Antidiarrheal effects of caffeic acid in castor oil–induced diarrhea in broiler chicks (Gallus gallus domesticus)

Introduction

World Health Organization (WHO) defined diarrhea as the passage of three or more loose or liquid stools per day because of the abnormally high fluid content of stool or an abnormal increase in daily stool frequency [1] . Diarrhea, which accounts for 9% of all under-five deaths worldwide, is the second-leading cause of mortality in children under the age of five [2] . More than 80% of the 1.8 million individuals who die each year in impoverished nations from diarrheal infections are children under the age of five [3, 4]. In low- and lower-middle-income nations, diarrhea kills more than 90% of children under the age of five. Regionally, South Asia and sub-Saharan Africa (SSA) accounted for 88% of deaths in the same age group [2] . Children who have diarrhea will experience a variety of issues such as loss of appetite, electrolyte imbalance, malnutrition, an increased risk of contracting other infectious diseases, and slowed physical and mental development [5, 6]. Diarrhea is linked to several issues due to its detrimental effects on physical and cognitive development. It results in 72.8 million years of disability and adjusted life years and damages family finances and the healthcare system [7, 8].

Every year diarrheal diseases kill millions of the world's poorest people due to inadequate supplies and quality of drinking water and a lack of sanitation facilities [9, 10]. Additionally, studies showed that factors such as child age [11–15], maternal education [11, 12, 16], lack of awareness of mothers' and caregivers' [17, 18] lower socioeconomic status [12] , distance from a source of drinking water [11, 19, 20], latrines and facilities for washing hands [21, 22], breastfeeding [21, 23], place of residence [14, 22, 24], how children's feces are disposed of [24, 26], family size [17, 27], the number of under-five children living in the home [13, 18], maternal age [19, 20] and the mother's employment status [3, 17, 19, 28] all affect diarrhea in young children under the age of five. Based on the frequency and kind of symptoms, diarrhea is divided into acute, chronic, and infectious diseases. An episode of acute diarrhea is one that lasts less than two weeks. Acute diarrhea is most frequently caused by infection. The majority of instances are caused by viral infections and the illness is self-limiting. Diarrhea that lasts more than two weeks is referred to as "chronic diarrhea" and is typically not contagious. Malabsorption, inflammatory bowel disease, and adverse drug reactions are typical causes [29] .

Replenishing fluid and electrolyte loss is a crucial part of managing diarrhea [30] . Encourage patients to sip on fruit juice that has been diluted, Pedialyte, or Gatorade. In cases of severe diarrhea, IV fluid rehydration may be required [31] . Foods lower in fiber may help to make stools more firm. Bananas, toast, oats, white rice, applesauce, and soup or broth make up the bland "BRAT" diet, which is well tolerated and may help symptoms [32] . To lessen the frequency of stools, anti-diarrheal therapy with anti-secretory or anti-motility drugs may be initiated. They should be avoided in adults with bloody diarrhea or high fever, however, because they have the potential to exacerbate serious intestinal infections. In patients with more severe symptoms, empiric antibiotic therapy with an oral fluoroquinolone can be taken into consideration. Probiotic supplementation should be advocated in patients with acute diarrhea since it has been demonstrated to lessen the severity and duration of symptoms. Depending on the etiology, persistent diarrhea is treated differently [33] . Diarrhea is first divided into watery, fatty, and inflammatory categories. The next stage in management can be decided using an algorithm after categorization. In the majority of cases, more fecal tests, lab work or imaging are necessary. More invasive treatments such as an upper endoscopy or a colonoscopy may be required.

The primary hydroxycinnamic acid present in the diets of people is caffeine (CA), a polyphenol produced by the secondary metabolism of vegetables such as olives, coffee beans, fruits, potatoes, carrots, and propolis [34–37]. These phenolic compounds can be found in their simple form (monomers) as amides, glycosides, organic acid esters, sugar esters, dimers, and trimers, as well as in more complex forms like dimers, trimers, and derivatives of flavonoids. They can also be bound to proteins and other polymers in the vegetable's cell wall [38] . Because CA inhibits the development of bacteria, fungi, and insects and promotes the protection of plant leaves against ultraviolet radiation, it contributes to the defense mechanism of plants against predators, pests, and infections by ultraviolet-B (UV-B) [39] . Numerous physiological effects of CA and its derivatives have been demonstrated through in vitro and in vivo studies, including antibacterial, antiviral, antioxidant, anti-inflammatory, antiatherosclerotic, immunestimulatory, antidiabetic, cardioprotective, antiproliferative, hepatoprotective, anticancer and anti-hepatocellular carcinoma activity [40–47]. Given that hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality worldwide, the anti-hepatocarcinoma activity of these properties is emphasized [48] . As a part of the phenolic acid family of polyphenols, CA [(E)3-(3,4-dihydroxyphenyl) prop-2-enoic acid] is a hydroxycinnamic acid which is widely present in the human diet. Several naturally occurring foods, including kiwis, blueberries, plums, cherries, and apples, are rich in CA. Additionally, cereals, vegetables, salad, and cabbage all contain CA [49] . It is important to note that CA can also be found in foods like propolis, a resin derived from beekeepers [50] .

