego supplementation.

The changes in the other cytokines were less marked. Whilst the reduction in the expression of IL6 showed a 21% decrease in Arm 2, this corresponded to a non-significant 1.27-fold reduction. IL-4, IL13, TGFβ, BMP-2 and CRP showed minimal reductions (with changes of 10% or lower).

Log₂ fold-change in expression of key pro-inflammatory and immune-regulatory genes (TNF, CSF2, CXCL8, IL10) at weeks 4 and 8 relative to baseline. Statistically significant and biologically meaningful reductions were observed in TNF, CSF2, and CXCL8 expression, with a stronger effect in the 4g/d group. X-axis labels include gene protein products (top), time points, and gene symbols (bottom). Error bars represent ±1.96 SEM. The stippled line at -0.585 marks the log2FC threshold for biologically relevant down regulation, representing a 1.5-fold reduction in gene expression. Asterisks indicate within-group statistical significance (*p < 0.05; **p < 0.01; ***p < 0.001).

Summary of statistically significant changes in inflammatory cytokine gene expression (TNF, CXCL8, CSF2, IL5, IL10) at week 8 relative to baseline, stratified by 2g/d and 4g/d doses. A threshold of 1.5-fold change with p<0.05 was used to determine significance. “ns” signifies non-significant differences. Statistical analyses were conducted using within-group pair wise comparisons from a general linear model.

Unprovoked Participant Feedback

Unprovoked feedback from study participants was categorized into positive, negative, or neutral reactions based on keywords extracted from written commentaries. These reactions were analyzed across the two supplementation groups, Arm 1 (2g/day) and Arm 2 (4g/day). A total of 121 responses were recorded and classified. Negative reactions were very low at less than one percent. The majority of responses can be grouped into platform-specific, such as ease of participation, supplement-specific, and outcome related, such as reduced symptoms and improved energy levels. The most frequent positive commentary was about ease of participation in the study and a positive experience of trying the oil, with both representing 16% of responses. Energy and wellbeing as well as improved sleep were reported in 14% of responses. Reduced allergies and improved skin and joint symptoms were also reported by 4% of participants (Figure 7).

Figure 7: Unprovoked Participant Feedback at Trial Completion.

Summary of unprovoked participant feedback collected at the conclusion of the trial, categorized and presented as percentages of total responses. Feedback categories highlight participants' experiences across various aspects of the study, including views on the research platform, perceived health benefits, and perception of the intervention (OmeGo).

To assess the relationship between response types and treatment arms, a chi-square test was conducted. The results revealed no significant association between treatment arm and response type (χ2 (2) =1.7315; p=0.421). This suggests that response types were similarly distributed between the two arms.

These results suggest high levels of participant satisfaction and engagement with the supplementation protocol with the positive reactions in the majority, minimal negative feedback and neutral reactions that described procedural aspects of the study without strong emotional sentiment.

Discussion

This clinical trial evaluated the potential health benefits of a whole salmon oil, OmeGo, in 127 adult participants experiencing sleep that was not fully refreshing, likely as a result of Particulate Matter (PM) exposure, with sleep disturbed by coughing. The study population consisted of otherwise fit and healthy individuals and the inclusion and exclusion criteria were typical of a study assessing sleep in healthy subjects. The results demonstrated that eight weeks of OmeGo supplementation, both at 2g and 4g daily, resulted in improvements in Visual Analogue Score (VAS) score of sleep and cough along with significant reductions in the expression inflammatory genes from nasal swab analysis. Wearable device sleep data showed significantly improved sleep efficiency in both arms and demonstrated an overall reduction in awakening events in the 4g per day arm, which combined is indicative of improved quality of sleep.

Epidemiological studies consistently demonstrate better overall health, including CV, brain and respiratory health, as well as improved sleep quality in populations that regularly consume fish [18,19,29]. OmeGo salmon oil is a food supplement and research to date suggests that OmeGo provides similar health benefits to eating fish [23,24]. The omega fatty acids in fish oil are known to help the body attain and maintain a healthier balance of inflammation. Part of the health benefit of natural fish oils comes from the metabolism of omegas into fatty acids, termed resolvins, protectins and maresins, that help to resolve inflammation [17]. Long chain polyunsaturated fatty acids also appear to play a crucial role in the initiation and maintenance of sleep [30]. This may be related to their role in the production of serotonin and melatonin [4,25] and previous studies of omega-3 nutritional supplements suggest they have a potential to improve sleep duration, although they did not specifically examine factors emanating from an urban lifestyle [31,32].

