Gut health, an increasingly common expression in the Western world, covers multiple aspects of the gastrointestinal tract (GI) and numerous intestinal complaints, including flatulence, bloating, heartburn, nausea, vomiting, constipation, diarrhoea, food intolerance, abdominal pain and cramps.1
Generally speaking, much attention is devoted to the intestinal tract and, in particular, the microbiota and barrier integrity. These medical targets are particularly relevant because of the fact that alterations to the microbiota or barrier are crucial events in the pathogenesis of intestinal disorders such as diarrhoea, IBD, IBS and coeliac disease, or extra-intestinal conditions such as allergies, obesity, liver dysfunction and malnutrition.
However, if we look at the major criteria for a healthy GI system — beyond a normal microbiota and a stable immune system — the efficient digestion and absorption of food are fundamental cornerstones for well-being. In the human digestive system, nutrients undergo mechanical digestion through the action of mastication (chewing).
In parallel, they are exposed to the wetting action of saliva, which contains salivary amylase, an enzyme that initiates starch digestion; the saliva also contains mucus, which lubricates the nutrients, and hydrogen carbonate, which provides the ideal pH conditions (alkaline) for the amylase to work.
After undergoing mastication and starch digestion, the ingested food is converted into a small, round slurry mass called a bolus (Step 1). It then goes down the oesophagus and into the stomach as a result of peristalsis. Here, gastric juice — composed of hydrochloric acid and pepsin — is responsible for protein digestion.
As these two chemicals may damage the stomach wall, mucus is secreted to provide a slimy layer that acts as a protective shield.
The treatment of gastroduodenal disorders has dramatically improved since the discovery of Helicobacter pylori and the development of targeted treatments to cure peptic ulcers
At the same time that protein digestion is taking place, muscular contractions of the stomach wall provide additional peristaltic mixing, further blending the contents of the stomach with digestive enzymes. After approximately 1–2 hours in healthy humans, the resulting semifluid mass (chyme) is discharged (Step 2) through the pyloric sphincter; the chyme enters the duodenum, where it mixes with pancreatic and hepatic digestive enzymes, and then passes through the small intestine where further digestion continues (Step 3). When the chyme is fully digested, nutrients are absorbed; 95% of absorption occurs in the small intestine.
Steps 2 and 3 are critical for the optimised absorption of nutrients and play a fundamental part in healthy energy intake. An inefficient step 2, but mostly step 3, results not only in “malnutrition,” but also in a poorer quality of life, characterised by the incidence of heartburn, acid regurgitation, belching, abdominal swelling, a “heavy” stomach, pain in the upper abdominal area, slow digestion, a post-meal sense of fullness, nausea and vomiting.
A balanced diet and moderate daily exercise are often suggested as ways to ensure good digestion and a healthy lifestyle. However, complying with these recommendations is not always easy. The question is how to manage chronic or relapsing gastrointestinal symptoms such as early onset satiety, fullness and epigastric pain.
Functional dyspepsia (FD)
Stomach discomfort and pain are nothing new. The term “dyspepsia” originates from the Greek language and is more popularly known as indigestion. The word was first recorded in the mid-18th century and, since then, has been widely used. At the time, dyspepsia was thought to be one of the “nervous disorders,” along with hypochondria and hysteria.2 In the following 200 years, however, its classification and criteria have been much developed and elucidated to meet the clinical need to systematically describe functional GI disorders.
Today, dyspepsia refers to a collection of symptoms that affect the gastroduodenal region of the upper GI tract (most commonly in adults).3,4 Globally, the prevalence of functional dyspepsia (FD) varies between 11–29.2%. FD is not life-threatening and has not been shown to be associated with any increase in mortality.
However, the impact of this condition on subjects and healthcare services is known to be considerable, owing to the fact that up to 40% of people had consulted either primary care physicians or hospital specialists, more than 50% of dyspeptic subjects were on medication most of the time and approximately 30% of dyspeptics reported taking off work or school time because of their symptoms. Costs associated with the condition in the United States were in excess of $18 billion in 2009.
