Abstract

Epidemiological data provide strong evidence of dramatically increasing incidences of many autoimmune diseases in the past few decades, mainly in western and westernized countries. Recent studies clearly revealed that ‘Western diet’ increases the risk of autoimmune diseases at least partially via disrupting intestinal tight junctions and altering the construction and metabolites of microbiota. However, the role of high sucrose cola beverages (HSCBs), which are one of the main sources of added sugar in the western diet, is barely known. Recently, a population study showed that regular consumption of sugar-sweetened beverages is associated with increased risk of seropositive rheumatoid arthritis in women, which provokes interest in the genuine effects of these beverages on the pathogenesis of autoimmune diseases and the underlying mechanisms. Here we showed that long-term consumption of caffeine-free HSCBs aggravated the pathogenesis of experimental autoimmune encephalomyelitis in mice in a microbiota-dependent manner. Further investigation revealed that HSCBs altered community structure of microbiota and increased Th17 cells. High sucrose consumption had similar detrimental effects while caffeine contamination limited the infiltrated pathogenic immune cells and counteracted these effects. These results uncovered a deleterious role of decaffeinated HSCBs in aggravating the pathogenesis of experimental autoimmune encephalomyelitis in mice.

Introduction

Autoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), type I diabetes, inflammatory bowel disease and psoriasis are multifactorial etiological diseases, involving T cell-mediated inflammatory pathology. Genetic factors are closely correlated with the development of autoimmune diseases [1, 2], but this could not explain the dramatically increasing incidences of these diseases in the past few decades, mainly in western and westernized countries [3]. Besides, studies in monozygotic twins showed a relatively low-concordance rate for most of the diseases [4], suggesting that environmental factors also play important roles in the pathogenesis of autoimmune diseases.

Recently, emerging works on the role of the gastrointestinal (GI) microbiota in the pathogenesis of autoimmune diseases were reported, providing clear evidence that dysbiosis of the microbiota is associated with these diseases [5,6,7, 8,9,10,11]. Depleting microbiota aborted the pathogenesis of experimental autoimmune encephalomyelitis (EAE) [12, 13], the most widely used animal model for human MS, suggesting a critical role of microbiota in EAE disease. Further investigations demonstrated that gut-residing segmented filamentous bacterium antigens, presented by DC, specifically drive Th17 cells differentiation, which is pivotal for the pathogenesis of EAE and RA [14,15,16,17]. Moreover, intestinal luminal adenosine 5′-triphosphate (ATP), which could be derived from commensal bacteria, was shown to activate a unique subset of lamina propria cells, CD70high CD11clow cells, leading to the differentiation of Th17 cells and an increasing risk for inflammatory colitis [18] and EAE [19]. These results corroborated GI microbiota and metabolites as pivotal internal environmental elements for triggering autoimmune diseases.

Dietary patterns have short- and long-term effects in shaping the composition of gut microbiota and modulating its metabolic machinery products. Increasing evidence suggests that dietary modulation of the microbiome is involved in the pathogenesis of autoimmune diseases such as inflammatory bowel disease and osteomyelitis [20,21,22,23]. The ‘Western diet’, characterized as high-fat and cholesterol, high-protein, high-sugar and excess salt intake, as well as frequent consumption of processed and ‘fast foods’ with industrial food additives, was found to increase the risk of many of these autoimmune diseases [21,23,24,25,2627,28,29,30]. Among these dietary factors, high fat and industrial emulsifiers have been found to trigger the disease at least partially via impacts on microtioba [23, 31,32,33,34]. Recently, consumption of sugar-sweetened soda (including high sugar contained regular cola, caffeine-free cola and other sugar-sweetened carbonated soda), but not diet soda (sugar-free), was reported to be associated with an increased risk of seropositive RA in women [35], suggesting a pro-inflammatory effect of refined sugars in pathogenesis. In fact, sugar consumption has rapidly increased in lower-middle and upper-middle-income countries in Asia, and carbonated soft drinks are the most significant vectors for the increasing sugar consumption [36]. However, we still lack the knowledge regarding the genuine effects of sugary cola beverages and the refined sugars in the pathogenesis of autoimmune diseases and whether the consumption of these beverages has any impact on the construction of GI microbiota.

Here we adopted a mouse model of EAE to assess the effects of several most popular HSCBs (regular Coca-Cola, caffeine-free Coca-Cola (Coca-Free), regular Pepsi, and caffeine-free Pepsi (Pepsi-Free)) and diet soda (Coca-Zero) on the pathogenesis of autoimmune diseases. The ingredients of these beverages are listed in Table 1. Results showed that long-term consumption of caffeine-free cola beverages (Coca-Free and Pepsi-Free), but not other cola beverages, aggravated disease development, as indicated by higher clinical scores, exacerbated demyelization and elevated central nervous system (CNS)-infiltrated pathogenic Th17 cells. Further research revealed that all the HSCBs and high sucrose markedly changed the community structure of intestinal microbiota to promote Th17 cells and feces transplantation from these groups also increased the risk of EAE. Caffeine, on the other hand, inhibited the number of CNS-infiltrated lymphocytes and counteracted the detrimental effects of high sucrose on both active- and passive-induced EAE. Moreover, we also found elevated luminal ATP levels in mice consuming HSCBs or high sucrose, but not Coca-zero. Taken together, the aforementioned findings converged to strongly support a detrimental potential of high sucrose in HSCBs on the pathogenesis of EAE through modulating the construction of intestinal microbiota, while caffeine contamination in regular HSCBs counteracts this effect and is protective.