Nutritional and Botanical Approaches for Inflammatory Bowel Disease

Abstract

Alternative and Complementary TherapiesVol. 27, No. 3 Free AccessNutritional and Botanical Approaches for Inflammatory Bowel DiseaseKhara LuciusKhara LuciusSearch for more papers by this authorPublished Online:15 Jun 2021https://doi.org/10.1089/act.2021.29331.kluAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionInflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are immune-mediated processes that lead to chronic inflammation of the digestive tract. The incidence of IBD is on the rise worldwide; according to data from the Global Burden of Diseases, Injuries, and Risk Factors Study, an estimated 6.8 million people worldwide were living with IBD as of 2017, with the highest incidence seen in North America.1 Per the Centers for Disease Control, 3.1 million adults (or 1.3% of the population) in the United States had IBD as of 2015, a substantial increase from 1999, when 1.8 million U.S. adults reported having IBD.2,3 By 2025, an estimated 2.2 million Americans are projected to be living with IBD.4 While IBD remains a greater concern in industrialized nations, developing countries around the world are also seeing steady rises in incidence.5Once assumed to be strictly autoimmune in nature, IBD is now thought to be more complex in its etiology, with a combination of immune-mediated and autoimmune factors potentially involved. Serum and mucosal autoantibodies to intestinal epithelial cells are seen in both CD and UC. Both conditions also involve a generalized increase in immune reactivity against gut bacterial antigens, and abnormalities of both cell-mediated and humoral immunity.6 It is likely that interactions between genetic factors, the gut microbiota, environmental factors, and immune factors may be involved in the pathogenesis of these conditions. The importance of the gut microbiome in IBD cannot be understated. Dysbiosis combined with genetic susceptibility and abnormal gut barrier function may drive a disordered mucosal immune response that promotes inflammation and tissue damage in IBD.7 Because this is such a central factor, we will further discuss the role of the microbiome in IBD below.It is suggested that 70% of IBD risk is driven by environmental or lifestyle factors, with 30% of risk attributable to genetics.8 Environmental or lifestyle-related risk factors for IBD are numerous. Hypovitaminosis D, cigarette smoking, infections, poor sleep function, and depression are all associated with incidence of IBD.8,9 A multitude of dietary factors are also implicated. Increased dietary consumption of saturated fats and animal fats, sugars, and linoleic acid is all associated with increased risk of IBD. Dietary fiber intake (especially from fruits and vegetables), ω 3 polyunsaturated fats, and citrus fruit appear to be protective.9–11 Rogler et al. point out that the effects of many of the above risk factors may be mediated by their impact on the microbiome (or, using the example of infections, may potentially reflect increased use of antibiotics, with resultant changes to the microbiome).8 Many of the same factors associated with risk of initially developing IBD are also associated with disease flares in those with pre-existing UC or CD.CD and UC both result in significant impairments to quality of life (QOL). QOL may be impacted not only by disease activity and recurrent symptoms, but also by side effects from medical or surgical management. In one survey, lower health-related QOL in people with IBD was associated with disease severity, poor sleep quality, and lack of folic acid consumption.12 In a review by van der Have et al., disease activity was responsible for 37% of health-related QOL in people with CD, while other determinants were responsible for the remainder (such as relapse rate, impact to work function, treatment with corticosteroids, or hospitalizations).13 Extraintestinal symptoms (including musculoskeletal pain, dermatologic symptoms, and hepatopancreatobiliary disorders) are also common, occurring in up to 40% of people with IBD, and often have a significant impact on day-to-day function.14While there are numerous commonalities between CD and UC, these two conditions are of course distinct pathophysiologically and in terms of disease distribution. While UC affects the colon only, CD may affect any portion of the gastrointestinal (GI) tract (most frequently the terminal ileum and right side of the colon) in a discontinuous distribution characterized by “skip lesions.” Histologically, inflammation in UC is limited to the mucosa, with distortion of crypts and cryptitis both being possible. In CD, however, inflammation may be transmural or submucosal, with fistulas, ulcerations, and granulomas seen histologically.15 There are also distinctions in the gut microbial signatures of each condition, although these differences are not completely elucidated or understood at this time.16Regarding the