Garcinia buchananii bark extract is an effective anti-diarrheal remedy for lactose-induced diarrhea☆
Graphical abstract
Introduction
Diarrheal diseases kill more children, especially those under five years of age than AIDS, malaria, and measles combined (UNICEF/WHO, 2009). Each year, 2.5 billion cases of acute infectious diarrhea occur in children below five years of age alone, and this accounts for over 1.5 million child deaths in low and middle-income countries, mainly in Africa and South Asia (Thapar and Sanderson, 2004, UNICEF/WHO, 2009). Furthermore, infectious diarrheal diseases are a significant cause of morbidity and mortality in HIV/AIDS patients, people displaced by disasters and wars and the elderly, (Nwachukwu and Okebe, 2008, Thielman and Guerrant, 1996) and a significant health care burden and loss of productivity around the world (Ocfemia and Taylor, 2004, UNICEF/WHO, 2009).
During the past four decades, concerted efforts have been made to combat the high morbidity and mortality rates associated with diarrheal diseases through improved sanitation and treatments using oral rehydration solution (ORS), anti-secretory and anti-motility agents, vaccinations, zinc supplements, antibiotics and other regimens (Guerrant et al., 2003, Kelly, 2011, UNICEF/WHO, 2009). These measures have succeeded in curbing the high mortality rates associated with diarrheal diseases (Guerrant et al., 2003, Kelly, 2011, UNICEF/WHO, 2009). However, millions of people are still dying from diarrheal diseases, suggesting a critical need for novel and affordable anti-diarrheal drugs.
The ultimate goal in diarrhea treatment is to prevent or reverse dehydration, gastrointestinal hyper-motility and fecal urgency, shorten the duration of the illness, reduce the pain or stress, and in some cases treat the infection and prevent nutritional complications (Brown, 2003, Field, 2003, Kelly, 2011, UNICEF/WHO, 2009). Key drawbacks to current treatment strategies are that they do not necessarily reduce the duration of the illness; as well as the fact that in developing countries 39% of the population have no access at all to modern anti-diarrhea therapies (UNICEF/WHO, 2009). It is therefore believed that over 80% of the population in developing countries depend on phytotherapy to treat diarrheal illnesses (Groombridge and Jenkins, 2002).
Garcinia buchananii (G. buchananii), Authority Baker, Family Clusiaceae (Brown, 1894), a plant native to Eastern, Central and Southern Africa is used by the indigenous population to treat dysentery, abdominal pain, and a range of infectious diseases (Balemba et al., 2010, Chinsembu and Hedimbi, 2010, Kisangau et al., 2007). In native communities, patients can treat themselves by either chewing the dried stem and root barks, or grinding the bark into powder, which is then added to water or beverages for drinking (Balemba et al., 2010, Chinsembu and Hedimbi, 2010). Recently, we showed that the aqueous extract from the stem bark of G. buchananii trees is a non-opiate preparation, which reduces peristalsis by inhibiting neurotransmission (Balemba et al., 2010) and 5-HT3 and 5-HT4 receptors (Boakye et al., 2012). Furthermore, the extract has anti-inflammatory, and anti-nociception effects (Castro et al., 2011). The compounds having anti-motility properties appear to be flavonoids, or a combination of flavonoids with alkaloids or steroids (Boakye et al., 2012). Clearly, research aimed at defining the bioactive components and mechanisms of action as well as indigenous uses suggest that G. buchananii could be an effective anti-diarrhea medication and also a source of novel non-opiate anti-diarrheal compounds. Currently, the only drugs available that rapidly shorten the duration of diarrhea and alleviate pain are opiates (Ruppin, 1987, Riddle et al., 2008). These drugs cause constipation, drowsiness and are addictive. Consequently they are not recommended for children (Kelly, 2011, Riddle et al., 2008). This indicates the unmet need for new non-opiate anti-motility compounds and the need for the formal testing of the efficacy of G. buchananii bark extract and its derivatives as treatments against diarrheal diseases. This also requires the use of diarrheal models.
