Short-term increases in sugar consumption could increase the risk of inflammatory bowel disease and have a significant impact on our health, a new study out of the University of Alberta suggests.
In a study published in Scientific Reports, U of A researchers found that mice had an increased susceptibility to chemically induced colitis and more severe symptoms after only two days of a high-sugar diet compared with those eating a balanced diet.
Karen Madsen, who specializes in diet and its effects on inflammatory bowel disease, said the results echo what many patients with colitis have been saying for a long time: small changes in their diet can make their symptoms flare up.
“It’s been previously shown that the type of diet that you are on can change your susceptibility to disease,” said Madsen, who led the new study.
“We wanted to know how long it takes before a change in diet translates into an impact on health. In the case of sugar and colitis, it only took two days, which was really surprising to us. We didn’t think it would happen so quickly.”
What could drive such a significant change in such a short time? It turns out it’s all about gut bacteria and the impact food has on them.
Fibre-rich foods act as fuel for the “good” bacteria that live in the gut and produce short-chain fatty acids, which are critical for an efficient immune response.
Eating high-sugar diets and decreasing intake of fibre feeds “bad” microbes, such as E. coli, that are associated with inflammation and a defective immune response.
Madsen’s study showed that the mice on the high-sugar diet had greater intestinal tissue damage and a defective immune response.
These problems were alleviated when their diet was supplemented with short-chain fatty acids normally produced by good bacteria.
“Surprisingly, our study shows that short-term sugar consumption can really have a detrimental impact, and so this idea that it’s OK to eat well all week and indulge in junk food on the weekend is flawed,” Madsen explained.
Followup studies could pave the way to possibly using short-chain fatty acids as dietary supplements, she noted.
“Changing someone’s diet is one of the hardest things to do, even if you tell them that it will fix their health problems,” she said.
“People want to eat what they want to eat, so short-chain fatty acids could possibly be used as supplements to help protect people against the detrimental effects of sugar on inflammatory bowel disease.”
Madsen and her colleagues also showed that just two days on the high-sugar diet and the absence of short-chain fatty acids caused an increase in gut permeability, opening interesting avenues of research on how diet may affect the bacteria in our gastrointestinal tract and brain health.
Madsen’s study showed that the mice on the high-sugar diet had greater intestinal tissue damage and a defective immune response.
“There is an increasing amount of evidence that suggests there’s a link between the bacteria present in our gut and neurodegenerative diseases such as Alzheimer’s and Parkinson’s,” explained Madsen.
“Because our study showed that gut permeability increased quite dramatically in the mice on the high-sugar diet–which means that bacterial products are free to move from the gut, where they normally stay, to the rest of the body–it raises the possibility that this phenomenon might be driving these diseases, but this needs to be looked into.”
Funding: The study was funded by the Canadian Institutes of Health Research, Alberta Innovates and the Canadian Association of Gastroenterology.
Crohn’s disease and ulcerative colitis, collectively known as inflammatory bowel disease (IBD), are chronic inflammatory disorders of the gastrointestinal tract that have an increasing incidence12 and affect over one million individuals in the US and 2.5 million in Europe 13, 14, resulting in substantial morbidity15, health care expenses and loss of productivity 16, 17. Although the pathophysiology of IBD is largely unknown, it is thought to be related to an inappropriate immune response to commensal bacteria in genetically susceptible hosts (FIG. 1).
A role for genetic risk factors in the development of IBD has been highlighted by the identification of >200 susceptibility loci in genome-wide association studies (GWAS)18, 19.
In addition to the genetic contribution to IBD pathophysiology, environmental factors also seem to substantially contribute to both the development and progression of IBD. For instance, twin studies have demonstrated a <50% concordance in the development of Crohn’s disease and ulcerative colitis20, 21.
In addition, epidemiological studies have confirmed the rapid increase in the incidence of IBD in the US and developing countries that have witnessed a dramatic ‘westernization’ of lifestyle with the worldwide prevalence of the disease surpassing 0.3% at the turn of 21st century. 12, 22.
Moreover, studies have shown that the incidence of IBD in immigrants to developed countries exceeds that of individuals from their country of origin23–26.
