Gastrointestinal symptom and stress recall survey in frontline healthcare workers after consumption of a combined quebracho/conker tree/M. balsamea willd extract during the COVID-19 pandemic

Since the coronavirus (SARS-CoV-2) pandemic began, frontline workers in general face the stress of uncertainty and fear in encountering infected individuals in the wider public. Frontline healthcare workers are at particular risk for increasing stress levels when treating and caring for COVID-19 patients. These healthcare professionals experience anxiety, psychological pressure and post-traumatic stress with their associated workloads [1-3]. Post-traumatic stress accompanying the COVID-19 outbreak in healthcare workers also elicits hyperarousal and decreased sleep quality [4]. Post-traumatic stress is known to induce somatization with gastrointestinal (GI) symptoms [5].


Introduction
Since the coronavirus (SARS-CoV-2) pandemic began, frontline workers in general face the stress of uncertainty and fear in encountering infected individuals in the wider public. Frontline healthcare workers are at particular risk for increasing stress levels when treating and caring for COVID-19 patients. These healthcare professionals experience anxiety, psychological pressure and post-traumatic stress with their associated workloads [1][2][3]. Post-traumatic stress accompanying the COVID-19 outbreak in healthcare workers also elicits hyperarousal and decreased sleep quality [4]. Post-traumatic stress is known to induce somatization with gastrointestinal (GI) symptoms [5].
For decades, the brain-gut axis has been implicated in disorders of abdominal pain and motility in the GI tract [6]. More recently, researchers and clinicians have shown that there is an interplay between diet, the microbiome and psychological stress on function of the endocrine and nervous systems with regard to digestive distress in functional GI disorders or more recently described as disorders of gut-brain interaction (DGBI) [7]. Irritable bowel syndrome (IBS) and functional dyspepsia are both DGBIs which can be triggered and exacerbated by psychological stress and anxiety [8,9]. The multiple factors involved in symptomatology of DGBI have greatly influenced the treatment of these disorders with numerous agents that directly predominant somatic effects of the anxiety during the pandemic [14]. Different surveys of healthcare professionals have found that the stress and anxiety can also contribute to GI symptoms. Nurses and nursing students, for example, reported significant increases in symptoms associated with DGBI [15,16]. And in a recent survey of Italian healthcare workers (N=1,153) assessing the effects of the COVID-19 pandemic on psycho-somatic symptoms, Barello et al. [17] found that 37% experienced GI symptomatology.
A marketed dietary supplement containing a blended extract of quebracho, conker tree and M. balsamea Willd (ATRANTIL  ) has been shown previously to improve bloating, abdominal pain/discomfort and constipation [18,19]. With the psychological stress of frontline healthcare workers in mind during the pandemic, ATRANTIL  was provided to a group of US healthcare professionals and the effect of the dietary supplement on GI symptoms, overall quality of life, anxiety and confidence assessed with an online recall survey.

Survey design and participants.
This was an open-label, non-controlled Healthcare Professional survey conducted using SurveyMonkey  in and around the Dallas-Fort Worth, TX metropolitan area. Thirty-five (35) frontline healthcare professionals participated in the survey. Survey participants were provided with a 30-day supply of an over-the-counter dietary supplement and then asked to answer survey questions. Survey responses represent their recollection prior to and after taking the product. Product consumption and survey participation occurred between June 1, 2020 to August 11, 2020 during the second peak of the coronavirus pandemic in the United States. This survey was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans and was exempt from IRB review. Consent was obtained from all participants for the use of survey data.

Intervention.
Participants were asked to take the recommended daily dose of the combined extract containing quebracho, conker Tree and M. balsamea Willd (ATRANTIL  , KBS Research LLC, 15660 N. Dallas Parkway, Suite 700, Dallas, TX 75248) for 30 days. There were no restrictions on taking any prescription drugs, over-the-counter products or diet. Survey questions. Questions used in the survey and descriptor answers were as follows: Statistical analysis. Data was accumulated and the percentage of patients responding with descriptor answers described above were tallied for each survey question.

Results
All participants worked in clinical settings as critical, essential frontline workers. Six (6) of 35 participants (17%) confirmed a previous diagnosis of IBS. Nine (9) of 35 participants (26%) were in close contact with COVID-19 patients but did not get infected. The majority of survey participants were from gastroenterology practices. The specific roles of each survey participants in the healthcare system are listed in Table 1.
Participation in this survey occurred between June 1, 2020 to August 11, 2020 during the peak of the first wave in positive SARs-CoV-2 case infections in Texas and the second peak of the coronavirus pandemic in the United States. A total of 35 participants (26 females, 5 males and 4 unknown) consumed product and answered the survey questions. Participant responses to the survey questions with the descriptor answers are shown in Table 2.
The majority of participants (80%) reported GI symptoms prior to taking the blended extract (i.e., bloating, abdominal discomfort and/or pain, diarrhea, constipation) with 77% percent experiencing these symptoms sometimes to very often. The primary symptoms that improved after taking the dietary supplement in participants were bloating (76%), constipation (44%), abdominal distention (38%) and abdominal pain/discomfort (44%). Overall, 89% of participants reported a moderate to complete improvement in quality of life (i.e., less anxiety, overall better health, fewer digestive issues) after taking the product. Knowing that a healthy gut is important for a healthy immune system, 89% felt that taking the product gave them moderately more to complete confidence. Finally, 91% (31/34) reported overall improvement in GI symptoms while on the combined extract.
There were no adverse events to the intervention reported over the course of consumption of the product or after while responding to survey questions.