immune response seen in these conditions, both UC and CD appear to involve alterations in T helper 17 (Th17) cell and regulatory T cell activity, important regulators of immunity versus tolerance.17 Both conditions have also been found to involve increased levels of interleukin (IL)-21, which promotes a positive feedback loop prolonging the inflammatory state.18 UC is thought to be a T helper 2-driven condition, with increased IL-5 and IL-13 cytokine levels. CD, however, is thought to be caused by an overactive T helper 1 response, with excess activation of IL-23/Th17 in response to microbial antigens. These distinctions are likely important for the way these conditions respond to varying types of treatment, and may point to future directions in creating therapies that are personalized and optimally effective for IBD, although the exact pathophysiology of CD and UC remains incompletely understood.17,18In this article, we will review the importance of the microbiome, and also discuss the role of nutritional approaches and botanical medicines in people with IBD. Several of the trials discussed below utilize either the Crohn's Disease Activity Index (CDAI)19 or the Short Inflammatory Bowel Disease Questionnaire (SIBDQ)20 to assess outcomes. Note that these questionnaires are generally reserved for clinical trials and are not typically used in the context of clinical practice. For ease of reference, these validated questionnaires are included in Appendix Table A1 (CDAI) and Appendix Table A2 (SIBDQ).The Microbiome in IBDAs mentioned above, it is thought that a disordered immune response to gut dysbiosis may drive disease activity in IBD. Cross-sectional studies have confirmed the presence of gut microbiome dysbiosis in subjects with IBD. IBD sufferers also experience more dramatic fluctuations in the composition of the microbiome compared with healthy individuals, with patients with ileal CD appearing to have the most dramatic deviations in fecal microbiome composition.21 In addition, people with IBD have been shown to have specific taxonomic alterations to the microbiome, such as enrichment of some proinflammatory bacteria, including adherent-invasive Escherichia coli and Fusobacterium species. This occurs in conjunction with an under-representation of anti-inflammatory bacteria, such as those from the Faecalibacterium genera, or short-chain fatty acid (SCFA) and butyrate-producing bacteria such as Odoribacter, Leuconostocaceae, Phascolarctobacterium, and Roseburia.22 Fermentation products such as butyrate or other SCFAs may participate in epigenetic regulation of inflammation, as may gut bacteria themselves, and therefore may serve as important modulators of pre-existing genetic risk for IBD.23 SCFAs also play an important role in helping maintain gut barrier integrity.Aside from bacteria, gut fungi are also altered in people with IBD. People with CD have been shown to have increased total gut fungal load in both fecal samples and the gut mucosa, especially Candida and Malassezia species. Specific polymorphisms in CD patients may contribute to gut colonization by Malassezia species, exacerbating gut inflammation. People with UC have also been demonstrated to have reduced gut fungal species diversity. How the mycobiome may interact with the microbiome in modulating the development of IBD is largely unexplored, but may be a target of future study and treatment.24How might interventions that modify the microbiome impact people with IBD? Numerous studies have examined the effects of probiotic supplementation in people with IBD. In people with active UC, meta-analysis indicates that bifidobacteria-containing probiotics are effective in inducing disease remission (P = 0.002), and probiotics also lead to significant increases in fecal SCFA content.25 Probiotics have also been shown to help prevent relapse in people with UC, with meta-analysis demonstrating an effect equivalent to aminosalicylate drugs (5-ASA).26 The efficacy of probiotics for inducing remission or preventing relapse in people with CD remains less certain, with meta-analysis demonstrating no significant effect of probiotic supplementation.26Fecal microbiota transplant (FMT) represents a new tool in altering the gut flora in people with IBD. A 2014 systematic review and meta-analysis examined data from cohort and case studies as well as one randomized clinical trial on FMT. One hundred twenty-two subjects were included in the analysis (the majority of whom had UC). The overall remission rate with FMT was 45%. While people with CD were a minority in this trial, subgroup analysis indicated that they were more likely to respond than those with UC (61% of CD patients achieved remission with FMT, while only 22% of people with UC did).27Specific to UC, two additional clinical trials on FMT were published in 2015, with mixed results. One of these randomized UC patients on immunosuppressants (N = 75) to either FMT (from one of six donors) or