Elsevier

Journal of Autoimmunity

Volume 116, January 2021, 102564
Journal of Autoimmunity

Resistant starch intake alleviates collagen-induced arthritis in mice by modulating gut microbiota and promoting concomitant propionate production

https://doi.org/10.1016/j.jaut.2020.102564Get rights and content

Highlights

  • Diet rich with RS, a new source of HFD, has a preventive effect on collagen-induced arthritis and bone damage.

  • RS-HFD exerts the anti-arthritic effect by altering gut microbial composition of CIA mice that promotes SCFAs production.

  • Propionate plays a role in RS-HFD-induced CIA relieve by expanding splenic Treg cells and enhancing IL-10 production.

Abstract

Gut dysbiosis precedes clinic symptoms in rheumatoid arthritis (RA) and has been implicated in the initiation and persistence of RA. The early treatment of RA is critical to better clinical outcome especially for joint destruction. Although dietary interventions have been reported to be beneficial for RA patients, it is unclear to whether diet-induced gut microbiome changes can be a preventive strategy to RA development. Here, we investigated the effect of a high fiber diet (HFD) rich with resistant starch (RS) on collagen-induced arthritis (CIA) and gut microbial composition in mice. RS-HFD significantly reduced arthritis severity and bone erosion in CIA mice. The therapeutic effects of RS-HFD were correlated with splenic regulatory T cell (Treg) expansion and serum interleukin-10 (IL-10) increase. The increased abundance of Lactobacillus and Lachnoclostridium genera concomitant with CIA were eliminated in CIA mice fed the RS-HFD diet. Notably, RS-HFD also led to a predominance of Bacteroidetes, and increased abundances of Lachnospiraceae_NK4A136_group and Bacteroidales_S24-7_group genera in CIA mice. Accompanied with the gut microbiome changes, serum levels of the short-chain fatty acid (SCFA) acetate, propionate and isobutyrate detected by GC-TOFMS were also increased in CIA mice fed RS-HFD. While, addition of β-acids from hops extract to the drinking water of mice fed RS-HFD significantly decreased serum propionate and completely eliminated RS-HFD-induced disease improvement, Treg cell increase and IL-10 production in CIA mice. Moreover, exogenous propionate added to drinking water replicated the protective role of RS-HFD in CIA including reduced bone damage. The direct effect of propionate on T cells in vitro was further explored as at least one mechanistic explanation for the dietary effects of microbial metabolites on immune regulation in experimental RA.

Taken together, RS-HFD significantly reduced CIA and bone damage and altered gut microbial composition with concomitant increase in circulating propionate, indicating that RS-rich diet might be a promising therapy especially in the early stage of RA.

Introduction

Rheumatoid Arthritis (RA) is a chronic, inflammatory autoimmune disease that affects mainly joints with a prevalence of about 0.5–1% globally [1]. Although there are multiple therapeutic strategies for treating established RA, accumulating evidence indicates that the pre-clinical and early stages of RA are likely to represent important therapeutic windows within which disease progression and outcomes can be dramatically modulated [2]. Therefore, identifying simple but effective methods to reduce risk factors, such as dietary changes, may offer promising strategies to block the progression of RA during the pre-arthritic stages.

Complex interplay between genetic and environmental factors contributes to RA etiopathogenesis [1]. Gut microbiome dysbiosis has been observed in both RA patients and experimental arthritic rodent models [[3], [4], [5]], and gut microbiota-induced mucosal immune activation precedes the onset of arthritis in collagen-induced arthritis (CIA) in mice [6]. The gut microbiota-dependent Th17 cell expansion in the small intestine lamina propria, rather than the colon lamina propria, contributes to the initiation of CIA [6]. Diet and derivatives of digestion and microbial metabolism can interact with the gastrointestinal epithelial barrier and mucosal immune system to affect regulation of local and systemic immune responses and inflammation [[7], [8], [9], [10]]. Recent evidence has demonstrated that gut microbiota can influence immune cell homeostasis [11] and susceptibility to RA [[3], [4], [5]]. T cell differentiation potential toward Th1, Th2 and Th17 cells are crucial to the immune response in the process of RA development. Tregs are known to negatively regulate the excessive T cell immune reaction and are a major source for IL-10 [12]. Reports from clinical studies have described significant remission in disease symptoms in RA patients that adopted a high fiber vegan or Mediterranean diet [[13], [14], [15]]. Nevertheless, it is unclear how the gut microbiota and consequential metabolic profile can be precisely modified by dietary supplementation in early stage RA to ameliorate disease symptoms and limit progression of this disease.

Resistant starch (RS) is a new type of soluble dietary fiber that is resistant to digestive enzymes in the upper digestive tract. Ongoing research has provided important evidence for the health benefits of RS on disease processes prevention, including colon cancer [16,17], diabetes [18,19], and obesity [20,21]. There are five different types of RS (RS I–V) classified by their mechanism of resistance to digestive enzymes [22]. Type 2 resistant starch widely exists in natural foods such as potatoes, bananas, rice and corn. It is often used as dietary fiber in health care products and are different from other kinds of RS made by physical or chemical modification [23] RS fermentation by bacteria in the large intestine generates important metabolites, including SCFAs [24]. SCFAs, especially propionate and butyrate, have well established ability to support gut epithelial integrity and produce anti-inflammatory and immunoregulatory functions [25]. In this study, we investigated the effects of a type 2 RS rich high fiber diet (RS-HFD) on inflammation, disease severity and progression in CIA, and the composition of intestinal microbiota in mice. Additionally, we also explored the key molecular factors and potential mechanism that determined how RS-HFD alleviates CIA.

Section snippets

Mice and diets

DBA/1 mice were purchased from Chengdu Dashuo laboratory animal company. All mice were maintained under specific pathogen-free (SPF) conditions at 25 °C with 12-h light and dark cycles. 8-Week old male DBA/1 mice were used for experiments in accordance with current ethical regulations for animal care and use in China. Mice were fed with either normal diet (ND) or a type 2 RS rich high fiber diet (RS-HFD) synthesized by Beijing Botai Hongda biotechnology company. The composition of the two diets

RS-HFD diet alleviates experimental arthritis

To determine the effect of the RS-HFD on collagen-induced arthritis, we monitored arthritis development from the second collagen immunization in CIA mice fed normal or RS-HFD diets. As shown in Fig. 1A, CIA mice had redness and swelling in ankles and fore- and hind-paws by day 36. Clinical scores gradually increased to reach a maximum around day 40 (Fig. 1 B). By comparison, the arthritis scores in CIA mice fed the RS-HFD diet (HFD-CIA) were lower than that in CIA mice from day 35, and were

Discussion

Evidence is emerging to suggest that dietary RS is protective against gastrointestinal disorders, asthma and cardiac vascular disease [[40], [41], [42]]. Similarly, dietary changes and supplementation are being considered as useful clinical strategies for RA therapy [[43], [44], [45], [46], [47]]. The main goal of this study was to explore whether RS-HFD may be therapeutic when fed to CIA mice at the onset of disease induction, and if so, potential mechanisms by which disease amelioration was

Conclusions

In summary, our findings show that RS-HFD reduces disease and improves bone destruction in CIA mice by changing the gut microbial composition that in turn promoted propionate production. In this study, we provided a metabolic and cellular mechanism for a gut-joint axis in controlling autoimmune arthritis and highlighted the importance of dietary fermentable fibers on RA intervention. Our study supports the concept that intervention strategies targeting diet adjustment are a valuable approach,

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgement

We gratefully acknowledge the assistance of Qiaorong Huang for flow cytometry analysis and Huifang Li for cell sorting.

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