Gelatin tannate in pediatric infectious gastroenteritis

Introduction

The gastrointestinal (GI) tract is continuously exposed to the outside environment. Therefore, the gut barrier fulfills a major protective role, preventing toxic substances or pathogenic microorganisms penetrate the GI mucosal layers. Impairment of the GI mucus and epithelium allows the passage of the luminal contents into the underlying tissues and hence into the bloodstream. This is called a leaky gut.

Acute gastroenteritis (AGE) is worldwide a major cause of morbidity and mortality of infants and young children. Worldwide, AGE occurs yearly in 3 to 5 billion children causing nearly 2 million deaths in <5 years old children (1). The most common causes include Rotavirus, followed by adenovirus and norovirus (2), although vaccination may change this pattern. Oral rehydration solution (ORS) and rapid refeeding are the cornerstone of the management of infectious AGE. However, ORS does not shorten the duration of infectious diarrhea (3). Although infectious AGE is a self-limiting condition with a natural spontaneous recovery, shortening of the duration of diarrhea has a major socio-economic impact (4). Therefore, adjuvant treatment to shorten the duration of diarrhea has become part of the management. An international survey from 2019 about 82% of European health care professionals recommend the intake of probiotics, especially during an antibiotic course (90.2%), for diarrhea (83.5%) or constipation (70.6%) (5). Antibiotics are only indicated in case of some specific aggressive bacteria causing severe colitis and bloody diarrhea (6). Motility inhibitors such as loperamide are not indicated in pediatrics (7). A different category of substances that shorten the duration of diarrhea are mucoprotectors, which will be further discussed in this manuscript (8).

What is gelatin tannate?

Gelatin tannate, a combination of gelatin and tannic acid, modulates the intestinal barrier function (9). Gelatin, named in Latin gelatus (meaning stiff, frozen), is a transparent, colorless, flavorless food ingredient. It originates from collagen, which is present in animals, mainly porcine body parts. When it is dry, it is brittle and has a rubber-like consistency when moist. For many years gelatin has been frequently used as a gelling agent in drinks and food, but also in capsules used for vitamins or medications. Gelatin is also used in photography, film, paper, and cosmetic industry.

Tannic acid is a specific presentation of tannin, a kind of polyphenol. It is weakly acidic, with a pKa around 6, because of the presence of many phenol groups. The chemical formula for commercialized tannic acid is C76H52O46, decagalloyl glucose. However, to be precise, it is a mixture of polygalloyl glucoses or polygalloyl quinic acid esters. The number of galloyl moieties per molecule range between 2 to 12 depending on the plant source used to extract the tannic acid (10). Commercial tannic acid is frequently extracted from one of these plant parts: Tara pods (Caesalpinia spinosa), gallnuts from Rhus semialata or Quercus infectoria or Sicilian sumac leaves (Rhus coriaria). Tannic acid is labeled as ‘generally recognized to be safe’ (GRAS) by the United States Food and Drug Administration for use in baking, drinks, frozen dairy products, candies, meat products and rendered animal fat. Historically, in the late 19th and early 20th centuries, tannic acid was used in combination with magnesium and activated charcoal, as a treatment for intoxications with strychnine, mushrooms, and ptomaine poisonings (11). Usage in the 1920s for the treatment of severe burn injuries reduced mortality. The EU directive 89/107/EEC concludes that tannic acid is not a food additive and therefore does not have an E number. Tannic acid is a ‘food ingredient’. Tannate is the salt or ester of tannic acid. Albumin tannate is antidiarrheal.

Gelatin tannate forms a protective film over the intestinal mucosa by binding to mucins. The mechanisms result in protecting the gut mucosa from penetration by invasive bacteria. Gastric acid does not change the composition or structure of gelatin tannate. When gelatin tannate comes into the intestine, it restores the physiological barrier function and has an indirect anti-inflammatory effect (12). Gelatin tannate will cover only these parts where there is a mucin deficiency caused by the attack on the intestinal wall (9).

The intestinal mucosa forms a multilayered barrier composed of mucus and epithelium. Inhibition of adhesion of pathogenic micro-organisms to the epithelium is the main protective function of the mucus, but at the same time it offers a habitat for commensal bacteria. The stomach and colon have a two-layered mucus system, but the small intestine has only one layer. Mucus consists of 98% of water, while mucins, large glycosylated proteins, are responsible for its structure (13). In non-inflammatory AGE, there is a failure of the protective function of the mucus layer allowing microorganisms to adhere to the small intestinal mucosa. An increased permeability of the small intestinal mucosa is the consequence. Inflammatory diarrhea is caused by microorganisms that target the colon.

