Ginger in gastrointestinal disorders: A systematic review of clinical trials

Abstract Ginger, the rhizome of Zingiber officinale, which is used as a spice globally has a long history of medicinal use that stimulates investigators to assess its potential roles as an adjuvant therapy or alternative medicine in a range of diseases. Anti‐inflammatory, antioxidant, antitumor, and antiulcer effects of ginger have been proven in many scientific studies, and some of the ancient applications of ginger as a home remedy has been confirmed in human. In this review, we summarized the current evidence on the effects of ginger consumption on gastrointestinal disorders based on clinical trials. Our data indicate that divided lower daily dosage of 1500 mg ginger is beneficial for nausea relief. Because of limited number of studies on some other gastrointestinal disorders, the results may not be as much powered as to find significant results. Therefore, more extensive and well‐controlled human studies of ginger or its standard extracts are required to demonstrate its efficacy as a gastroprotective agent. Dose‐finding studies should be undertaken to accurately determine the effective dose and preparation of ginger in further clinical trials protocol.


| G A S TRI C EMP T YING AND DYS PEPS IA
Ginger as an important dietary agent which possesses carminative effect, decreases pressure on lower esophageal sphincter, reduces intestinal cramping, and prevents dyspepsia, flatulence, and bloating (Ali et al., 2008;Chrubasik, Pittler, & Roufogalis, 2005;Lohsiriwat, Rukkiat, Chaikomin, & Leelakusolvong, 2010). A clinical trial  investigated the effects of ginger extract (100 mg, corresponding to 2 g of rhizome twice a day) on gastrointestinal motility and showed a significant increase in gastrointestinal motility in the intervention group in comparison with the placebo (Micklefield et al., 1999). Wu et al. (2008) showed that ginger accelerates gastric emptying and stimulates antral contractions in healthy individuals; studies on patients with functional dyspepsia have shown the same results with no alterations in the fundus dimension, gastrointestinal symptoms, or serum level of gut peptides such as GLP-1, motilin, and ghrelin (Hu et al., 2011). Impaired gastric emptying is a well-recognized contributor to the pathophysiology of gastrointestinal problems such as functional dyspepsia and nausea. Functional dyspepsia is defined as postprandial fullness, early satiety, or epigastric pain/burning or discomfort centered in the upper abdomen in the absence of any known structural cause and without features of irritable bowel syndrome or gastroesophageal reflux; symptoms are frequently correlated to meals and may include abdominal pain, bloating, early satiety, fullness, belching, and nausea (Talley et al., 1999).
Prodigest is the standardized combination of ginger extracts and artichoke extract. Artichoke completes the effects of ginger because ginger is active on stomach while artichoke on small bowel. A randomized, 4-week trial on patients with functional dyspepsia showed that daily consumption of Prodigest before lunch and dinner resulted in a significant amelioration of functional dyspepsia symptoms including nausea, epigastric fullness, epigastric pain, and bloating as compared with placebo (Giacosa, Guido, et al., 2015). A randomized crossover study investigated the effects of Prodigest on gastric emptying in 11 healthy volunteers. In this study, the baseline area of gastric volume was determined by ultrasonography 10 min before the main meal.
Then, the subjects were given one Prodigest or placebo capsule and consumed a standardized meal. One hour after the meal, the gastric volume was measured again. The gastric emptying was compared by differences between gastric volumes. Finally, the results indicated that the after-meal gastric area was significantly smaller, with a −24% difference, following the combination of extracts, as compared with placebo. So, Prodigest significantly promotes gastric emptying in healthy volunteers without being associated with notable adverse effects (Lazzini, Polinelli, Riva, Morazzoni, & Bombardelli, 2016). These effects on gastric emptying are mostly dependent upon the peculiar molecular actions of the ginger extract. Gastric hypomotility involves a temporary dysfunction of the integrated network of cholinergic M3 and serotonergic 5-HT3/5-HT4 receptors.
Delayed gastric emptying leads to gastric intolerance to gavages and increases gastric residual volume, vomiting, risk of aspiration, and the length of stay in hospital in 30-51% of the patients (Davies, 2010;Landzinski, Kiser, Fish, Wischmeyer, & MacLaren, 2008).
Delayed gastric emptying and gastrointestinal motility disorder are the main gastrointestinal problem in the severely ill patients undergoing mechanical ventilation. A double-blind randomized controlled clinical trial showed that consumption of 120 mg ginger extract for 4 days significantly lowered mean residual volume of feeding with a standard gavage solution, on the fifth and the sixth days of feeding (Ghochae et al., 2013). Another study also showed that ginger extract increases the amount of tolerated food, and the amount of calorie intake in patients with adults respiratory distress syndrome under mechanical ventilation (Shariatpanahi, Taleban, Mokhtari, & Shahbazi, 2010).

