Consuming Green Vegetables and Certain Supplements Suppresses Inflammatory Bowel Disease
Authors: Tianci Zhang, Ruofei Zhang, Guangfu Zhao, Wei Liu, Liwei Pan, Ying Tong, Mingshan Jiang, Hu Zhang, Zhixiong Xiao, Stephen J. Pandol, Xiansheng Fu, Yuan-Ping Han, and Xiaofeng Zheng
Link to Study: Plant green pigment of chlorophyllin attenuates inflammatory bowel diseases by suppressing autophagy activation in mice | American Journal of Physiology-Gastrointestinal and Liver Physiology
Inflammatory bowel diseases (IBDs) are chronic and relapsing gastrointestinal disorders, featured as ulcerative colitis (UC) and Crohn’s disease (CD) (1). Although the etiology of IBD remains poorly understood, accumulating evidence suggests that dietary, environmental, genetic, epigenetic, and immunological factors may promote initiation and progression of the disease (2–5). Two forms of IBD syndromes share certain common mechanisms but are distinct in their pathophysiological characteristics. In Crohn’s disease (CD), inflammation is typically segmental, asymmetrical, and transmural. CD impacts the whole gastrointestinal tract and pathological findings are mostly found in the terminal ileum and colon (6). Conversely, UC exhibits a continuous pattern of illness, involving superficial mucosal and submucosal, and is limited to the colon (7).
The prevalence of IBD is high in Europe and North America, while the rate is rising in Asia, Africa, and South America (8). The rising costs for health care for IBD have become a global health burden (9). Current therapeutic strategies for IBD are often based on anti-inflammatory drugs, immunosuppressive agents, biological therapy, and surgery (10, 11). However, these treatments have shortcomings such as serious side effects and surgical risk. Moreover, many patients do not respond well to these treatments. Therefore, alternative therapeutic approaches and even diets or dietary supplements should be explored.
Imbalanced diet composition is well known for the pathogenesis of IBD. Diets rich in high sugar and high fat are closely related to the incidence of IBD (12, 13), whereas fruit and vegetable diets are negatively correlated (12, 14). Consistent with this notion, incidences of IBD are high in Western Europe and North America in association with diet and lifestyle. Conversely, low incidences of IBD in Asia and other regions are related to a diet rich in green vegetables. Various vitamins and fiber in green vegetables are beneficial for human health and can prevent many illnesses including IBD. However, the green pigment in green vegetables, namely chlorophyll, has yet to be examined for improvement of IBD. Chlorophyllin (CHL, C34H31CuN4Na3O6) is a water-soluble and semisynthetic food-grade derivative of chlorophyll, which is widely used in food industry (15). Numerous studies have demonstrated the roles of CHL in antigenotoxicity, antioxidation, and anticarcinogenesis (16–20), however, the potential therapeutical effects of CHL on IBD have yet to be investigated.
On the other hand, autophagy in physiological dynamics is essential for maintaining intestinal homeostasis. Autophagy is a basic biological process for all eukaryotes and it is vital for environmental response and adaptation machinery for nutrient and calorie availability (21). A major function of autophagy is turnover of long-lived or misfolded proteins and damaged organelles for metabolic recycling (22). Autophagic flux is concerted with lysosomal digestion and plays an important role in maintaining metabolic homeostasis in programmed cell death, cell differentiation, intracellular pathogen clearance, and immunomodulation (23, 24).
Previous studies showed that genetic variation of autophagy genes, including autophagy-related 16-like 1 (ATG16L1), immunity-related GTPase family M (IRGM), and Unc-51-like kinase 1 (ULK1), is associated with IBD susceptibility (25–27). Mice with Atg16l1 deletion are susceptible to dextran sulfate sodium (DSS)-induced colitis partly due to Paneth cell abnormalities or enhanced IL-1β production (28, 29). Conversely, abnormal activation of intestinal autophagy can aggravate IBD progression (30–32). Given the fundamental roles of nutrients in regulation of mTOR and autophagy, it is thus interesting to know if chlorophyllin, a dietary green pigment, can regulate intestinal autophagy in the context of IBD. In this study, we found persistent activation of autophagy in experimental colitis. Furthermore, we uncovered that CHL could alleviate experimental colitis partly due to activation of Akt/mTOR pathway, leading to suppression of autophagic flux in the IBD model. Thus, this study indicates a potential beneficial role of CHL and green vegetables in mitigation of IBD syndromes.
Inflammatory bowel diseases including Crohn’s disease and ulcerative colitis are associated with environmental factors, intestinal infection, and genetic susceptibility/predisposition, which ultimately lead to abnormal mucosal immune response against the intestinal microbiome. Diet habit and composition are critical for human health and well-being. It is known that high-sugar and high-fat diets are strongly correlated with IBD (12, 43, 44), while consumption of high amounts of fiber, particularly fiber from vegetables and fruits, is negatively correlated with IBD (2, 45). However, the role of chlorophyll, a major component in green vegetables, in IBD progression is still unclear.