Particulate Matter (PM) pollution appears to impact sleep through multiple mechanisms including neuroinflammation. This has been shown to impact the function of numerous regions of the brain, including those involved in sleep control and breathing with reduced sleep duration and quality and an increased risk of sleep apnoea [33]. Not surprisingly, PM pollution also acts as a significant irritant to the respiratory system, impacting lung function and increasing the risk of a number of conditions including rhinosinusitis, asthma and sleep apnoea [34-37]. PM exposure induces a broad inflammatory response in the respiratory tract, with pro-inflammatory IL-6, IL-8, Il-1β, GM-CSF and TNFα released from alveolar macrophages. Further, as levels of fine PM pollution increase so too do those of inflammatory cytokines [38-40]. However, fine PM also elicits an eosinophilic inflammatory pattern with raised levels of IL-5, IL-13 and eotaxin-1 and an increased risk of asthma exacerbations [41-44].

The Minimal Clinically Important Difference (MCID) for cough improvement on VAS score has been defined as a reduction of 17mm or 20-30% [45,46]. In this study, the overall mean reduction in VAS was just over 17mm. Regarding the individual arms, with 2g daily the improvement was 19.5 points, corresponding to a 65% reduction, and with 4g per day it was 14.9 points, a 46% reduction. Therefore, the magnitude of both looks to be highly relevant for health. Both of these outcomes were also highly statistically significant (p<0.00001). The difference in the mean change between the two arms, however, was not statistically significant (p=0.316). The powering assumptions for the study included a baseline VAS cough score of at least forty, however the actual mean baseline score was just below thirty-five. This difference could potentially have blunted the magnitude of benefit but nevertheless, a consistent and meaningful reduction in cough was seen over the eight weeks of the study.

The cough reduction observed in this study is highly encouraging and consistent with both respiratory and overall health benefits demonstrated in previous studies with OmeGo [23,24]. Fish oil contains an array of fatty acids. Omega-3 has been the most researched, however, natural fish oil also contains omega-5, -6, -7, -9 and -11 with research indicating that these fatty acids bring complementary and different anti-inflammatory health benefits to omega-3. For example, the omega-6 linoleic acid can reduce cholesterol, whereas omega-3 reduces plasma triglycerides [47,48]. Oleic acid, an omega-9 fatty acid, and pentadecanoic acid provide anti-inflammatory effects with cardiometabolic benefits [49,50]. Indeed, oleic acid is a major constituent of olive oil and a significant component of the Mediterranean diet, long recognised for its beneficial impact on health [51,52]. Fish oil also contains astaxanthin with antioxidant effects reported to be up to one hundred times greater than vitamin E [53].

In this study, the gene expression of key inflammatory markers, assessed via nasal swabs, showed consistent and significant declines that were supportive of an improved inflammatory balance within the body in these healthy participants. This conclusion is based upon the concept of an integrated and unified respiratory system with inflammation in the nasal epithelium likely to reflect inflammatory changes lower down in the respiratory tract, as seen in allergic rhinitis and asthma [54]. We set a threshold of a 1.5-fold change (0.585 log2 fold change) in gene expression combined with statistical significance of at least p<0.05 for the change in gene expression to be considered as likely to provide a meaningful physiological effect [55,56]. Log2 fold change was utilised for graphical purposes as a reduction in expression from baseline is expressed as a negative result and an increase as a positive result.

The greatest impact with OmeGo was observed on TNF and CSF2 (GM-CSF) expression, both of which showed 2-fold reductions in expression at the higher dose. A dose response was also observed for both these cytokines with TNF showing significant reductions of a 36% in expression at the 2g per day dose and a 50% reduction at the 4g dose. TNFα is an important driver of the inflammatory response to PM and induces GM-CSF, a hematopoietic growth factor associated with many inflammatory diseases [57]. Unsurprisingly, therefore, GM-CSF showed a similar pattern with significant reductions of 42% and 52% at 2g/d and 4g/d respectively. The change in gene expression of CXCL8 (IL-8) also met the threshold of a 1.5-fold reduction in both arms. This corresponded to significant reductions of 40% at 2g/d and 45% at 4g/d.

A similar pattern was seen in IL10 expression with a 37% and 44% reduction respectively although these changes were non-significant. Changes in expression IL6, IL13, CRP, TGFβ and BMP-2 were limited at 10% or lower and therefore unlikely to have any physiological relevance.

In terms of drivers of type II / allergic inflammation, an apparent dose-response was seen in the reductions in the expression of IL5 of 31% and 36% for the lower and higher doses. However only the higher, 4g/d dose resulted in a fold change above 1.5 which was also significant (p<0.01). IL4 and IL13 showed little change.

The reductions in TNF, CXCL8, CSF2 and IL5 are supportive of a reduction in respiratory tract irritation from PM exposure and consistent with the reduction in cough as assessed by VAS score. These changes are also consistent with changes seen in a previous study with OmeGo in adults suffering with mild COVID-19 [24]. Despite its nonsignificance, the decrease in IL10 looks consistent with reduced lung irritation. Exposure to PM has been observed to not only increase inflammatory cytokines such as TNFα but also levels of IL-10 [40]. This increase in IL-10 presumably represents a protective effect to attempt to limit inflammatory-driven damage and hence with reduced inflammation levels IL-10 may be expected to decline in parallel. However, as a non-significant finding this is purely speculative.

