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. 2022 Jul 6;31(10):1335–1342. doi: 10.1007/s10068-022-01116-w

Roasted garlic protects against leaky gut syndrome in dextran sodium sulfate-induced colitis mice

Divya Sharma 1,#, Madhuri Sangar 1,#, Jeom-Leon Park 1, Seong-Gook Kang 1, Kyung-Sik Ham 1,✉
PMCID: PMC9385892  PMID: 35992316

Abstract

Garlic (Allium sativum) is a potentially beneficial functional food that is extensively grown around the globe. We have investigated the effect of roasted garlic on a dextran sodium sulfate (DSS)-induced intestinal permeability model in mice. Mice were divided into four diet groups: CON, DSS, RG (roasted garlic), and RG + Purple bamboo salt (RGP) in the AIN 93G diet for 3 weeks. All groups except the CON group received 2% DSS in drinking water at the last week of the experiment. DSS groups showed significantly elevated gut permeability levels and decreased tight junction protein expression compared to CON. However, RG and RGP displayed remarkably lower trends of gut permeability, increased tight junction protein expression, increased number of goblet cells than the DSS group in hematoxylin and eosin and alcian blue-nuclear fast red stained colon sections. These results indicate that roasted garlic could prevent gut leakage induced by DSS.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10068-022-01116-w.

Keywords: Gut permeability, Tight junctions, Goblet cells, Purple bamboo salt

Introduction

The intestinal epithelium, which contains intestinal epithelial cells (IECs) that separate luminal contents from interstitium tissue, serves as the first line of defense against potentially hazardous stimuli. The regulation of luminal materials passing from the gastrointestinal (GI) tract through the epithelial cells of the gut into the rest of the body is referred to as intestinal permeability (Slifer and Blikslager, 2020). The intestinal epithelium is the most essential structural component of the physical barrier, providing two crucial functions: as a barrier to potentially hazardous stimuli and as a selective filter that allows for selective nutrient absorption (Anderson and Van Itallie, 2009). Transepithelial and paracellular permeability are the two major channels of selective permeability of the intestinal barrier, involving intracellular tight junctions (TJs) regulating the paracellular space (Lee, 2015). Occludin, claudins, junctional adhesion molecule (JAM), and tricellulin are integral transmembrane proteins that create a network connecting plaque proteins. Peripheral membrane adaptor proteins, on the other hand, include zonula occludin (ZO-1), ZO-2, and ZO-3, which serve as a bridge between integral membrane proteins and actin or other signalling proteins. The interactions of these integral transmembranes and peripheral membrane proteins, as well as the organization of actin, are all crucial for TJ integrity (Lee et al., 2018). TJ plays a crucial role in protecting the body against stressors like inflammation and infection. When intestinal permeability increases, germs and dangerous toxins “leak” through the intestinal wall, a condition known as “leaky gut.“ Alteration or disruption of TJ homeostasis may be a trigger for the development of a variety of illnesses, and vice versa (Lee et al., 2018; Mu et al., 2017).

Garlic, a common culinary spice, contains organosulfur compounds (allicin) which give a pungent smell, spicy taste and is widely distributed all over the world (Hirsch et al., 2000). It also contains natural prebiotic fructooligosaccharides (FOS), phenolic compounds, and rich in inulin-type fructan, a type of non-digestible carbohydrate or “functional fiber” that feeds the good bacteria in the digestive tract ( Sunu et al., 2019; Zhang et al., 2013). Recent studies showed the role of garlic in promoting the growth of friendly bacteria (Bifidobacteria specifically) in the gut, and its preventing disease-promoting bacteria growing at the same time (Filocamo et al., 2019). There are also numerous scientific reports about the medicinal effects of garlic, for example, preventing high lipid levels and oxidation of low-density lipoprotein (Jain et al., 1993; Sumiyoshi, 1997). Moreover, several researches demonstrated strong antimicrobial, antioxidant, antidiabetic, antiatherogenic, and anticancer effects of garlic (Eidi et al., 2006; Gonen et al., 2006); Li et al., 2018. Purple bamboo salt (PBS) is a traditional healthy salt in Korea and prepared by roasting mineral-rich solar sea salt in the presence of bamboo. It was previously reported that PBS suppresses chemically induced colon carcinogenesis in mice (Ju et al., 2016). In addition, PBS has antioxidant activity and reduces oxidative stress and inflammation in rats (Gao et al., 2015). Various antioxidants have been reported to be good for gut health (Rajoka et al., 2021). Therefore, PBS may be beneficial for gut health. It becomes clear that numerous dietary components affect the intestinal barrier and may increase permeability or promote barrier integrity. However, the role of garlic and its combination with PBS on gut permeability in diseased conditions have not been investigated yet. Thus, we have investigated the effect of roasted garlic and its combination with PBS on DSS-induced intestinal permeability model in mice.