Ingesting large quantities of lactose (45%–87%) causes osmotic diarrhea through increased secretion in the small and large intestine of animals (Bueno et al., 1994, Lawrence et al., 1956, Liuzzi et al., 1998) and lactose causes diarrhea in humans with lactose-intolerance accounting for over 50% of the world population (Haemmerli et al., 1965, Lomer et al., 2008). A novel hypothesis suggests that diarrhea, flatulence, nausea, pain and other symptoms of lactose-intolerance arise from the effects of toxic bacterial metabolites such as alcohols, acids, ketones and methylgyoxal on gut effector tissues including the epithelium, muscle and nervous tissue (Campbell et al., 2010). It has been shown that a high-lactose diet induces severe and persistent diarrhea, intestinal damage and malnutrition in experimental animals (Arciniegas et al., 2000, Bueno et al., 1994, Fijlstra et al., 2010, Liuzzi et al., 1998, Norton et al., 2001). These effects of lactose-induced diarrhea are to some extent, similar to changes seen in children suffering from gastroenteritis or chronic diarrhea (Bueno et al., 1994). Interestingly, diarrhea due to lactose intolerance is a common complication of infectious diarrhea in children with malnutrition (Brown, 2003, Moore et al., 2010, Nyeko et al., 2010).
The aims of this study were to investigate the effectiveness of G. buchananii stem bark extract in treating lactose-induced diarrhea in rats, determine the effective dose, and test the effectiveness of its anti-motility fractions PTLC1 and PTLC5 as anti-diarrheal agents.
Section snippets
Inducing diarrhea in rats using a high-lactose diet
The study was conducted in accordance with the regulations of the University of Idaho Institutional Animal Care and Use Committee (IACUC). Sixty two, 10 week old Wistar rats (389.2+/−6.3 g) were obtained from Harlan Animal Research Laboratory (Hayward CA, USA). Rats were individually caged (23–24 °C; 12:12 h light-dark cycle) and quarantined for one week. Rats were fed a standard chow diet ad libitum (Animal Specialties, Hubbard, OR, USA) and had free access to water for four days prior to the
Effect of a HLD on the form of feces, fecal fluid content and urine production
We found that all rats fed a SD diet produced many well-formed, rounded, oblong fecal pellets (20+/−2 pellets; 5.82+/−0.15 g per day), whilst mucus was not readily observable by visual inspection. However, the consumption of a HLD caused diarrhea in 67% of rats within 24 h and all rats within 48 h. The majority of diarrheic rats (46%) had severe diarrhea characterized by profuse, watery stools visibly containing lots of mucus (Table 1). Twenty three percent (23%) of rats produced wet, mucuoid,
Discussion
The purpose of this study was to examine the effectiveness of G. buchananii extract and its fractions with anti-motility actions as a treatment against diarrhea using a model of lactose-induced diarrhea. We provide evidence that G. buchananii extract and its anti-motility fractions are capable of treating HLD-induced diarrhea, whilst significantly increasing food and fluid consumption and significantly increasing body mass. The efficacy of G. buchananii bark extract treatment when used at
Conclusions
This study shows that G. buchananii is an effective remedy of lactose-induced osmotic diarrhea, with an efficacy comparable to loperamide. The complete reversal of weight loss, increase in food and fluid consumption are additional benefits that are required to effectively treat diarrhea. There is the need to establish the exact bioactive compounds and the mechanisms underlying the anti-diarrheal effects of G. buchananii in order to better understand how the extract works and lay the basis to
Conflict of interest
There are none.
Acknowledgments
Drs. Sofie Pasilis and. Onesmo B. Balemba are supported by the University of Idaho College of Science. Dr. Stuart M. Brierley is supported by a National Health and Medical Research Council of Australia (NHMRC) Australian Biomedical Fellowship. We thank Drs. Patrick J. Hrdlicka, Andrzej Paszczynski, and Lee Deobald for using their laboratory facilities.
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Author contributions: PAB was involved in all aspects of research, analyzed data and wrote the paper; SMB contributed to research design, critical review and intellectual content; SPP contributed to research design, supervision of research, critical review, intellectual content, and wrote the paper; and OBB was involved in research design, supervision of the study, data analysis, and interpretation and wrote the paper.