Treating FD
Within the population of FD sufferers, specific conditions are treated in different ways. Subjects without identifiable pathological conditions are observed and reassured. Actual symptoms are treated with PPIs, H2 blockers or a cytoprotective agent. Despite evidence of the impaired duodenal clearance of gastric acid and duodenal hypersensitivity to infused gastric acid, the efficacy of acid-suppressing agents such as PPIs or histamine H2-recptor antagonist is reported to be modest.
A substantial proportion of patients with FD have gastric motility and fundal accommodation abnormalities. Prokinetic agents, including cisapride, domperidone and itopride, have all been tested in FD and have been shown to be more effective than a placebo in a meta-analysis of 24 randomised trials.5
A balanced diet and moderate daily exercise are often suggested as ways to ensure good digestion and a healthy lifestyle
Cisapride was withdrawn because of its increased risk of adverse cardiac events and itopride was no more effective than a placebo in two large trials. Metoclopramide is not routinely recommended because of its uncertain efficacy and side-effects, and the prescription of domperidone has recently been restricted by the European Medicines Agency.6
Given the limited efficacy of the majority of conventional drugs, it is not surprising that up to 50% of subjects with FD seek out alternative therapies. However, for acupuncture, homeopathy or probiotics, evidence-based support is lacking. In this context, botanical supplements showed great potential.
Botanical ingredients for FD
Several botanicals have been studied or are under investigation for FD. In one placebo-controlled, double-blind study, it was found that an artichoke leaf extract was an effective treatment for FD.7 A multicomponent herbal preparation — Iberogast (a nine-herb combination product also known as STW5) — has demonstrated gastric fundus relaxation activity.8
Furthermore, a Chinese herbal preparation appears to be effective with no serious side-effects, even if the evidence remains weak (owing to publication bias and methodological flaws).9 And capsaicin resulted in the reduction in symptom scores in one small trial.10 Larger trials are, however, needed to support this hypothesis.
Major hurdles for botanicals in FD are the limited amount of evidence-based medicine and the lack of standardization, both in terms of ingredient quantity and the quality, which translates into a lack of consistency regarding physiological and clinical effects.
Recently, a promising patented and proprietary combination of Cynara and ginger extracts (CGs) has shown interesting results in GI discomfort studies. So far, two clinical trials are available to support their use in functional dyspepsia and promoting healthy digestion.11,12
In the first randomised, double-blind and placebo-controlled clinical study, conducted with 126 subjects, short-term supplementation with CGs (PRODIGEST) before meals showed a statistically significant relief of symptoms compared with a placebo in 14 days (p=0.017).11 It is interesting to note that the efficacy was maintained until the 28th day of intervention. This study’s primary outcome factor is the subject-reported change in FD intensity measured on a scale from 0–3 (0 = no improvement or worse, 1 = slightly improved, 2 = markedly improved and 3 = completely improved).
The percentage difference between the supplement and the placebo scores at the end of the study approached 34%, which is greater than the 15% range previously observed in clinical trials using synthetic (antisecretory and gastrokinetic agents) or natural products. Furthermore, 86.2% of the treated subjects reported the amelioration of FD, with a marked reduction of FD intensity in 63.1% (ratings of 2 or 3) compared with 24.6% of those in the placebo group. No adverse side-effects were observed.
Of significant relevance is the concomitant evaluation of CGs’ effects on single and specific symptoms of FD. The supplementation was associated with a reduction of epigastric fullness severity, bloating, early onset satiety and both nausea (p=0.03) and epigastric pain (p=0.036) scores. On the contrary, in the placebo group, there was an increase in the intensity of all observed symptoms.
In a second published clinical study, a randomised crossover trial involving 11 healthy volunteers showed that CGs consumed before a standardised meal significantly promoted gastric emptying, supporting its prokinetic activity (Figure 1).12
The administration of PRODIGEST before a standardised meal reduced the mean gastric area measured 1 hour after the meal in a significant way (8.4±0.7cm2 after supplementation versus 11.0±1.5cm2 for the placebo, p<0.001).