Discussion
Quebracho extract contains tannins, large delocalized flavonoid structures found in wine [20]. Tannins act to disrupt bacterial lipid bilayers and bind excess hydrogen and methane [21,22], impacting the microbiome by a reduction in gas-producing microbes in the gut and the bloating caused by these microorganisms [23]. Conker tree extract contains saponins, also known as escins, which act as antimicrobial agents against methane-producing archaebacteria and also promote intestinal motility [23][24][25]. Finally, M. balsamea Willd extract contains peppermint oil which has been shown to act as an analgesic and antispasmodic in the gut to reduce abdominal pain/discomfort [26]. This combination extract improves symptoms associated with IBS with constipation (IBS-C); bloating, abdominal pain/discomfort and constipation [18,19].
In addition to the antibacterial activity of polyphenolic compounds of saponins and tannins, the molecules also possess potent antioxidant, anti-inflammatory and antiviral activities [27,28]. Escins, or saponins, have a glucocorticoid-like activity and down-regulate nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) p65 subunit expression, a key transcription factor involved in gene expression of inflammatory cytokines [29]. In a mouse model of indomethacininduced ulceration, escin's antioxidant and anti-inflammatory action alters catalase, glutathione peroxidase and superoxide dismutase activities as well as significantly reduces TNF-α, P-selectin, vascular cell adhesion molecule 1 (VCAM-1), malondialdehyde and myeloperoxidase activity, respectively, in gastric tissue [30]. Tannins not only act as a "sink" for hydrogen and methane in the gut, but also as potent antioxidants. Quebracho tannins are not absorbed in an ovine model, but increase antioxidant capacity of purified hepatic tissue and plasma compared to animals not fed tannins [31].
Reactive oxygen species (ROS) are by-products of normal cellular metabolism but when generated in overabundance due to a pathological condition, they contribute to metabolic diseases. In general, the primary ROS-induced inflammatory pathway involves NFκB activation by TNFα, lipopolysaccharide, thrombin, shear stress within blood vessels, mitochondrial metabolism and dietary factors such as elevated fatty acid and glucose intake [32]. Though endogenous antioxidants in the body respond to ROS challenge, dietary antioxidants, including vitamins C, D and E as well as carotenoids and polyphenols supplement the body's antioxidant capabilities both to reduce the risk for and mitigate damage in cardiovascular disease, chronic obstructive pulmonary disease, inflammatory bowel disease and certain cancers [33]. The highly polymerized quebracho tannins are not highly digestible in the human gut, but bind dietary glucose from starch which helps mitigate elevated blood glucose activation of NFκB-induced inflammation [34]. Colonic microbial digestion of the polymerized tannins leads to a more anti-inflammatory gut microbiome compared to diets with limited polyphenol intake [35]. Finally, a recent in vitro model of digestion demonstrates that quebracho tannins [36] yield not only short chain fatty acids (i.e., propanoic and butyric acids) which can support growth of beneficial microbiota, but also the release of anti-inflammatory flavonoids such as epicatechin gallate and gallocatechin that are more readily absorbed into systemic circulation [37]. The antioxidant properties of these and related polyphenols which down-regulate inflammatory pathways in the body may provide some measure of protection against certain diseases and the impact of viral infection.
It has also long been known that polyphenolic compounds improve antioxidant and anti-inflammatory status linked to lower rates of cardiometabolic disorders [28,38] and better outcomes in certain cancers [28,39,40]. In addition, polyphenols also mitigate the effects of certain viral infections [41][42][43]. Multiple natural compounds and extracts including polyphenols inhibit in vitro growth and plaque formation for SARS-CoV and MERS as well as seasonal coronaviruses [44].
The hypoxic phase of the SARS-CoV-2 infection and COVID-19 disease with pneumonia contributes to a ROS-mediated cytokine upregulation, increased inflammation in endothelial tissue and subsequent coagulation in blood vessels [45][46][47]. Many different polyphenolic compounds reduce ROS-induced inflammation in respiratory viral infection models of influenza and respiratory syncytial virus [48]. The potential protective effects of polyphenols against respiratory virusinduced ROS-mediated inflammatory disease is intriguing, though studies need to be conducted examining nutritional and oxidative status as a marker for more severe COVID-19 outcomes.

Conclusion
In IBS and inflammatory bowel disease, psychological stress induces permeability of the intestinal epithelium, a contributor to systemic inflammation [49][50][51]. A small study (N=73) of healthy older adults for self-reported GI symptoms (i.e., diarrhea, constipation, indigestion, abdominal pain, reflux) also demonstrates a link between psychological stress and a release of higher zonulin levels in the plasma, a marker for intestinal permeability [52]. Polyphenols in combination with other natural molecules such as analgesic peppermint provide a way to reduce psychological stress-related GI dysfunction by increasing Moderately Improved 7 (20) Greatly Improved 14 (40) Completed Improved 10 (29) Were you exposed to COVID-19 during the time you were on ATRANTIL  ? Yes 9 (26)

(74)
Knowing that a healthy gut leads to a healthy immune system, did you have more confidence taking care of your patients while taking ATRANTIL?  The current survey results in a frontline healthcare worker population suggest that the combined extract of quebracho, conker tree and M. balsamea Willd reduces both stress levels in response to the coronavirus pandemic as well as stress-induced GI symptoms to improve their overall quality of life and confidence. Results herein are viewed in the context that the survey is conducted by recall and inaccuracies may exist. A larger, controlled study analyzing specific markers of gut permeability and symptomology is warranted to delineate the exact mechanism by which this dietary supplement improves GI symptoms during elevated periods of psychological stress.