Materials and methods

Materials

Garlic was procured from Seonglim Farming Association Co. (Muan, Korea). Garlic (400 g) was divided into five parts, wrapped in paper foil, then roasted in a Korean cauldron for 20 min. The roasted garlic was pulverized and the paste of roasted garlic was mixed in AIN-93G diet in which garlic accounts for 3% of the total diet (equivalent to approximately 60–70 g/day for 60 kg human). Antibodies for occludin, ZO-1, and, Epithelial cell adhesion molecule (EpCAM) were purchased from Invitrogen (Waltham, USA). Antibodies for β-actin and Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were purchased from Thermo Fisher Scientific Inc. (MA, USA). FITC-dextran 4 kDa was obtained from Sigma-Aldrich Chemical (St. Louis, US). Dextran sulfate sodium salt, (colitis grade 36,000–50,000 Da, DSS) was purchased from MP Biomedicals (Canada). Purple bamboo salt (PBS) was obtained from Salthill Co. Ltd (Sinan, Korea). PBS was prepared as described previously (Gao et al., 2015) with minor modification. Instead of using roasted mineral-rich solar sea salt which was further roasted twice in the presence of bamboo, mineral-rich solar sea salt was roasted three times in the presence of bamboo at 800 °C for 30 min and then roasted one more time with bamboo at 1100 °C. After removing charcoal, PBS was obtained.

Animal studies

Thirty-two male C57BL/6 mice (6 weeks old) were purchased from Orient Bio co. (Seongnam, Korea). The animals were housed under standard housing conditions of temperature (23 °C ± 2 °C), relative humidity (55% ± 10%), and light (12/12-h light/dark cycle). The animals had ad libitum access to a standard laboratory diet and ion-sterilized tap water. Ethical approval for this study was obtained from the Institutional Animal Care and Use Committee (IACUC) of Mokpo National University (Jeonnam, Republic of Korea) (MNU-IACUC-2020-011). All animal experiments were performed according to the National Institutes of Health (NIH) guidelines for the care and use of laboratory animals and the guidelines of the IACUC. Mice were adapted for 1 week and after acclimatization mice were divided into the following experimental groups (n = 8/group): Control (CON), DSS treated (DSS), roasted garlic (RG), roasted garlic + purple bamboo salt (RGP). Control and DSS groups were fed with AIN-93G diet, RG group was fed with AIN-93G diet containing 3% roasted garlic and RGP group was fed with AIN-93G diet containing 3% roasted garlic along with 0.7% PBS for 3 weeks. All groups except CON received 2% DSS in drinking water during 3rd week. At the end of the experiment (week 3) animals were orally injected with FITC dextran- 4 kDa, and euthanized through draining blood by cardiac puncture. Blood was collected in black Eppendorf tubes and kept at 4 °C until analysis. Colons were surgically removed and tissue was flushed with 0.9% NaCl, followed by storage at − 80 °C and an 0.5 cm segment, excised from the end of the proximal colon (Kamphuis et al., 2017), and soaked into 10% neutral, buffered formalin solution.

In vivo intestinal permeability assay

Intestinal permeability was determined by measuring the permeability of FITC-dextran 4 kDa in blood serum. One day before in the evening water bottles were removed from the cages to restrict water intake of the mice overnight in order to restrict excretion of FITC dextran by limiting the excretion of urine. The next day freshly prepared FITC dextran which was dissolved in phosphate-buffered saline at a concentration of 50 mg/ml was orally injected to each mouse (40 mg/100 g body weight). Exactly 4 h after dosing, mice were euthanized and blood was collected by cardiac puncture in black microcentrifuge tubes. Blood was centrifuged and serum collected, which was then mixed with an equal volume of PBS and stored at 4 °C until analysis on the same day. Fluorescence was measured in three replicate wells for each sample in a black 96-well microtiter plate using a Victor 3 plate reader (Perkin Elmer) with excitation at 485 nm and emission at 535 nm. Concentrations were calculated from a standard curve prepared using standard containing serially diluted FITC-dextran.