water enemas on a weekly basis for six weeks. FMT resulted in significantly greater remission rate than the placebo (25% compared with 5%, P = 0.03). One interesting observation from this trial was that FMT from one specific donor was significantly more likely to induce remission than FMT from the other donors. FMT from this single donor induced remission in 39% of patients, while FMT from other donors induced remission in just 10% of patients. FMT was also more successful in people who had been more recently diagnosed (less than one year disease duration, with three of four of those subjects achieving remission).28 A second trial in people with mild-to-moderate UC randomized participants (N = 48, with 37 subjects completing endpoint assessment) to receive either two FMT treatments or an autologous stool transplant at week 0 and week 3. In this trial, 41% of FMT subjects and 25% of placebo subjects achieved clinical remission (CR) and at least a 1-point decrease in the Mayo endoscopic score at 12 weeks, a nonsignificant difference (P = 0.29).29Additional placebo-controlled clinical trials in people with UC have since been performed by Paramsothy et al. and Costello et al. Including all four trials from 2015 onward, 28% of people overall with UC achieved remission with FMT compared with 9% of those who received placebo (P = 0.0002). A clinical response was seen in 49% of people who received FMT compared with 28% of those who received placebo (P = 0.0003).30Specific to CD and FMT, published data are not abundant. Pooled data as part of a meta-analysis of six cohort studies (N = 71) found that FMT resulted in remission in 52% of CD subjects, with clinical response seen in 63%.31 Levy et al. point out that disease heterogeneity may impact these results, with some CD phenotypes potentially responding to FMT better than others, although which phenotype may most benefit remains an unanswered question.30Nutritional Approaches in IBDAs mentioned above, various nutritional factors have been linked with risk for IBD. As the diets of people in developing countries shift and change, the incidence of IBD also increases. Nutrition may play an important role in IBD for a variety of reasons. Diet modifies the gut microbiome and provides substrates for bacterial fermentation end products and SCFAs. Diet is also a well-known gene expression modifier.23 Various nutrients may reduce inflammation or modify the immune response. Polyphenols from plant foods, or additional dietary nutrients (such as folate, choline, B vitamins, and methionine) may modulate or provide substrates required for DNA methylation (an epigenetic modification that has been correlated with IBD pathogenesis, with both aberrant hyper- and hypomethylation having been demonstrated in tissue specimens from people with IBD32).Several specific diets have been assessed for their impact in people with IBD, including an elemental diet,33,34 low fermentable oligosaccharides, disaccharides, monosaccharides, and polyol (FODMAP) diet,35 the autoimmune protocol (AIP) diet,36 and a diet targeting elimination of foods with high immunoglobulin G 4 (IgG4) titers by enzyme-linked immunoassay (ELISA).37The elemental diet provides a complete complement of basic proteins (as free-form amino acids, without whole proteins or small peptides), fats (often as medium-chain triglycerides), and carbohydrates, along with essential micronutrients sufficient to meet Recommended Dietary Allowances (RDA) requirements. Traditionally administered via tube feeding due to poor palatability, elemental diet formulas have improved in taste over time, resulting in the availability of oral formulas as well. The elemental diet has been studied in people with both UC and CD,38 and small trials of the elemental diet as the primary therapy for people with CD indicate a comparable benefit to steroids.Elemental DietMay be administered as tube feeding or oral formula.Provides complete complement of: Basic proteins as free-form amino acids, without whole proteins or small peptidesFats, often as medium-chain triglyceridesCarbohydratesEssential micronutrients sufficient to meet RDA requirements.The first trial included 22 people with moderate CD (median age of 30 years) who were randomized to receive an oral elemental diet or high-dose corticosteroids for two weeks. The elemental diet group experienced significant amelioration of CDAI, erythrocyte sedimentation rate (ESR), body mass index, and prealbumin levels (P < 0.01, P < 0.05, P < 0.02, P < 0.01, respectively), while those in the steroid group experienced significant improvement in CDAI and fat-free body mass (P < 0.04 and P < 0.05). In addition, the elemental diet subjects experienced improved measures of intestinal permeability (as measured by a levulose[fructose]/mannitol ratio assessment, P < 0.01), an effect not seen with steroid treatment. The authors concluded that a short-term elemental diet in people with moderately active CD was