| NAUS E A AND VOMITING
The most common cause of nausea and vomiting is pregnancy.
Administration of pyridoxine or doxylamine-pyridoxine might be beneficial. Medications such as dimenhydrinate, promethazine, ondansetron, or chlorpromazine can be used in severe cases, while 250 mg of ginger taken orally every 6 hr might be added at any time (Arsenault et al., 2002). The impact of ginger consumption as an antiemetic in nausea and vomiting of pregnancy has been extensively investigated in clinical studies for at least 30 years . The studies have shown that ginger in dose of 1 g/day is effective in pregnancy nausea and vomiting with no significant side effects (Firouzbakht, Nikpour, Jamali, & Omidvar, 2014;Haji Seid Javadi, Salehi, & Mashrabi, 2013;Saberi, Sadat, Abedzadeh-Kalahroudi, & Taebi, 2014;Thomson, Corbin, & Leung, 2014;Viljoen, Visser, Koen, & Musekiwa, 2014). American College of Obstetricians and Gynecologists (ACOG), and the National Institute for Health and Clinical Excellence, has accepted ginger as a remedy for nausea and vomiting during early pregnancy   (Table 1).
Another disturbing cause of nausea and vomiting is the side effects of chemotherapy (Ryan, 2010). Some chemotherapeutic agents, including cyclophosphamide and cisplatin, can lead to a high incidence of nausea and vomiting (Herrstedt & Dombernowsky, 2007). The standard of care for chemotherapy-induced vomiting is antiemetics, most notably serotonin (5-HT3) receptor antagonists and glucocorticoids, such as dexamethasone; however, efforts to control nausea have not been successful (Bloechl-Daum, Deuson, Mavros, Hansen, & Herrstedt, 2006;Herrstedt & Roila, 2008). The summary of studies evaluating the effects of ginger consumption on chemotherapy-related nausea and vomiting is shown in Table 2 ( Ansari et al., 2016;Arslan & Ozdemir, 2015;Fahimi et al., 2011;Manusirivithaya et al., 2004;Marx et al., 2013;Panahi et al., 2012;Pillai, Sharma, Gupta, & Bakhshi, 2011;Ryan et al., 2012;Sanaati, Najafi, Kashaninia, & Sadeghi, 2016;Sontakke, Thawani, & Naik, 2003;Thamlikitkul et al., 2017;Zick et al., 2009). Nausea and vomiting can occur after surgery, medications, or even exercise. Despite advances in surgical techniques and introduction of less-emetogenic anesthetic methods and drugs, postoperative nausea and vomiting, which occurs within 24 hr after surgery, are one of the common and distressing symptoms, following anesthesia and surgery . The frequency of upper and lower gastrointestinal disturbance as a consequence of exercise is reported to be between 30 and 70%, with the severity of symptoms ranging from mild stomach discomfort to severe diarrhea (Ball, Ashley, & Stradling, 2015). As it is shown in Table 3, 500 mg ginger per day can reduce postsurgery nausea and vomiting.
Generally, the most common and well-established use of ginger is its utilization in alleviating symptoms of nausea and vomiting (Lete & Allué, 2016).
Although the included studies generally reported statistically significant reductions in nausea and vomiting measures, the clinical significance of these results was controversial, which could perhaps be explained by the nonstandardized preparations of ginger used and inconsistencies in study methods and outcomes. Multiple potential mechanisms of action have been identified including 5-HT3 receptor antagonism, anti-inflammatory properties, and the modulation of gastrointestinal motility (Marx, Kiss, & Isenring, 2015;Marx et al., 2013) (Table 4).