This research uses a castor oil-induced diarrheal model to assess the anti-diarrheal effects of caffeine. Additionally, a traditional co-treatment chick model has been used to assess the potential anti-diarrheal mechanism of this phenol derivative.

Materials and Methods

Chemicals and Reagents

All chemicals and reagents used in this study were of analytical grade. The details of the chemicals and their sources are presented in Table 1 . Figure 1 illustrates the chemical structures of loperamide (LOP) and caffeic acid, which are two significant chemicals that are used.

Selection and Preparation of Test/Control Groups

Two-day-old broiler chicks ( Gallus gallus domesticus ), weighing 40–42 g, were purchased from Khulna, Bangladesh, and housed in the Pharmacology Laboratory of Bangabandhu Sheikh Mujibur Rahman Science and Technology University (BSMRSTU), Gopalganj, Bangladesh. The chicks were maintained under standard laboratory conditions with a controlled temperature of 27 ± 1 °C and a 12 h light/dark cycle. Animals had free access to standard feed and water ad libitum.

All experimental procedures were conducted between 08:00 am and 3:00 pm. Following the experiment, the chicks were observed for an additional 17 hours to monitor any possible mortality. The experimental protocol was approved by the Department of Pharmacy, BSMRSTU (Approval No. #bsmrstu16-11/22).

Study Design (Castor Oil-Induced Diarrhea in Chicks)

The antidiarrheal activity was evaluated using a castor oil–induced diarrhea model following the protocol described by Sera et al. (2017) [51] , with slight modifications. After a 2-day acclimatization period, the chicks were fasted for 2 hours prior to the experiment, with free access to water. A total of twenty-five chicks (45–48 g body weight) of either sex were randomly divided into six experimental groups (n = 5 per group), as shown in Table 2 . Body weights were recorded before treatment administration. The respective treatments were administered orally via gavage at a volume of 10 ml/kg, 30 minutes before the oral administration of castor oil (1.0 ml) to induce diarrhea ( Figure 2 ).

To evaluate the possible interaction between the test compound and the reference drug, an additional combined treatment group (caffeic acid + loperamide) was included. After castor oil administration, the onset of diarrhea (latent period) and the total number of diarrheic stools over a 4-hour observation period were recorded for each group.

Statistical Analysis

All results are expressed as mean ± SEM (standard error of the mean) or as percentage values where appropriate. Statistical analysis was performed using one-way analysis of variance (ANOVA), followed by Student–Newman–Keuls post hoc test. Data analysis was carried out using GraphPad Prism software (version 6.5). Experimental groups were compared with the vehicle-treated control group, and differences were considered statistically significant at P < 0.05 with a 95% confidence interval.

Results

The effects of caffeic acid (CA) on the onset of castor oil–induced diarrhea in broiler chicks are presented in Table 3 and Figure 3 . Administration of CA at 30 mg/kg (Gr-II), the standard drug loperamide (Gr-V), and the combined treatment of CA with loperamide (Gr-VI) produced a statistically significant (P < 0.05) prolongation of the latent period when compared with the vehicle-treated control group (Gr-I). Among the CA-treated groups, the highest dose (30 mg/kg; Gr-II) markedly delayed the onset of diarrhea (47.33 ± 16.05 min), whereas the lower dose group (5 mg/kg; Gr-IV) did not exhibit a significant effect relative to the control. Notably, the combined treatment group (Gr-VI: CA + LOP) demonstrated the most pronounced delay in diarrhea onset (52.66 ± 5.83 min), exceeding that observed in all individual treatment groups, including loperamide alone. This finding suggests a potential synergistic or additive interaction between caffeic acid and loperamide in delaying the initiation of diarrheal episodes.

The effects of caffeic acid on the frequency of diarrheic stools over a 4-hour observation period are summarized in Table 4 and Figure 4 . Compared with the vehicle-treated group (Gr-I), administration of CA at 30 mg/kg (Gr-II) resulted in a statistically significant (P < 0.05) reduction in the number of diarrheal stools. A dose-dependent trend was observed, with the 15 mg/kg CA group (Gr-III) showing moderate efficacy, while the lowest dose (5 mg/kg; Gr-IV) exhibited minimal effect.

The greatest reduction in diarrheal frequency was observed in the combined treatment group (Gr-VI: CA + LOP), which recorded the lowest mean number of diarrheic stools (4.00 ± 0.89), closely followed by the loperamide-treated group (Gr-V). Importantly, the combined therapy demonstrated superior antidiarrheal efficacy compared with either CA or loperamide administered alone, indicating an enhanced therapeutic effect when both agents were co-administered.

These findings demonstrate that caffeic acid significantly attenuates the severity of castor oil–induced diarrhea in chicks, with enhanced efficacy observed at higher doses and in combination with the standard antidiarrheal agent.