Western blotting

Colon tissue (0.15 g) were homogenized with 0.8 ml RIPA buffer containing 0.01 M NaF, 2 mM phenylmethyl sulfonyl fluoride, 10 mM sodium pyrophosphate, aprotinin (0.1 µl/ml), pepstatin (1 µl/ml) and leupeptin (1 µl/ml). Protein concentration extracted from the colon tissue homogenate was assayed using Bradford method. Proteins were separated by SDS-polyacrylamide gel electrophoresis and transferred to PVDF membrane and blocked by 0.05% tween-20 (TBST) buffer containing 3% bovine serum albumin (BSA). The membranes were incubated with primary antibodies (occludin, ZO-1, and EpCAM) overnight at room temperature with gentle agitation. The membrane was washed and incubated with secondary antibody [horseradish peroxide (HRP)-conjugated goat anti-rabbit immunoglobulin G] at room temperature for 1 h. After washing, the membranes were reacted with enhanced chemiluminescence (ECL) solution containing luminol and visualized using Davinch chemil system (Bio Co., Ltd). Obtained images were analyzed using Image J software (Maryland, USA).

Colonic histomorphology

The colon samples after being fixed in 10% neutral formalin were paraffin-embedded and sectioned transversely. The cross-sections of colon tissues (5 μm) were prepared for rehydration and passed through a series of xylene-alcohol (100%, 95%, 70%). The slides were dyed with H&E and AB-NFR solutions, respectively. The slides were dehydrated with a series of alcohol (70%, 95%, 100%). Finally, slides were placed in xylene and mounted using Canada balsam. For each stained section, at least 30 bright-field images were captured by a digital camera, under 20–40× magnification, using an Olympus BX43 microscope (Olympus, Japan). Histological damage and goblet cell number were evaluated. The Image J software was used to determine the goblet cells number.

Statistics

Data were expressed as mean ± standard deviation or mean ± SEM. The differences among groups were analyzed by one-way analysis of variance (ANOVA) followed by Tukey’s method or independent sample t-test. Values were considered to be statistically significant as a value of p < 0.05 or p < 0.001.

Results and discussion

Effect on gut permeability and expression of tight junction proteins

In the digestive system, the gastrointestinal tract is the first organ exposed to dietary substances as it takes in food, digests it and absorbs food-derived nutrients. According to several studies, the incidence and severity of gastrointestinal diseases such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can be predicted by intestinal permeability caused by various conditions like infections, high levels of stress, certain drugs and allergic foods (Nafiseh et al., 2019). Our data showed DSS administration increased intestinal permeability, as indicated by FITC-dextran absorption (Fig. 1A). DSS (p < 0.001) group showed significantly elevated gut permeability as compared to the CON group. However, RG- and RGP- fed groups displayed remarkably lower trends (p < 0.001) in gut permeability compared with the DSS group suggesting that RG and RGP prevent gut permeability induced by feeding DSS. Meanwhile, TJs, which are the main molecules that form the gut barrier, were also affected in the colon. Expression of the integral transmembrane protein occludin (Fig. 1B) was significantly decreased only in the DSS group (p < 0.05), while RG and RGP group exhibited feeble reduction but it was not as significant as the DSS group when compared to the CON group. There were no significant differences among CON, RG, and RGP groups. Also, RG (non-significant)- and RGP (p < 0.05)- fed groups showed higher protein expression level of occludin compared to DSS group. In Fig. 1C, expression level of another tight junction protein ZO-1 was remarkably lower only in the DSS group (p < 0.05) as compared to that of the CON group, while RG and RGP groups showed significantly higher ZO-1 protein expressions (p < 0.05) compared to DSS group. We also investigated the expression of a putative epithelial cell adhesion molecule (EpCAM) which is known to contribute to the formation of tight junction in the intestinal epithelium by recruiting claudin proteins (Lie et al., 2012). It has been reported that mutation of EpCAM can cause intestinal and ion transport dysfunction (Kozan et al., 2015). The result (Fig. 1D) showed a significant decrease in EpCAM protein expression levels in DSS, RG, and RGP groups as compared to that in the CON group. However, only the DSS group (p < 0.001) showed a trend of more severe reduction in protein expression level of EpCAM as compared to the CON group. The DSS-induced colitis animal model is used to directly harm the colonic epithelium, resulting in a disruption of barrier integrity characterized by increased gut permeability and intestinal inflammation (Pastorelli et al., 2013). It has been previously reported that allicin, a significant organosulfur compound found in garlic, plays a role in the protection of gut homeostasis by maintaining the integrity of tight junctions and avoiding damage to the intestinal barrier through immunomodulation (Yuan et al., 2021), which was consistent with our findings of significantly increased tight junction protein expression and decreased gut permeability after DSS treatment in the RG and RGP groups. Additionally, it has been previously reported that the antioxidant activity of organosulfur compounds found in garlic provides protection against free radicals (Chung, 2006), which induce inflammation and may cause damage to the intestinal barrier, increasing gut permeability. Moreover, some researches showed that feeding rats with inulin-type fructans stimulated the growth of Bifidobacteria and Lactobacilli both in the gut lumen and at the colonic mucosal surface, which was associated with an increased number of goblet cells and thicker mucus layer on the colonic epithelium and, maintained gut permeability (Filocamo et al., 2019; Guarner, 2007). Thus, the protective activity of garlic against gut leakage could be attributed to the presence of organosulfur compounds in garlic, which might reduce intestinal inflammation by maintaining tight junction protein integrity and antioxidant activity against free radicals, resulting in preventing intestinal barrier damage induced by DSS. Also, the presence of inulin (fructans) in garlic could be a plausible reason for the protective effect of garlic against gut leakage, as it might increase friendly bacteria on the mucosal surface, preventing leaky gut syndrome and increasing the relocation of occludin and ZO-1 into the tight junction area between epithelial cells. However, there was no significant difference between RG- and RGP- fed groups on gut permeability and TJs proteins. In this case, we are not sure whether PBS does not have protective activity against gut leakage or the amount of PBS used was not enough to improve the protective activity of garlic when they are used together. Further dose-dependent studies are required to assure the role of purple bamboo salt on DSS-induced gut permeability.