| FAT T Y LIVER
Nonalcoholic fatty liver disease (NAFLD) is one of chronic liver diseases throughout the world that mostly is seen in obese, low active people, and patients with type II diabetes (Ong & Younossi, 2007).
There is no proven medical treatment for this disorder; however, following a healthy life style, modified diet and exercise are suggested by researchers (Thoma, Day, & Trenell, 2012). Previous studies have shown that a diet rich in antioxidants and anti-inflammatory agents can be effective in the treatment of NAFLD (Eslamparast, Eghtesad, Poustchi, & Hekmatdoost, 2015). Rahimlou, Yari, Hekmatdoost, Alavian, & Keshavarz (2016) conducted the first randomized, double-blind clinical trial study that examined the effects of ginger supplementation with lifestyle intervention on liver enzymes, inflammatory markers, steatosis, and hepatic fibrosis scores in patients with nonalcoholic fatty liver disease (NAFLD). In this study, 44 patients with NAFLD consumed 2 g of ginger supplement or placebo per day for 12 weeks. In both groups, patients were advised to follow a balanced diet and physical activity program and resulted in a significant decrease in inflammatory marker levels, liver enzymes, hepatic steatosis, and insulin resistance (that is one of the major risk factors in the pathogenesis of NAFLD) in ginger group. Inflammatory cytokines such as TNF-a play critical role in development of insulin resistance and liver fibrosis and increase fatty acids oxidation. Active compounds in ginger can enhance the antioxidant defense systems such as glutathione peroxidase and glutathione S-transferase, and reduce levels of malondialdehyde (MDA) and hepatic steatosis. Thus, reduction of TNFα and other inflammatory factors resulted in improvement of the NAFLD characteristics. In this study, no significant decrease was observed in liver fibrosis score in the ginger group compared to the placebo group. This can be due to the short term of the intervention, because it takes a long time for regeneration of hepatic tissue and reduction of fibrotic tissue. Further RCTs are needed to find the mechanism of action and ideal dose of ginger supplementation for NAFLD management.

| IRRITAB LE BOWEL SYNDROME (IBS)
Irritable bowel syndrome (  who were randomly consumed placebo, or 1 g of ginger, or 2 g of ginger daily for 28 days. Ginger was well tolerated but it did not show better effects in comparison with placebo. Since this is the first clinical trial on this topic and is a pilot study, it may not be powered enough to find significant results. The investigators also examined trends of these effects, and they found a trend of more improvement of IBS symptoms with placebo (brown sugar) than ginger. The placebo response in this study was 57% with twice as many side effects as the ginger group. In this study, the efficacy of ginger decreased with increase in dosage (26% decrease in symptoms with 1 g versus 12% decrease in symptoms with 2 g of ginger). Optimal ginger dosing should be examined in future trials. Both groups showed a relevant and significantly lowered arthritic pain, both on standing and moving, so that ginger was as effective as Diclofenac in reducing pain, while it was safer.