The exact cause and the pathogenesis of IBD are poorly understood. However, IBD is generally a consequence of defective host immunity. Persistent activation of intestinal immune system caused by viruses, bacteria, and food antigen may exert inflammation and tissue injury in gastrointestinal tract. Autophagy, a basic cellular program, is essential for intestinal homeostasis in part through degradation of damaged cell organelle and maintaining metabolic turnover (28). Previous studies reported that knocking out autophagy-related key genes, including Atg16L1, Atg4B, Atg5, and Atg7 worsens the IBD symptoms in animal models (28, 46–48).
These works indicate that basal or physiological levels of autophagy are critical for the maintenance of intestinal integrity. Notably, deletion of Atg16L1, Atg5, and Atg7 in mice displays impairment of Paneth cells, the α-defensin-producing cells in the crypts of small intestine (28, 48). Therefore, loss of physiologically autophagic turnover leads to deterioration of IBD. However, on the other hand, persistent activation of autophagy and its disassociation with the consequent lysosomal degradation may also provoke tissue damage in IBD (49, 50). Indeed, it is known that persistent activation of autophagy can aggravate IBD by inducing autophagic cell death, leading to the destruction of the intestinal barrier and the overproduction of proinflammatory cytokines (30, 31, 51). Likewise, modulation and suppression of autophagy may be used as a potential therapeutical treatment for IBD (31, 32, 51–53). Previous studies showed that persistent activation of autophagy may serve as a potential signal for cell death (54, 55).
In this study, we found persistent autophagy activation in colon tissue of experimental IBD mice. Specifically, DSS as an immunogen or damage signal can provoke autophagic activation and inflammation in the intestinal tissues of the disease models, and such notion is further demonstrated by the experiment with cell culture models. We found that excessive activation of autophagy without subsequent orderly lysosomal degradation may create lysosomal stress, which may release autolysosome contents such as cathepsins for tissue damage and inflammation. Indeed, cathepsin G was found in the supernatants from tissues of patients with IBD compared with healthy controls (49).
Dietary compositions are crucial for pathogenesis and progression of IBD. Western diet with excessive consumption of sugar and fat is regarded as a risk factor for IBD development (56, 57). Appropriate nutrition may improve the quality of the patients. In this study, we found that a water-soluble form of chlorophyll, namely CHL, can attenuate autophagy in the intestinal cells and alleviate the DSS-induced experimental IBD in mice. In particular, DSS as a negatively charged polysaccharide can activate cellular autophagy.
Conversely, attenuation of autophagy by chloroquine improves DSS-mediated IBD. CHL treatment can modulate and suppress autophagy both in vivo and in vitro. Our previous study showed that CHL could directly inhibit LPS-initiated cellular response and downregulate inflammatory cytokines (58). CHL was known for its role in neutralization and sequestration of carcinogens (17–19). In summary, our study revealed a potential application of chlorophyllin for treatment of IBD, and the implication may be further extended to the consumption of green vegetables for mitigating IBD (see graphic summary).
Summary: Consuming green vegetables and adding a daily chlorophyllin supplement helps alleviate symptoms of inflammatory bowel disease, researchers report. Additionally, chlorophyllin supplements help significantly reduce mortality risks associated with IBD.
The dietary supplement chlorophyllin alleviates inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, according to researchers from the Center for Diabetes and Metabolism Research at Sichuan University in China and from Cedars Sinai Medical Center in Los Angeles.
In addition, chlorophyllin significantly reduces mortality related to IBD, weight loss, diarrhea and hidden blood in the stool, intestinal epithelial damage and infiltration of inflammatory cells.
The findings are published ahead of print in the American Journal of Physiology-Gastrointestinal and Liver Physiology, and the study has been chosen as an APS select article for August.
Chronic gastrointestinal disorders such as IBD affect tens of millions of people living in the U.S. IBD has created a global health burden because of the rising cost of treating the condition.
While the exact cause of IBD isn’t fully understood, some contributing factors include stress and environmental, lifestyle, and dietary choices, such as high consumption of meat or fish.
Chronic inflammation, abnormality in autophagy—the body’s process of cleaning out damaged cells to make room for newer, healthier cells—and lysosomal stress (an abnormality in an organelle leading to inflammation) are also linked to the condition.
Current therapeutics for IBD include medications that suppress the immune system (immunosuppressants) and surgery. However, long-term use of immunosuppressive treatments could result in severe adverse effects, including opportunistic infections and even organ failure.
In this study, researchers found taking an oral chlorophyllin supplement—a compound derived from the green pigment found in plants—reduced colitis and abnormalities in the intestinal epithelia of mice.
Also, consumption of green vegetables and chlorophyllin may be helpful for IBD recovery, in part through alleviation of inflammation and autolysosomal flux (a process that uses lysosome to degrade and remove toxic molecules and organelles).
Green pigment found in these foods and supplements can initiate a feeding signaling to modulate autophagy in the cells, which suppresses IBD symptoms.
Researchers believe these findings could be a pathway to a less intrusive treatment for IBD.
“Consuming green-colored vegetables or green pigment supplement such as chlorophyllin might help people with inflammatory bowel disease,” said Xiaofeng Zheng, Ph.D., of Sichuan University and a co-author of the study.