Fig. 1.

Fig. 1

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Intestinal permeability alterations and tight junction protein expression in the colon of mice fed diets containing 3% roasted garlic for 3 weeks. (A) In vivo intestinal permeability is analyzed by measuring FITC-dextran (4 kDa) concentration in serum. (B) The integral transmembrane protein occludin expression. (C) Barrier-forming ZO-1 peripheral membrane protein expression. (D) Expression of the putative cell adhesion protein EpCAM. CON control, DSS dextran sodium sulfate, RG roasted garlic, RGP roasted garlic with purple bamboo salt. All groups except control group were treated with DSS. Values are represented as mean ± SD (n = 8). *p < 0.05 vs. CON, **p < 0.001 vs. CON, #p < 0.05 vs. DSS, ##p < 0.001 vs. DSS

Effect on colonic histo-morphology and goblet cells

In DSS-fed mice, significant histological changes were observed as revealed by H&E (Fig. 2) and alcian blue-nuclear fast red (AB-NFR) (Fig. 3) staining of colon sections. Colon wall thickness was evaluated using H&E stained colonic tissue sections and scored by a blinded observer using a previously published system (Detel et al., 2012) for the following measures: neutrophil infiltration score (0 points, presence of occasional inflammatory cells in the lamina propria; 1 point, increased number of inflammatory cells in the lamina propria; 2 points, inflammatory cells extending into the submucosa; and 3 points, transmural extension of the infiltrate), colon tissue damage score (0 points, no mucosal damage; 1 point, discrete epithelial lesions; 2 points, surface mucosal erosion; and 3 points, extensive mucosal damage with progression into deeper structures of the bowel wall). Colonic tissue damage score was calculated and it showed inflammatory alterations in the DSS-fed mice. The colon tissue damage score is the sum of each score. Also, AB-NFR stained sections showed changes in mucus-filled goblet cell numbers.

Fig. 2.

Fig. 2

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Effect of roasted garlic on hematoxylin and eosin (H&E) stained histo-morphological changes in the colon of mice fed with diet containing 3% roasted garlic for 3 weeks. (A) Cross-section of colonic tissue stained with H&E; the symbols (↔) and (★) indicate colon wall thickness and neutrophil infiltration, respectively. (B) Colon wall thickness. (C) Neutrophil infiltration score. (D) Colon tissue damage score. CON control, DSS dextran sodium sulfate, RG roasted garlic, RGP roasted garlic with purple bamboo salt. Values are represented as mean ± SD (n = 8). *p < 0.05 vs. CON, **p < 0.001 vs. CON, #p < 0.05 vs. DSS, ##p < 0.001 vs. DSS

Fig. 3.