| G A S TROINTE S TINAL MALIG NAN CIE S
In a randomized clinical trial, 20 subjects at increased risk for colorectal cancer were assigned to receive either 2 g/day ginger or placebo for 28 days. They showed that ginger was tolerable and safe; however, it did not decrease eicosanoid levels in people at increased risk for colorectal cancer (Zick et al., 2015). Moreover, Zick et al. reported no significant difference in eicosanoids level in 30 subjects at normal risk for colorectal cancer. However, they found a significant decrease in PGE2 and 5-hydroxyeicosatetraenoicacid (HETE) and a trend toward significant decrease in 12-HETE and 15-HETE normalized to free arachidonic acid (Zick et al., 2011). In another trial, the effects of ginger (2 g for 28 days) on apoptosis, proliferation, and differentiation in the normal-appearing colonic mucosa from 20 patients at increased risk for colorectal cancer showed that ginger supplementation may reduce proliferation in the crypts of normalappearing colorectal epithelium, increase apoptosis and differentiation relative to proliferation, especially in the differentiation zone of crypts. This beneficial effect of ginger was found to be associated with downregulation of Bax, human telomerase reverse transcriptase (hTERT), and MIB-1, while p21 and Bcl-2 expression remained relatively unchanged. The estimated treatment effect on MIB-1 was not as strong, the estimated effect was more pronounced in the upper sections of the colorectal crypts, suggesting that ginger may decrease proliferation in the parts of the colorectal crypts most exposed to bowel lumen carcinogens (Citronberg et al., 2013). These findings are consistent with previous studies that suggested that the chemopreventive properties of ginger may be due to regulate cell function and viability (Keum et al., 2002;Lee & Surh, 1998;Miyoshi et al., 2003;Pan et al., 2008). In vitro and animal studies also suggest that ginger and its constituents may act as chemopreventive agents by reducing COX-2 expression immune function, lowering the activity of microbial enzymes (β-glucuronidase and mucinase), and blocking angiogenic signals that supply blood to tumor cells (Brown et al., 2009;Khater, 2010;Lu et al., 2011;Seo, Lee, & Kim, 2005;Yagihashi, Miura, & Yagasaki, 2008). Ginger has anti-inflammatory activities that play roles on its chemopreventive potential against colorectal cancer. In a study on 30 normal participants and 20 participants at increased risk for colorectal cancer, ginger significantly lowered COX-1 protein expression in participants at increased risk for colorectal cancer but not in the participants at normal risk.
However, ginger did not alter 15-hydroxyprostaglandin dehydrogenase (PGDH) protein expression in either increased or normal risk participants (Jiang et al., 2013). Some findings of other studies about beneficial effects of ginger and its constituents in GI cancer patients included: inhibition of COX and decrease in PGE2 concentrations in colorectal cancer (Levine et al., 2008), reduction in the incidence and multiplicity of adenomas (Zick et al., 2015), decrease in proliferation (hTERT and MIB-1) and differentiation (p21waf1/cip1) in colonocytes (Stoner, 2013), inhibition of CYP450, 1-aminobenzotriazole, and aldo-keto reductase in human liver microsomes, prevention of the formation of M14 and M15 and 18β-glycyrrhetinic acid in human liver microsomes (Chen, Soroka, Zhu, & Sang, 2013).

| DYS PH AG I A
Dysphagia is a major alarm sign in gastroenterology; however, impaired swallowing function from a combination of underlying disease and reduced physical and cognitive abilities could be a result of elderly. This phenomenon and, in particular, dysphagia are associated with reduced cough reflex leading to increased risk of aspiration pneumonia (Hirata et al., 2016). Furthermore, it may result in malnutrition, dehydration, and decreasing the patient's quality of life.
The swallowing reflex is controlled by substance P (SP) that released by nerve endings in the bronchial mucosa and oral cavity (Jin et al., 1994;Ujiie, Sekizawa, Aikawa, & Sasaki, 1993). Reduced salivary SP levels in older people are reported to be lower than in healthy younger individuals (Sekizawa, Ujiie, Itabashi, Sasaki, & Takishima, 1990  showed that stimulus on lingua-palatal swallowing pressure and rising and releasing lingua-palatal pressure duration were greater for carbonation + gingerol and carbonation than for water.

| ADVER S E EFFEC TS AF TER ING E S TI ON OF G ING ER
Ginger consumption rarely induces side effects such as mild gastrointestinal complications such as heartburn, belching, bruising or flushing, rash, and gastrointestinal discomfort. Adverse events were generally not significantly higher in the ginger group compared to the control group (Lete & Allué, 2016;Marx et al., 2013). In a study of 27 healthy volunteers who consumed a single oral dose of 100 mg to 2 g ginger, minor gastrointestinal upset was the major adverse effect (Zick et al., 2009). Despite previous studies indicating that ginger could interfere with platelet aggregation and cause excessive bleeding (Srivastava, 1986), a recent crossover study of 12 healthy volunteers who consumed 1.2 g of dried ginger rhizome three times per day for 2 weeks, ginger did not affect platelet aggregation and had no effect on the pharmacokinetics or pharmacodynamics of a single 25 mg dose of warfarin taken on day 7 (Jiang et al., 2005). Viljoen et al. (2014) also reviewed the safety of ginger as a secondary objective in their meta-analysis of nausea and vomiting of pregnancy and found that ginger did not have a risk for side effects or adverse events during pregnancy. In a prospective study,