The observed 24% area variation between CGs and the placebo supports the hypothesis that CGs promote gastric emptying without being associated with notable adverse effects. PRODIGEST is a good example of how to redesign well-known extracts such as Cynara and ginger to develop a product that offers exhaustive clinical data supporting both functionality (gastric emptying) and efficacy (relief of discomfort).
What’s next?
The treatment of gastroduodenal disorders has dramatically improved since the discovery of Helicobacter pylori and the development of targeted treatments to cure peptic ulcers. However, the incidence of functional disorders is growing and there are new frontiers to be explored.
The increase of eosinophils in the duodenum and defects in barrier function may reflect an FD-associated micro-inflammation.13 Furthermore, an emerging gut condition, SIBO, like FD, also shares a motility disorder as one of its main etiologies.14 PRODIGEST, with an effective dose of 120mg (also available as a premix), could be the next major ingredient to target these conditions and further expand the range of available remedies for gut health applications.
References
1. S.C. Bischoff, “Gut Health: A New Objective in Medicine?” BMC Medicine 9, 24–37 (2011).
2. E. Hare, “The History of “Nervous Disorders” from 1600 to 1840 and a Comparison with Modern Views,” Br. J. Psychiatry 159, 37–45 (1991).
3. S. Mahadeva and K.L. Goh, “Epidemiology of Functional Dyspepsia: A Global Perspective,” World J. Gastroenterol. 12, 2661–2666 (2006).
4. N.J. Talley and A.C. Ford, “Functional Dyspepsia,” N. Engl J. Med. 373, 1853–1863 (2015).
5. P. Moayyedi, et al., “Pharmacological Interventions for Non-Ulcer Dyspepsia,” Cochrane Database Syst. Rev. 2006 (4): CD001960.
6. European Medicines Agency, “PRAC Recommends Restricting Use of Domperidone (7 March 2014): www.ema.europa.eu/ema/index.jspcurl=pages/news_and_events/news/2014/03/news_detail_002039.jsp&mid=WC0b01ac058004d5c1.
7. G. Holtmann, et al., “Efficacy of Artichoke Leaf Extract in the Treatment of Patients with Functional Dyspepsia: A Six-Week Placebo-Controlled, Double-Blind, Multicentre Trial,” Aliment. Pharmacol. Ther. 18, 1099–1105 (2003).
8. A.N. Pilichiewicz, et al., “Effects of Iberogast on Proximal Gastric Volume, Antropyloroduodenal Motility and Gastric Emptying in Healthy Men,” Am. J. Gastroenterol. 102: 1276–1283 (2007).
9. F. Qin, X. Huang and P. Ren, “Chinese Herbal Medicine Modified Xiaoyao San for Functional Dyspepsia: Meta-Analysis of Randomized Controlled Trials,” J. Gastroenterol. Hepatol. 24, 1320–1325 (2009).
10. M. Bortolotti, et al., “The Treatment of Functional Dyspepsia with Red Pepper,” Aliment. Pharmacol. Ther. 16, 1075–1082 (2002).
11. A. Giacosa, et al., “The Effect of Ginger (Zingiber officinalis) and Artichoke (Cynara cardunculus) extract Supplementation on Functional Dyspepsia: A Randomized Double-Blind and Placebo-Controlled Clinical Trial,” Evid. Based Complement. Alternat. Med. (2015): http://dx.doi.org/10.1155/2015/915087.
12. S. Lazzini, et al., “The Effect of Ginger (Zingiber officinalis) and Artichoke (Cynara cardunculus) Extract Supplementation on Gastric Motility: A Pilot Randomized Study in Healthy Volunteers,” Eur. Rev. Med. Pharmacol. Sci. 20, 146–149 (2016).
13. G. Holtmann and J. Talley, “Functional Dyspepsia,” Curr. Opin. Gastroenterol. 3, 492–498 (2015).
14. M. Gabrielli, et al., “Diagnosis of Small Intestinal Bacterial Overgrowth in the Clinical Practice,” Eur. Rev. Med. Pharmacol. 17, 30–35 (2013).