Overall, the reductions in TNF, CXCL8 and CSF2 in this study point to a decrease in type I inflammation, which is well recognised as being elevated in response to PM pollution. Higher levels of diesel exhaust particles have been noted to increase airways hyperresponsiveness, especially in the presence of allergens, with a type 2 inflammatory response. OmeGo appeared to reduce type II inflammation with a significant reduction in IL-5, a cytokine associated with the activation and recruitment of eosinophils. This is consistent with animal model data in induced allergic asthma with OmeGo [21,22]. IL-4 and IL 13, other important cytokines in type II inflammation, showed little change. However, IL-4 has not been noted to rise in response to PM pollution in contrast to IL-5 and IL-13. The mixed results in terms of IL5 and IL-13 may reflect the type of particulate matter pollution that the participants were exposed to, with airway irritation perhaps being driven more by type 1 inflammation.

We also assessed BMP-2 as raised levels have been associated with respiratory disease, including the accelerated development of chronic obstructive airways disease (COPD) [58]. Oxidised LDL-cholesterol (oxLDL-C) has also been observed to induce BMP-2 production whilst OmeGo has demonstrated significant reductions in oxLDL-C levels in healthy adults [23,59]. Nevertheless, no impact was seen on BMP-2 expression after eight weeks of OmeGo supplementation. Finally, although the lack of signal for change in CRP expression would appear inconsistent with the change in gene expression of TNF, the literature regarding CRP and PM pollution is mixed with most randomised studies failing to show a significant association between these two variables [60].

A reduction in cough and respiratory irritation, as indicated by VAS cough score and markers of inflammation, would be anticipated to help improve sleep metrics. This study used wearable devices to assess wake up events after sleep onset and Total Sleep Time (TST), coprimary endpoints relating to sleep quality and quantity respectively. Secondary endpoints included sleep efficiency, light sleep and REM and deep sleep. Overall, wake up events showed a reduction over time and the 10% decline in the 4g/d group was statistically significant (p=0.021). The shallower downward trend in the 2g/d group was not significant. TST was unchanged through the study.

The wearable devices performed inconsistently in the detection of the different sleep phases limiting the robustness of analysing change in REM and deep sleep. REM sleep showed a clear upward trend but there was no apparent signal in change for deep or light sleep.

However, the strength of these observations is reduced by the wearables failing to record almost a third of data points for phase of sleep over the 8-week trial period. Previous publications have noted that wearables, such as smart watches, have a lower sensitivity to measuring the different phases of sleep, apart from perhaps REM sleep, compared to sleep-wake states [61,62]. An increase in awakening events typically results in an increase in the duration of lighter phases of sleep and a reduction in deeper phases of sleep [63]. The reduction in awakening events in this study would suggest the potential to increase the duration of deeper phases of sleep and we saw a trend in a progressive increase in REM sleep but this was non-significant and the robustness of this signal is hampered by the missing data issue noted above. This potential signal for improved REM sleep should, therefore, be considered as hypothesis-generating and future studies will explore this potential benefit further. It should also be considered whether the unchanged total sleep time could have moderated any improvements in deep sleep. A recent study based on Fitbit sleep analysis suggested that total sleep time was important to the timing of deep sleep [64]. In any case, the impact of alarm clocks on waking time and the impact of social/family demands on time to bed, likely made it a high bar to observe a marked change in total sleep time [65].

Sleep efficiency improved significantly in both groups. An improvement in sleep efficiency is consistent with the reduction in the expression of genes encoding inflammatory cytokines. Healthy diets, such as the Mediterranean diet, are associated with improved sleeping patterns in subjects with sleep disorders and reducing the inflammatory potential of the diet has been shown to both increase sleep efficiency and reduce awakenings with no change in sleep duration [29,66]. Furthermore, the combination of improved sleep efficiency and less sleep fragmentation are key metrics in the assessment of sleep quality [67]. Lower inflammatory diets have shown an overall reduction in wakening after sleep onset of twenty-five minutes, or 6.4% of the total sleep time of 6.5 hours. This coincided with a 2.6% increase in sleep efficiency from baseline and 4.7% increase versus those consuming an unhealthy, pro-inflammatory diet [66]. This work also showed reductions in inflammatory markers, including TNFα. The average sleep duration of 6.5 hours was similar in our study. The overall improvement in the mean number of wake-up events was also similar at just below 6% and sleep efficiency a touch higher at just over 5%, suggesting an overall benefit consistent with the sleep benefits seen previously with a reduced inflammatory burden [66].