The pathophysiology of inflammatory bowel disease.The pathophysiology of inflammatory bowel disease (IBD) is related to an inappropriate host immune response to commensal bacteria in genetically susceptible individuals. Environmental influences alter the composition of the gut microbiota and change mucosal barrier function. Dendritic cells and macrophages are antigen-presenting cells involved in activation of T cells and production of pro-inflammatory cytokines. Dendritic cells are activated through the the recognition of luminal antigens by Toll-like receptors (TLRs) and are in turn necessary for activation of naïve T cells. Macrophages could also serve as antigen-presenting cells once stimulated by INFγ secreted by T cells. Activated macrophages and dendritic cells also produce pro-inflammatory cytokines including TNF-alpha, IL212, and IL23. The result of this pro-inflamamtory cytokine cascade is loss of immune tolerance to commensal bacteria and the production of pro-inflammatory cytokines by activated T cells. INF, Inteferon-gamma;TNF, tumour necrosis factor; IL-312, interleukin-12; IL-23, interleukin-23;
Among environmental factors, diet is widely thought to have a pivotal role in the development of IBD. Although the exact pathophysiological mechanisms remain unknown, a number of plausible explanations have been proposed (FIG. 2) Firstly, diet has a key role in defining the composition of the human gut microbiota and, consequently, that of microbial metabolites 27.
Secondly, food and nutrients associated with a Western diet, characterized by high intakes of red meat, sugary desserts, high-fat foods, and refined grains have been linked to increased mucosal inflammation as measured by stool calprotectin in human subjects 28.
Lastly, animal studies have demonstrated that dietary composition regulates mucosal barrier function, a crucial factor in the pathogenesis of IBD29, 30. Despite these data, human observational studies investigating the role of diet in IBD have yielded contradictory and inconclusive results.
Potential mechanisms underpinning the relationship between diet and inflammatory bowel disease.As compared to Mediterranean diet which is characterized by high intake of fruits and vegetables, whole grains, and sea good, western diet characterized by high intake of red and processed meat, saturated fat, and refined sugar is widely thought to increase risk of IBD. Although the exact mechanism underpinning the association between diet and risk of IBD is unknown, a number of plausible mechanisms have been proposed. Specifically, western diet has been linked to changes in the gut microbiome and epithelial barrier function and appears to have a direct impact on the immune function triggering a pro-inflammatory environment characterized by an imbalance in the TH17/Treg axis.
In this Review, we will discuss the available data on the role of diet in the pathogenesis of IBD, with a focus on epidemiological,, gene–environment interaction, intervention, gut microbiome, and animal studies. We will also highlight limitation of prior studies, particularly epidemiological and gene-environment studies and review future directions that build on these preliminary studies.
Intervention studies
Recently, there has been a resurgence of interest in the potential of dietary intervention for the treatment of IBD. Although a comprehensive discussion of prior dietary intervention studies is beyond the scope of this Review and has been previously published31, the early success of these studies further supports a role for diet in the pathogenesis of IBD.
For example, several studies have demonstrated that exclusive enteral nutrition (EEN), which involves the administration of a liquid diet formula for a defined period of time, improves both clinical symptoms and intestinal inflammation in patients with Crohn’s disease; one randomized controlled trial demonstrated that a short-term EEN was superior to corticosteroids in promoting mucosal healing in paediatric patients with Crohn’s disease32, 33.
Nevertheless, similar studies in adults, where compliance to such a restrictive diet might be challenging, have not been as promising33. Lastly, a number of uncontrolled human intervention studies have also reported promising results for other diets in the treatment of IBD including specific carbohydrate diet (SCD), low-fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet and Paleolithic diet 34.
Although large, well-designed, randomized studies in humans are needed to fully examine the therapeutic effects of these diets in IBD. These early results suggest a role for diet in IBD pathogenesis and support the need for further investigation in this area.
Gut microbiota studies
Diet is widely linked to the composition of the human gut microbiome and microbial metabolites91. Although much of the microbial diversity seen in the adult gut might be attained by the age of 4 years, the adult microbiome remains susceptible to the influence of diet92. Indeed, dietary patterns have been proposed to explain greater than half of the variation in the adult intestinal microbiome92.
Accordingly, the gut microbiome has a crucial role in the pathogenesis of IBD, as evidenced by observations that infusion of intestinal luminal contents into excluded ileum triggers post-operative recurrence in patients with Crohn’s disease93. Furthermore, in mice models of colitis, microbial colonization is required for the development of active inflammation94, 95. Thus, diet, through its modulatory effect on the gut microbiota, might modify the risk of developing IBD (Figure 2)
Patients with established IBD have dysbiosis of the gut microbiome, characterized by reduced bacterial diversity, enrichment of bacteria of the family Enterobacteriaceae and reduced abundance of bacteria of the phylum Firmicutes and the genus Bacteroides (Figure 2)92, 96–98. Interestingly, similar patterns of bacterial enrichment have been reported in observational studies of healthy volunteers fed a high-fat, low-fiber diet, suggesting that prior epidemiological findings demonstrating an inverse association between fiber intake and risk of Crohn’s disease might in part be explained by diet-mediated alteration of the gut microbiota in genetically susceptible individuals99, 100.