There are several therapeutic possibilities to decrease GI permeability, including corticosteroids, amino-salicylates and antitumor necrosis factor-α. Probiotics enhance mucin production to modulate the proteins of the epithelial tight junctions (14). Mucosal protectors or mucoprotectants, forming a protective layer over the epithelium, are an alternative option (9). Examples of mucosal protectors are bismuth and sucralfate. These substances are well documented to protect the GI epithelium from gastric acid and other digestive enzymes in peptic ulcer disease. Gelatin tannate and xyloglucan are substances that offer protection to the intestinal mucosa and have anti-diarrheal effects (8). Gelatin tannate remains a stable complex within the small intestine. Gelatin tannate exerts mechanical protection of the intestinal mucosa to pathogens (15). Gelatin tannate reduces the increased permeability between the jejunal tight junctions caused by Escherichia coli induced enteritis in an animal model (15). The gelatin tannate binds electrostatically with the mucin, creating a protein-based protecting layer over the intestine length, restoring the mucus layer. Gelatin tannate is also reported to modulate the composition of the gastro-intestinal microbiota (15). All these effects of gelatin tannate are synergetic and contribute to the restoration or normalization of the intestinal permeability.

Classification of mucoprotectors

Mucoprotectors are classified among the medical devices class IIa or III (16). These products are approved for the restoration of the mucus layer and its functions on the intestinal mucosa, and consequently, its efficacy in the shortening of the duration of diarrhea in AGE. A medical device is any appliance, apparatus, software, material, or other articles, which may be used in isolation or combination (as defined by the manufacturer) for a medical purpose. A medical device can have many different indications and/or compositions, ranging from breast implants over eye lenses to walking sticks. A medical device can be indicated and used in prevention and treatment of several conditions and diseases but is not metabolized or does not have any immunological or pharmacological action. The structure or composition of a medical device is not changed by any metabolic activity within the human body, but the medical device may have a mechanism of action facilitating immunological or metabolic activities of other substances. Tracheotomy tubes, dental fillings and surgical clamps are classified as class IIa medical devices; examples of Class III include cerebral stimulators, cardiac valves or pacemakers which are implanted. Some products indicated for multiple and repeated oral intake are commercialized in the European Union as Medical Devices (17). The monitoring after being put on the market of medical devices differs substantially from the assessments of medications (17).

Mucoprotectors in the clinical setting

Not many other mucoprotectors were tested in acute diarrhea. Two trials were performed in adults. Forty adults with AGE were included in a double-blind placebo-controlled trial in an Italian general practice setting (18). Responders were patients showing a reduction of at least 30% in both the stool (reduction of frequency of watery stools) and pain (assessed with a visual analog scale) indices. The gelatin-tannate group had 85% responders compared to 25% in the placebo group (P<0.001) (18). Gelatin-tannate was also evaluated in a community-based, multicenter, prospective observational Spanish trial in 54 adults with AGE (19). Diarrhea improved within 12 hours after starting the treatment, both for frequency and consistency of the stools (19).

More studies have been performed in children (Table 1). In a retrospective, observational study in Romania, children admitted for AGE received ORS and gelatin tannate or other antidiarrheal medications (both n=46) (20). Gelatin tannate was concluded to be more effective than the other medications, showing a decrease in the duration of the diarrhea (29.0 vs. 45.4 hours, P<0.001) and a larger proportion of children with a normalized stool consistency at 72 hours (87.0 vs. 30.4%; P=0.026) (20). Within the first 24 hours, a difference favoring the gelatin tannate was already observed (20). In Poland, a randomized controlled trial in 72 Polish children presenting with AGE was performed, comparing the effect of gelatin tannate (n=36) or placebo (n=36) above the rehydration therapy (21). Diarrhea duration showed no difference between the two groups: 75.6±27.8 hours in the gelatin tannate group vs. 75.5±29.0 hours in the placebo group (21). The negative outcome of this study may have been influenced by the fact that a duration of diarrhea for up to 5 days was allowed for inclusion (21). No information is provided on the number of children who had diarrhea for 3 days or more at inclusion (21). However, the natural recovery of AGE is estimated to be 4–5 days (26). A Turkish randomized, controlled, double-blind, parallel-group, single-center study compared ORS versus the efficacy of ORS with gelatin tannate (n=71) or placebo (n=73) in 3 months to 12 years old children with AGE (22). Within the first 24 hours, the number of watery stools had decreased significantly in the gelatin tannate group (after 12 hours: 59.2% vs. 77.0% with watery stools; P=0.010) (22). Consequently, a difference in defecation frequency was observed as well (mean 2 vs. 3 stools between start and 12 hours; P<0.010) (22). The ’stool Decrease Index’ improved significantly more in the intervention than in the placebo group (at 12 hours: 66.6% vs. 33.3%; P<0.010) (22). Another Turkish randomized, placebo-controlled, single-blinded, prospective study involved children aged from six months to 10 years with acute diarrhea (23). The authors concluded that gelatin tannate resulted in a decreased stool frequency at 12 hours and resulted in a better weight gain compared to placebo (23). However, duration of diarrhea did not significantly differ between both groups: 42 (6–260) vs. 44 (8–360) hours (P=0.38) (23). A multicenter, randomized, controlled, single-blinded and open label trial was performed in Italy in 60 children (3–72 months old) with AGE (24). Randomization was generated by a central computer: 29 children were only rehydrated with ORS and in 31 the rehydration therapy was supplemented with gelatin tannate (24). The intervention group had a significant shorter duration of diarrhea (76.8±19.2 vs. 108±24.0 h; P<0.001) (24). Safety of gelatin tannate was confirmed since no adverse events were mentioned (24). After three days, the number of defecations was significantly lower in the gelatin tannate group (24). The improvement of the diarrhea was reported sooner in the gelatin tannate group, and the duration of diarrhea was shorter (24). In another pediatric trial involving 3 months–12 years old children, the use of ORS and gelatin tannate was associated with a greater decrease in stool after 12 hours (25). A different tannate was tested in a trial including 3–21 months old infants with AGE (27). All infants were hospitalized, and AGE of both viral and bacterial origin were included (27). All patients were treated with ORS and received or placebo (n=20) or the tannin-rich carob pod powder (n=21) (27). Diarrhea duration in the intervention group was 2.0±0.27 days versus 3.75±0.30 days in the placebo group (P<0.001) (27). Secondary outcomes such as normal stool consistency, fever, weight gain and emesis improved all significantly better in the tannate-group (27). The tannate was well accepted (27).