Fig. 3

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Effect of roasted garlic on alcian blue-nuclear fast red (AB-NFR) stained morphological changes in the colon of mice fed with diet containing 3% roasted garlic for 3 weeks. (A) Cross-section of the colonic tissue stained with AB-NFR. (B) Intestinal goblet cells per crypt ratio. CON control, DSS dextran sodium sulfate, RG roasted garlic, RGP roasted garlic with purple bamboo salt. Values are represented as mean ± SD (n = 8). *p < 0.05 vs. CON, **p < 0.001 vs. CON, #p < 0.05 vs. DSS, ##p < 0.001 vs. DSS

As previously reported, DSS administration causes an increase in colon wall thickness, neutrophil infiltration, and tissue damage (Gong et al., 2017). In Fig. 2, only the DSS group showed remarkably higher colon wall thickness, neutrophil infiltration, and tissue damage compared to the CON group, which might be due to tissue edema (p < 0.001). However, the RG-and RGP-(p < 0.001) groups showed surprisingly significantly lower damage than the DSS group, suggesting protective activity of RG and RGP. Also, AB-NFR stained colon sections showed higher goblet cell counts in the RG and RGP groups (p < 0.001) as compared to that of the DSS group (Fig. 3A, B). However, the goblet counts in the RG-and RGP-fed groups were significantly lower than that in the CON group (p < 0.05). These findings are consistent with previous findings that showed garlic inhibits neutrophil infiltrations in inflamed colonic tissue by inhibiting chemotaxis, which leads to inhibition of neutrophil transmigration through the epithelial cell layer (Hsu et al., 2010). In addition, in another study, it was found that garlic extract increases goblet cell number and antioxidant enzymes in E. vermiformis (a parasite)-infected mice (Khalil et al., 2015). Moreover, treatment with garlic oil has been reported to increase goblet cell number in DSS-induced ulcerative colitis in rats (Balaha et al., 2016). Also, studies showed that treatment with fructans increases goblet cells in gnotobiotic rats by stabilizing the gut mucosal barrier via the stimulation of mucosa-associated Bifidobacteria (Filocamo et al., 2019; Kleessen et al., 2003). However, to the best of our knowledge, no one has studied the effect of garlic on a “leaky gut” syndrome, which can be a possible cause of gastrointestinal diseases like IBS or IBD. This study, for the first time, demonstrated the effect of garlic on inhibiting neutrophil infiltration and colon wall thickening as well as increasing goblet cells in a DSS-induced intestinal permeability. This protective activity might be due at least partially to the presence of a fructan compound, organosulfur compounds and antioxidants in garlic. In this sudy, we used 3% garlic in the diet, which is equivqlent to approximately 60–70 g garlic/day for 60 kg human when we assumed that mouse consumes about 10 g diet/day and weighs 20 g (Nair and Jacob, 2016). This quantity is quite higher than normal consumption although people in some contry consume about 40 g garlic/day. Therefore, more researches focusing on dose dependence are necessary. Additionally, it is needed Additionally, it is needed to elucidate the effects of roasting on the activities of garlic and the bioactivities of roasted garlic, as well as the mechanism by which roasted garlic protects against leaky gut.

In conclusion, roasted garlic is beneficial in the DSS-induced colitis mice model as it lowers gut permeability, increases tight junction proteins expression, prevents colonic damage, and increases goblet cells count compared to the DSS group. Therefore, roasted garlic could be a promising functional food in the prevention of leaky gut syndrome.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 29.3 kb) (29.3KB, docx)

Acknowledgements

This study was supported by the “Leaders in Industry-university cooperation +” Project which was funded by the Ministry of Education and National Research Foundation of Korea.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Divya Sharma and Madhuri Sangar have contributed equally to this work.

Contributor Information

Divya Sharma, Email: sharma.divya2101@gmail.com.

Madhuri Sangar, Email: madhurysangar@gmail.com.

Jeom-Leon Park, Email: gg4369@naver.com.

Seong-Gook Kang, Email: sgkang@mokpo.ac.kr.

Kyung-Sik Ham, Email: ksham@mokpo.ac.kr.

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