Sleep quality, assessed subjectively via VAS score, also improved significantly. Over the eight weeks of the study there was an increase of 14mm (25% increase) (p=0.001) and 17.7mm (29% increase) (p<0.0001) for the 2g and 4g daily doses, respectively. While the higher dose showed a numerically greater improvement in VAS sleep score the difference between the arms was not statistically significant (p=0.51). To put the result into context, a 10mm increase in self-scored VAS on sleep quality has been shown to be clinically meaningful [68]. Polysomnography-based sleep assessments have indicated that sleep efficiency and deeper phases of sleep to be the predictors of subjective sleep quality as well as the number of awakenings [69,70]. As noted earlier, the wearable devices failed to record 30% of the different sleep phases, reducing the robustness of any analysis of sleep phases but sleep efficiency and awakening events showed positive objectively assessed benefits. Overall, this reduction in awakening events and improved sleep efficiency points to improved sleep quality and a likelihood of an improved duration in deeper phases of sleep, consistent with the improved VAS scores.

Our study has a number of weaknesses. It was conducted entirely virtually, which presented a number of challenges related to the monitoring of participants; we attempted to mitigate these challenges through the inclusion of both subjective reported measures (e.g. participant reported outcomes and surveys) as well as more objective measures (e.g. nasal swabs, wearables data), but further efforts, such as telehealth visits or video recordings from participants to ensure dosage compliance could be incorporated for future studies. The failure of the wearable devices to consistently capture the different sleep phases reduces the read-through from subjectively assessed sleep quality. Nevertheless, improvements in sleep efficiency with reduced awakenings provides robust objective data in support of the VAS scores. The variation in how different device families (such as Garmin vs. Fitbit) collect sleep data could also affect our interpretation; future studies beyond this pilot study could choose to leverage only a single wearable to strengthen our interpretation. We advised participants that dietary intake over the course of the study should not change significantly but it might have been prudent to check that this had been adhered to as well as any significant changes in the use of screens at night [71]. Whilst the consumption of a whole fish oil appeared to reduce systemic inflammation as well as respiratory tract irritation, as measured by gene expression markers and cough severity scores, this was not confirmed by assessing blood serum markers. Indeed, changes in gene expression do not necessarily fully reflect the degree of mRNA levels and protein transcription and thereby cytokine production. However, it should be noted that this was a pragmatic decision in the running of this decentralized study and the changes seen in gene expression were both consistent with previous studies of OmeGo as well as studies of PM-induced inflammation. Furthermore, a dose response was seen with the 4g/d dose of OmeGo which would suggest moderately higher levels of anti-inflammatory action. The eight-week duration of the study may not have been sufficiently long to see the full benefits of supplementation with the oil. There was no signal of plateauing of benefit and hence a longer study could have better approximated to the likely impact of long-term supplementation. Finally, the study did not contain a placebo arm as it was designed as a pilot study following on from an immune health and inflammation-resolution study in individuals suffering from milder forms of COVID-19. Nevertheless, the study has provided important insights into the potential for supplementation with a whole salmon oil to support improved health metrics in adult subjects with a noticeable sensitivity to PM pollution. Furthermore, unprovoked feedback from participants indicated a strongly positive experience from the improvement of health and the simplicity of taking part in a decentralized study.

Conclusions

In conclusion, eight weeks of OmeGo, a whole salmon oil, helped to improve sleep metrics in adults troubled by the effects PM pollution. This was likely achieved by reducing lung and systemic inflammation with an associated reduction in cough symptoms and a decline in the expression of genes encoding inflammatory cytokines. Both daily doses, 2g/d and 4g/d, provided similar health benefits with a suggestion of a slightly greater impact from the 4g/d dose, although there were no significant differences between the two arms. This work is consistent with the inflammation-resolving effects seen with OmeGo in subjects with milder forms of COVID-19 as well as the published literature around the health benefits associated with regularly eating fresh fish. This highlights the importance of trying to ensure that any supplementation strategy replicates, as closely as possible, the nutrition upon which it is based.

Acknowledgments

The authors would like to acknowledge Anne Rørvik Standal for her review and comments regarding the manuscript and the Alethios platform and staff, the combination of which enabled the conduct of this study from recruitment to data collection.

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Article Type: RESEARCH ARTICLE

Citation: Currie C, Myklebust TÅ, Bjerknes C, Framroze B (2025) The Impact of Eight Weeks Supplementation with OmeGo Salmon Oil Capsules on Sleep and Coughing in City-Dwelling Adults. Nutr Food Technol Open Access 10(1): dx.doi.org/10.16966/2470-6086.189

Copyright: ©2025 Currie C, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication history: 

Received date: 06 Feb, 2025

Accepted date: 21 Mar, 2025

Published date: 27 Mar, 2025