Discussion

Diarrhea arises primarily from impaired intestinal water absorption, excessive electrolyte secretion, or a combination of both mechanisms. Clinically, diarrhea is commonly classified into acute and chronic forms, with infectious etiologies accounting for the majority of acute cases. Chronic diarrhea is further subdivided into watery, fatty (malabsorptive), and infectious types. From a mechanistic perspective, diarrheal disorders may be broadly categorized into secretory and osmotic forms. Osmotic diarrhea, such as that associated with lactose intolerance, results from the accumulation of osmotically active solutes within the intestinal lumen, leading to increased water retention and stool liquidity [52] . In contrast, fatty diarrhea is frequently associated with malabsorption syndromes, including chronic pancreatitis and celiac disease, where insufficient digestive enzyme secretion impairs nutrient absorption, particularly lipids, thereby increasing fecal fat content and stool volume [53] .

Castor oil–induced diarrhea is a well-established experimental model used to evaluate antidiarrheal agents due to its reproducible and predictable mechanism of action. Upon hydrolysis in the small intestine, castor oil releases ricinoleic acid, which induces irritation and inflammation of the intestinal mucosa. This process stimulates the release of prostaglandins, leading to altered intestinal electrolyte transport, inhibition of sodium and water reabsorption, increased intestinal secretion, and enhanced gastrointestinal motility, ultimately resulting in a hypersecretory form of diarrhea [54–56]. The ability of test compounds to counteract these effects is indicative of their potential antidiarrheal efficacy.

A wide range of medicinal plants and naturally occurring phytoconstituents have been reported to possess antidiarrheal properties through diverse mechanisms of action. Bioactive compounds such as tannins, flavonoids, and alkaloids exert antidiarrheal effects by reducing intestinal secretion, enhancing mucosal resistance, inhibiting prostaglandin synthesis, or modulating intestinal motility. Several plant-based remedies, including Psidium guajava (guava), Cuminum cyminum (cumin), and Cinnamomum verum (cinnamon), have demonstrated efficacy against diarrheal disorders. Additionally, natural products such as honey, ginger, and apple cider vinegar exhibit antimicrobial activity that may suppress diarrhea-causing pathogens. The growing interest in identifying specific phytochemicals with defined mechanisms of action reflects the urgent need for safer, cost-effective, and accessible antidiarrheal therapies, particularly in resource-limited settings [57] . However, despite their widespread use, natural antidiarrheal agents are not entirely devoid of adverse effects, underscoring the importance of rigorous pharmacological evaluation [58] .

The μ-opioid receptor plays a pivotal role in the regulation of gastrointestinal motility and fluid homeostasis. Activation of μ-opioid receptors decreases intestinal peristalsis and enhances fluid absorption, leading to reduced stool frequency and liquidity, whereas receptor blockade produces the opposite effect, resulting in increased motility and fluid secretion [59–61]. Loperamide, a peripherally acting μ-opioid receptor agonist, is widely used as a standard antidiarrheal agent due to its efficacy in reducing intestinal transit and secretion.

In the present study, caffeic acid administration significantly attenuated the severity and duration of castor oil–induced diarrhea in broiler chicks. Treatment with caffeic acid (Gr-II) resulted in a marked prolongation of diarrhea onset and a significant reduction in diarrheal frequency compared with the vehicle-treated control group. These findings suggest that caffeic acid exerts a protective effect against diarrheal insult, potentially through modulation of intestinal secretion, enhancement of mucosal integrity, and suppression of inflammatory mediators triggered by ricinoleic acid. Furthermore, the combined treatment of caffeic acid with loperamide (Gr-VI) produced superior antidiarrheal effects relative to either agent alone, indicating a possible additive or synergistic interaction between the two compounds.

Overall, the results of this study support the therapeutic potential of caffeic acid as a natural antidiarrheal agent. Its efficacy in delaying diarrhea onset and reducing stool frequency, particularly when co-administered with a standard μ-opioid receptor agonist, highlights its promise as an adjunct or alternative treatment strategy. Further investigations are warranted to elucidate the precise molecular mechanisms underlying its antidiarrheal action and to explore its translational applicability in clinical and veterinary settings.

Conclusion

The findings of the present study demonstrate that caffeic acid exhibits significant antidiarrheal activity in broiler chicks subjected to castor oil–induced diarrhea. Caffeic acid effectively delayed the onset of diarrhea and reduced diarrheal frequency, indicating its capacity to attenuate both the severity and progression of diarrheal episodes. Notably, co-administration of caffeic acid with loperamide produced enhanced antidiarrheal effects compared with either treatment alone, suggesting a potential additive interaction. These results support the potential utility of caffeic acid as a natural antidiarrheal agent in poultry, offering a promising alternative or adjunct to conventional pharmacological interventions. Given growing concerns regarding antibiotic use in animal production, caffeic acid may represent a viable non-antibiotic strategy for managing diarrheal disorders. However, further studies are required to elucidate the precise mechanisms underlying the antidiarrheal action of caffeic acid, to establish its optimal dosage and route of administration, and to clarify the nature of its interaction with loperamide. Additional investigations in other animal models and clinical settings are warranted to determine its broader therapeutic applicability.

List of Abbreviations

SSA - sub-Saharan Africa; CA - Caffeine; LOP - Loperamide; UVB - Ultraviolet-B; HCC - Hepatocellular carcinoma; ANOVA - Analysis of variance; SEM - Standard error of the mean; Gr - Group

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