as effective as corticosteroids for inducing remission. They also suggest that the elemental diet may potentially be superior to steroids for improving nutrition status due to positive effects on intestinal permeability.33The second trial of the oral elemental diet in comparison with steroids involved 21 people with active CD (with disease activity severe enough to warrant hospitalization) who were randomized to one of these interventions for a four-week period. Both treatments resulted in significant equivalent improvements in average clinical scores within one week, with continued improvements in both groups during the course of the trial. Both groups also experienced significant increases in serum albumin (P < 0.05), although the increase was greater with the elemental diet than with steroids. In addition, ESR decreased significantly and comparably for both groups (P < 0.05). Hemoglobin increased significantly in both groups by four weeks (P < 0.05), but only elemental diet subjects maintained this increase through three months of follow-up (P < 0.05). The authors concluded that the elemental diet was as effective as steroids in inducing remission in active CD, with 80% of people in both groups achieving remission by four weeks.34Low FODMAP DietDiet restricts intake of fermentable carbohydrates, including oligosaccharides, disaccharides, monosaccharides, and polyols.Based on the concept that fructose and lactose may be malabsorbed in susceptible individuals, driving increased gas production and small intestinal distension.Turning to the low FODMAP diet, several trials have been performed in people with IBD, mostly involving subjects with CD. Popa et al.'s 2020 review identified 12 studies examining the effects of the low FODMAP diet in IBD. While trials were small (ranging from 8 to 100 participants) and had a variety of designs, this review identified several effects from the low FODMAP diet in people with IBD. These included reduction of GI symptomatology (such as bloating, abdominal pain, flatulence, and diarrhea), improved health-related QOL, improved abundance of butyrate-producing gut bacteria, and better stool frequency and consistency.35 Fructose malabsorption appears to be more common in people with CD than in people without. In addition, lactose malabsorption has been shown to occur more often in people with UC than in healthy controls. It is suggested that restricting intake of these easily fermentable carbohydrates by utilizing a low FODMAP approach may reduce gas production and distension in the small intestine.39 Because IBD may involve some degree of visceral hypersensitization,40 it seems plausible that measures that reduce small bowel distension would lead to improvements in GI symptoms.AIP DietEliminates numerous foods or food groups thought to increase gut inflammation or dysbiosis, including:LegumesNightshadesGrainsDairyEggsCoffeeAlcoholNuts and seedsOilsRefined sugarsAdditives.The AIP diet, which eliminates several food groups that are thought to increase gut inflammation or contribute to dysbiosis (such as legumes, nightshade plants, grains, dairy, eggs, coffee, alcohol, nuts, seeds, oils, refined sugars, and food additives), has been studied in a pilot-scale, open uncontrolled trial in adults with IBD. Subjects (N = 15, 9 with CD and 6 with UC) had active CD (defined as a Harvey–Bradshaw index [HBI] ≥5) or UC (defined as a partial Mayo clinic score ≥3), plus objective evidence of active disease by either imaging or endoscopy. The AIP diet intervention consisted of a six-week elimination diet (staged elimination of the food groups mentioned above), with a five-week subsequent maintenance phase. Subjects also received Vitamin D and iron supplements if indicated to achieve repletion. At week 6, 73% (11 of 15) of subjects overall had achieved CR. All 11 of these subjects maintained this remission through the maintenance period of the trial. There was a significant improvement of mean total SIBDQ scores at both week 6 and week 11 of the trial (P = 0.017 and P = 0.045). Achievement of CR was similar for those with CD and with UC. Some participants were able to discontinue the use of corticosteroid medication during the trial. The authors noted that in the two CD patients who had ileal strictures, either worsening of disease activity or partial small bowel obstruction (attributed to a large increase in the consumption of raw vegetables, salads, and meat) was seen, highlighting the need for close follow-up, and the important role of individual anatomic variations in response to dietary change.36Elimination Diet Based on IgG4 ReactivityBased on the concept that specific protein antigens may promote inflammation in some IBD sufferers.IgG4 titers determined against foods using ELISA.Foods with highest antibody titers are then excluded from the diet.As a separate approach to the elimination diet, an exclusion diet program based on IgG4 reactivity has also been assessed for its