The majority of prior studies investigating the interaction between diet, the microbiome and intestinal inflammation have been conducted in animal models of colitis. In mice, dietary heme iron was shown to directly injure the colonic surface epithelium through the generation of cytotoxic and oxidative stress101, 102.
Moreover, increased dietary heme iron intake has also been associated with marked changes in the composition of the gut microbiota, with an increased ratio of Gram-negative:Gram-positive bacteria in mice103.
This effect was primarily driven by the increased abundance of Gram-negative species, including those belonging to the genus Bacteroides and Akkermansia, leading to a marked increase in lipopolysaccharide production103.
In a 2017 study, Akkermansia muciniphila was shown in mice to be a pathobiont, promoting colitis in genetically susceptible hosts104. Interestingly, alteration in the function of the gut mucosal barrier related to dietary intake of heme iron seems to be dependent on the presence of sulfide-producing and mucin-degrading bacteria (for example, Akkermansia)101.
By contrast, in a mouse model of spontaneous ileitis, depletion of luminal iron altered gut microbial composition to promote inflammation105.
Finally, a high-fat diet has been linked to changes in phospholipid profile and bacteria taxa in the gut, highlighting the complex interactions between the host and the gut microbiome in response to high fat intake106, 107. More specifically, high intake of saturated fat altered the gut microbiome, characterized by an increase in the sulfite-reducing pathobiont Bilophila wadsworthia, and induced colonic inflammation in Il10-knockout mice 108.
This data provided a potential mechanism by which diets high in saturated fat might increase the risk of IBD in a susceptible host.
Human observational studies examining the interaction between diet, the microbiome and IBD are scarce. Among these studies is the ongoing multinational Genetics, Environment and Microbiome study that aims to identify factors that increase the risk of IBD109, 110. This study is examining several environmental exposures, such as being breastfed and the composition of the microbiome, in a cohort of patients at high risk of IBD. Interestingly, preliminary data from this study has not shown a correlation between intestinal permeability110 — a key pathogenic pathway in IBD that is known to be influenced by diet78 — and the gut microbiota. Specific patterns of association have been reported in a large Dutch cohort, in which total carbohydrate intake and features of a Western diet, including high caloric intake and consumption of sugar-sweetened beverages, were negatively associated with gut microbiome diversity 111.
By contrast, features of a Mediterranean diet, such as consumption of fruits, vegetables and red wine, were associated with increased diversity of the gut microbiome. Red wine consumption was also associated with the increased abundance of Faecalibacterium prausnitzii, which has been proposed to have anti-inflammatory properties in patients with IBD112 .
Several studies have examined the correlation between host genetics and the gut microbiome in healthy individuals and patients with IBD113–115.
Generally, these studies have established a potential association between several genetic variants, including IBD-specific risk variants, and the gut microbiome. However, perhaps the most intriguing finding has been the observation that gene–diet interaction could in part regulate the composition of human gut microbiome. Using metagenomic data from >1500 healthy individuals, it was found that the abundance of bacteria of the genus Bifidobacterium was regulated by a functional variant within the LCT gene, which encodes lactase, the enzyme responsible for the breakdown of lactose116. Interestingly, this association was further modified by dairy intake.
These studies further illustrate the interaction between diet, host genetics and the gut microbiome in human health and diseases of the gastrointestinal tract and highlights the complex relationship between these factors in studying IBD pathogenesis (FIG. 3).
The complex causal relationship between diet and inflammatory bowel disease-.The pathophysiology of IBD is thought to be related to inappropriate immune response to the gut microbiome in the genetically susceptible host. The composition of the gut microbiome is primarily dictated by environmental determinants particularly diet and the host genetics. In turn dietary factors may have differential influence on the immune function and risk of IBD according to the host genetics. Studies examining the role of diet, gut microbiome, and host genetics on risk of IBD are particularly complicated by the reciprocal effect of active disease on the gut microbiome and individuals’ dietary choices.
Source:
University of Alberta
Media Contacts:
Ross Neitz – University of Alberta
Image Source:
The image is in the public domain.
Original Research: Open access
“A high-sugar diet rapidly enhances susceptibility to colitis via depletion of luminal short-chain fatty acids in mice”. Michael Laffin, Robert Fedorak, Aiden Zalasky, Heekuk Park, Amanpreet Gill, Ambika Agrawal, Ammar Keshteli, Naomi Hotte & Karen L. Madsen.
Scientific Reports doi:10.1038/s41598-019-48749-2.