Placebo standard preoperative antiemetic
Consumption: 1 capsule 30 min before induction of anesthesia and the second 2 hr after surgery evaluation: 0, 2, 2 ½ and 24 hr after surgery Ginger reduced the number of episodes of intraoperative nausea, but it had no effect on incidence of nausea, vomiting, or pain during and after an elective cesarean section under spinal epidural anesthesia Placebo+ IV Ondansetron (4 mg) Consumption: 1 hr prior to induction of general anesthesia Evaluation:18 h postoperation Significantly reduced the incidence of postoperative nausea and vomiting compared to ondansetron alone Placebo Consumption:1 hr before surgery, evaluation: 2, 4, 6 hr postoperation The frequencies of nausea in the experimental group at 2 hr postoperation were borderline significant but no significant differences between two groups in the intensity of vomiting The frequency and intensity of nausea and the frequency of vomiting among those ginger consumers in 2 separate 500 mg doses were less than the one dose and they both were less than placebo Placebo Consumption: 30 min before each dose of antiretroviral Regimen for 14 days Frequency of mild, moderate, and severe nausea and reported at least one episode of vomiting were significantly lower in the ginger than placebo Placebo Consumption one-half hour before each daily dose of antituberculosis drugs (fasting) for 4 weeks Nausea was more common in the placebo than the ginger group Placebo Consumption: 1 hr before the procedure Evaluation: at 2, 4 and 24 hr after operation The incidence of the nausea and visual analogue nausea scores was lower in ginger group than placebo at 2 and 4 hr. No difference at 24 hr was found in both groups. Incidence and frequency of vomiting between 2 groups were not statistically different Placebo Consumption: 1 h before the procedure Evaluation: at 2 and 6 h after operation.
At 6 h postoperation, ginger lowered nausea and borderline vomiting but at 2 hr, differences between the two groups for nausea and vomiting were not significant Placebo + dexamethasone (IV, immediately before the induction of anesthesia) the pregnancy outcome of 187 women who were exposed to ginger during the first trimester of pregnancy was compared with women who had been exposed to non-teratogenic drugs that were not antiemetic. There were no statistically significant differences between the two groups in terms of live births spontaneous abortions, therapeutic abortions, birth weight, or gestational age (Portnoi et al., 2003). A larger population-based cohort study in Norway (68,522 women) showed that the use of ginger during pregnancy (1020 women, 1.5%) was not associated with an increased risk of congenital malformations, still birth/perinatal birth, low birth weight, or preterm birth (Heitmann, Nordeng, & Holst, 2013).

| CON CLUS ION
Based on evidence from this systematic review, ginger could be considered a harmless and possibly effective alternative option for women suffering from the symptoms of nausea and vomiting in pregnancy. It seems that divided lower daily dosage of 1500 mg ginger is beneficial for nausea relief. Ginger did not pose a risk for side effects or adverse events during pregnancy. Ginger and its polyphenols have been shown to target multiple signaling molecules that provide a basis for its use against multifactorial human diseases such as cancer. Moreover, most of the known activities of ginger components are based only on in vitro and in vivo studies, except for a few clinical studies in some gastrointestinal disorders especially nausea and vomiting in human subjects and limited number in some other complications that may not be as much powered as to find significant results. Therefore, more extensive and well-controlled human studies are required to demonstrate its efficacy as gastroprotective agent, as it is a safe and cost-effective alternative. Dose-finding studies should be undertaken to accurately determine the effective dose and preparation of ginger.

FU N D I N G
There is no funding associated with this study.

E TH I C A L S TATEM ENT
This study does not involve any human or animal testing.
[Correction added on November 23, 2018 after online publication: the Ethical Statement was changed from "Since it." to "This study does not involve any human or animal testing.".]

CO N FLI C T O F I NTE R E S T
The authors declare there is no conflict of interest.