effects in people with IBD (specifically, CD). This approach is based on the hypotheses that specific protein antigens may promote inflammation in some people with CD. In a double-blind randomized sham-controlled trial of 98 people with CD, IgG4 reactivity was utilized to guide food exclusion. Subjects were randomized to either a true diet group (avoiding the foods to which they were found to be sensitive) or a sham diet group for four weeks. Seventy-six subjects eventually completed the trial. Overall, titers for beef, pork, egg, and dairy were highest, and titers for rice, chicken, potato, and tomato were generally low. At the conclusion of the trial, the decrease in SIBDQ score and CDAI was significantly greater in the true diet group than in the sham diet group (P < 0.05 and P = 0.009). C-reactive protein (CRP) and fecal calprotectin levels were not significantly changed.37Despite the above, there is no general consensus on the best dietary approach overall for people with IBD.41 As Owczarek et al. point out, no one diet will be the solution for every person with IBD, and “dietary recommendations must be individually developed for each patient, depending on the course of the disease, past surgical procedures, and type of pharmacotherapy.”10 As mentioned above, anatomic factors may also play a role in how well a patient with IBD may tolerate a particular dietary approach.36Botanical Medicines in IBDA number of botanical medicines have been studied in people with IBD, including in those with both active disease and in maintenance. Table 1 lists the botanical medicines discussed in this article.Table 1. Botanical Medicines in Inflammatory Bowel DiseaseBotanical medicine, constituent, or formulaScientific name(s)Studied in people with Crohn's DiseaseStudied in people with ulcerative colitisThunder duke vineTripterygium wilfordii Hook F✓ AndrographisAndrographis paniculata ✓Aloe veraAloe vera ✓CurcuminCurcuma longa✓✓Chios mastic gumPistacia lentiscus var. Chia✓✓WormwoodArtemisia absinthium✓ CannabisCannabis sativa✓ Thunder Duke VineTripterygium wilfordii Hook F (TWHF) sometimes called thunder god vine, but more appropriately translated as thunder duke vine, has a lengthy history of use as an anti-inflammatory in Traditional Chinese Medicine, with the plant being native to portions of China, Korea, Japan, and Taiwan. Thunder duke vine contains several constituents thought to be responsible for the plant's medicinal properties, including triptolide and celastrol, which have been found to reduce cytokine production, inhibit tumor growth, and ameliorate inflammation in various animal models.42A number of clinical trials of TWHF have been performed in people with CD. This includes trials examining efficacy for induction of remission in active disease, for prevention of postoperative disease recurrence, and for maintaining remission.Ren et al. and Gong et al. both assessed TWHF for the induction of remission in people with active CD. Ren et al. enrolled 20 people with active CD to receive TWHF at a dose of 60 mg daily for 12 weeks (with 16 people completing the trial). CDAI scores declined quickly and significantly over the first eight weeks, reaching the lowest point by 10 weeks (P < 0.001). CR (defined as CDAI score <150) was seen in eight participants by week 10 (50% of subjects) and nine participants by week 12 (56% of subjects). The CD Endoscopic Index (EI) of Severity was significantly improved at 12 weeks (P < 0.01). In addition, subjects experienced significant improvement of CRP, tumor necrosis factor-α (TNF-α), and IL-1β with herbal treatment (P < 0.01, P < 0.01, and P < 0.001, respectively).43 Gong et al. treated 62 people with active CD with either total enteral nutrition (TEN) tube feeding plus TWHF, or TWHF alone. TWHF was dosed at 1–1.5 mg per kg body weight per day. Clinical response (defined as a decrease of 70 or more points in CDAI score) was achieved in 40% of subjects who received TWHF alone, and in 79% of people who received TEN plus TWHF. CR (defined as achievement of absolute CDAI score <150) was observed in 30% of people who received TWHF alone, and 69% of people who received TEN plus TWHF. Patients who received the combination treatment also had greater improvements in nutrition status (P < 0.05). This trial demonstrated superiority of TEN combined with TWHF in this group of individuals with active CD.44Regarding CD recurrence specifically for postoperative patients, trials comparing use of TWHF with mesalamine,45,46 sulfasalazine,47 and azathioprine48 have been performed, all for periods of one year. Trials were small in size, ranging from 39 to 90 participants. TWHF supplementation was found to be comparable or superior to mesalamine for maintaining remission in the two trails that used this medication as comparison.45,46 TWHF was found to be comparable with azathioprine for preventing clinical recurrence, although less effective in maintaining endoscopic remission.48 