Data from MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials, LILACS and grey literature, published from inception to October 2018, were included in a meta-analysis and systematic review (28). Only three studies (276 children) out of 797 identified papers could be included. Significant differences between placebo and gelatin tannate were not observed regarding duration of diarrhea [mean difference (MD)=−15.85 hours; 95% confidence interval (CI): −42.24 to 14.82, I²=92%; three studies], stool frequency at day 2 (MD =0.11 stools/day; 95% CI: −0.39 to 0.62: I²=26%; two studies), diarrhea at day 3 [risk ratio (RR) =0.46; 95% CI: 0.06 to 3.47: I²=73%; two studies], vomiting (RR =1.31; 95% CI: 0.95 to 1.80: I²=0%; two studies) or adverse events (RR =0.86; 95% CI: 0.27 to 2.66: I²=0%; two studies) (28). The most frequently reported adverse events were abdominal pain and nausea (28). The authors concluded that the gelatin tannate did not shorten diarrhea and defecation frequency on day 2 compared to placebo (28). However, the outcome of meta-analyses is influenced by the inclusion criteria, which for this manuscript were: (I) limitation to randomized controlled trials, quasi-randomized controlled trials assessing gelatin tannate compared to no intervention or placebo in children up to the age of 18 years; (II) presumed or proven presence of an infectious agent; (III) diarrhea-definition similar to that of the World Health Organization or American Academy of Pediatrics definition (28). Another meta-analysis analyzed the effect of gelatin tannate in pediatric AGE (n=203 patients) in three randomized controlled trials (RCTs) versus placebo (n=204) (29). The authors reported that gelatin tannate resulted already after 12 hours of administration in a significant (P<0.01) decrease of stool frequency in two RCTs (29). Gelatin tannate administration resulted in a significantly reduced risk ratio (0.74; P<0.01) for diarrhea or liquid stools after 24 hours (29).

More evidence is needed on the efficacy of gelatin tannate in well-designed RCTs in infants and young children with infectious AGE before active recommendations can be made. Most of the data come from studies performed in Eastern Europe. Therefore, more data from other parts of the world would be welcomed. Since probiotics and racecadotril are as well positioned as “reducing the duration and severity of AGE”, it would be interesting to perform blinded comparative clinical trials. Vaccinations change the etiology of infectious AGE. Since the morbidity and mortality of AGE are most important in the developing world, it is recommended to set up clinical trials in this part of the world. From the point of view of mode of action, it would be of interest to analyze the loss of electrolytes when gelatin tannate is administered in comparison to placebo.

Conclusions

Pediatric AGE is still a frequent and important cause of morbidity and even mortality. Since dehydration is the major consequence of the condition, ORSs are the cornerstone of its management. However, ORS does not reduce the duration of infectious diarrhea. Therefore, the social and economic impact of AGE in children cannot be neglected. Gelatin tannate was shown to be an effective and safe medical device that shortens the duration of infectious AGE by about 24 hours by reducing the duration and severity of diarrhea. The administration of gelatin tannate is easy, not very costly and effective. Therefore, considering the safety profile and mechanisms of action viewpoint, gelatin tannate is an option that should be considered and could maybe be preferred to probiotics or racecadotril. Gelatin tannate can be considered as a “mucus regenerator”, a new class of substances (it is registered as a medical device) with an indication in pediatric AGE. Gelatin tannate restores the increased intestinal permeability by improving the quality of the intestinal mucus layer and modulates and restores the intestinal microbial composition (15,30). Gelatin tannate was shown in vivo conditions to be a mucoprotector (30). This efficacy and safety profile makes this medical device attractive in the management of AGE in developing countries (30).

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-44/prf

Funding: This work was supported with an unrestricted grant from Noventure.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-44/coif). The authors have no conflicts of interest to declare.

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