Resistant starch intake alleviates collagen-induced arthritis in mice by modulating gut microbiota and promoting concomitant propionate production
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.
References (65)
- et al.
Specialized metabolites from the microbiome in health and disease
Cell Metabol.
(2014) - et al.
From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites
Cell
(2016) - et al.
Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis
Mucosal Immunol.
(2010) - et al.
Dietary starch type affects body weight and glycemic control in freely fed but not energy-restricted obese rats
J. Nutr.
(2009) - et al.
Resistant starch: promise for improving human health
Advances in Nutrition
(2013) - et al.
Resistant starch: promise for improving human health
Adv Nutr
(2013) - et al.
From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites
Cell
(2016) - et al.
Euphorbia factor L2 alleviates lipopolysaccharide-induced acute lung injury and inflammation in mice through the suppression of NF-kappaB activation
Biochem. Pharmacol.
(2018) - et al.
Induction of intestinal Th17 cells by segmented filamentous bacteria
Cell
(2009) - et al.
Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice
Mucosal Immunol.
(2017)
The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids
J. Biol. Chem.
Epidemiology and genetics of rheumatoid arthritis
Arthritis Res.
Preclinical rheumatoid arthritis and rheumatoid arthritis prevention
Curr. Rheumatol. Rep.
Altered gut microbiota in RA: implications for treatment
Z. Rheumatol.
Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis
Int J Rheum Dis
Infectious agents and inflammation: the role of microbiota in autoimmune arthritis
Front. Microbiol.
Microbiota-dependent involvement of Th17 cells in murine models of inflammatory arthritis
Arthritis & Rheumatology.
Signals from the gut microbiota to distant organs in physiology and disease
Nat. Med.
Dietary factors in rheumatic autoimmune diseases: a recipe for therapy?
Nat. Rev. Rheumatol.
Defective T-cell apoptosis and T-regulatory cell dysfunction in rheumatoid arthritis
Cells
Effects of a very low-fat, vegan diet in subjects with rheumatoid arthritis
J. Alternative Compl. Med.
The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies
Rheumatol. Int.
The role of dietary fiber in rheumatoid arthritis patients: a feasibility study
Nutrients
Effect of high red meat intake and resistant starch in humans on risk factors for colorectal cancer
J. Gastroenterol. Hepatol.
Suppression of azoxymethane-induced colon cancer development in rats by dietary resistant starch
Canc. Biol. Ther.
Resistant starch supplementation influences blood lipid concentrations and glucose control in overweight subjects
J. Nutr. Sci. Vitaminol.
The effect of a pre-load meal containing resistant starch on SpontaneousFood intake and glucose and insulin responses
CABI Agriculture and Bioscience
Effects of resistant starch, a non-digestible fermentable fiber, on reducing body fat
Obesity
Resistant starch–A review
Compr. Rev. Food Sci. Food Saf.
Critical role of M. tuberculosis for dendritic cell maturation to induce collagen-induced arthritis in H-2b background of C57BL/6 mice
Immunology
Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45beta-deficient mice
Arthritis Rheum.
Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss
Nat. Commun.
Cited by (52)
Harnessing and delivering microbial metabolites as therapeutics via advanced pharmaceutical approaches
2024, Pharmacology and TherapeuticsAmelioration of obesity and inflammation by polysaccharide from unripe fruits of raspberry via gut microbiota regulation
2024, International Journal of Biological MacromoleculesAdvances in the effect of gut-joint axis dysfunction on rheumatoid arthritis and the intervention of natural products
2024, Chinese Journal of Analytical ChemistryGut microbiota in pre-clinical rheumatoid arthritis: From pathogenesis to preventing progression
2023, Journal of AutoimmunityBenefits from a plant-based diet, intermittent fasting and aspects of ayurvedic nutrition in rheumatoid arthritis – A case report
2023, Advances in Integrative MedicineMuscadine grape (vitis rotundifolia) and wine polyphenols alleviated arthritis and restored the gut microbial composition in mice
2023, Journal of Nutritional Biochemistry
- 1
These authors contribute to this article equally.