TWHF was found to be effective compared with sulfasalazine, with 5.6% of TWHF subjects experiencing clinical recurrence, and 25% of sulfasalazine subjects experiencing clinical recurrence.47Lastly, regarding maintenance of remission, a one-year trial compared TWHF in either lower dose or higher dose (1.5 or 2.0 mg/[kg·day]) to mesalamine (3.0 g daily) for maintenance of remission in 198 people with CD, 137 of whom completed the trial. Higher dose TWHF compared favorably with mesalamine, with 7 of 71 people in the high-dose TWHF group experiencing clinical recurrence compared with 17 of 59 in the mesalamine group (P = 0.006). Recurrence rate with low dose TWHF was not significantly different than with mesalamine. In addition, higher dose TWHF was significantly superior to low-dose TWHF or mesalamine in decreasing endoscopic and CDAI scores (P < 0.05).49Outside of research trials, clinical use of this plant has been limited in the West due to the plant's toxicity. Many of the bioactive components of the plant are also toxic constituents. The triptolide compound is thought to be the main toxic constituent, and most clinical trials have utilized tgpolyglycoside preparations, which are triptolide free.50 The root of TWHF must be properly and carefully prepared (peeled) in the preparation of the extract. The root bark and the aerial parts of the plant are considered toxic. Even with a properly prepared supplement, there is a risk of adverse events with this plant. In a 2016 systematic review and meta-analysis of 594 TWHF trials, the overall rate of adverse events was 26.7% among 23,256 people who received TWHF. The most commonly reported adverse effects were GI, with an incidence of 13.3%. Reproductive (including irregular menstruation), dermatologic, hematologic, and cardiovascular side effects were also reported. The rate of side effects with TWHF overall was less than that seen with long-term aspirin (incidence of 31%).51 A 2019 study reported a slightly higher rate of overall adverse events specifically with TWHF tgpolyglycoside preparations, with a 31% incidence of adverse effects in people treated with TWHF (with intestinal toxicity being most commonly reported), and a 4.7% incidence of severe adverse effects. There was an increased incidence of adverse events with more than three months of TWHF administration. Toxicity was also dose related.50Ru et al. have suggested that the therapeutic window of TWHF is quite narrow, but that safety of the plant may still be acceptable in some situations. They recommend strict control of dosage and treatment course. They also recommend subjects be closely observed for side effects. They point out that women may more often experience side effects than men. In addition, they urge that additional toxicology studies should be performed.50 These factors may contribute to limited availability of standardized commercial TWHF extract supplements in the United States.AndrographisKnown traditionally as “the king of bitters,” Andrographis paniculata has been found to contain anti-inflammatory and antimicrobial constituents.52 An extract of A. paniculata has also been shown to reduce expression of proinflammatory cytokines and proliferation of T cells in a mouse model of colitis.53Two randomized double-blind trials of A. paniculata extract have been performed in people with UC. The first randomized 120 subjects with mild-to-moderate UC to either A. paniculata extract 1200 mg daily, or slow release mesalamine 4500 mg daily for eight weeks. CR as assessed by colonoscopy occurred in 28% of people in the A. paniculata group and 24% of people in the mesalamine group, and clinical response occurred in 76% of people in the A. paniculata group and 71% of people in the mesalamine group. There was no significant difference between the two interventions, demonstrating comparability of A. paniculata with mesalamine in this trial.54The second trial randomized 224 people with mild-to-moderate UC to A. paniculata extract at either 1200 or 1800 mg daily, or a placebo. After eight weeks, 45% of people receiving the herb at 1200 mg daily, and 60% of people receiving the herb at 1800 mg daily achieved CR as assessed by Mayo score, compared with 40% of people in the placebo group (P = 0.5924 and P = 0.0183). Adverse events were frequent, but also not significantly different between herbal groups and the placebo group (occurring in 60% of people in the lower dose herbal group, 53% of people in the higher dose herbal group, and 60% of people in the placebo group). Adverse events included rash, abdominal pain, and headache. This study demonstrated a dose response effect with A. paniculata extract, without dose-dependent toxicity.55Aloe VeraA 2004 double-blind randomized placebo-controlled trial assessed the use of aloe vera gel in 44 participants with active mild-to-moderate UC. Subjects were randomized to receive either aloe vera gel, or a matched placebo liquid, 100 mL two times daily, for