| Inflammatory bowel disease(IBD)is characterized by chronic remittent inflammation in the gut,including ulcerative colitis(UC)and Crohn’s disease(CD),with the main symptoms of diarrhea,abdominal pain,blood in the stool etc.Current medications used to manage colitis often involve side effects,seeking safe and effective alternative treatments is critical.Polysaccharides are widely available macromolecular active compounds that have many beneficial effects.In this paper,we first examined the effectiveness of ten polysaccharides with different structures for the mitigation of colitis and found that not all polysaccharides could alleviate colitis,with barley-derivedβ-glucan showing superior improvement than the others.β-glucan has such effects as anti-inflammatory and improving intestinal barrier,but the molecular mechanism is still unclear.Therefore,this paper is focused on investigating the mechanism of β-glucan in alleviating colitis.The main findings and results are as follows:(1)Ten different polysaccharides were systematically evaluated for their effect in alleviating colitis.The study was conducted using inulin,β-glucan,arabinogalactan,glucomannan,apple pectin,carrageenan,guar gum,arabinoxylan,xanthan gum,and xylan for the intervention in mice,respectively,and dextran sulfate sodium salt(DSS)was used to induce UC in mice.Disease severity was evaluated by weight,disease activity index score,and colon length.The results showed that not all polysaccharides had the effect of alleviating colitis.A comprehensive assessment revealed that β-glucan had the relatively best alleviating effect on colitis in mice,followed by arabinogalactan and apple pectin,and glucomannan,arabinoxylan and guar gum also had certain ameliorating effects on colitis.On the contrary,inulin,carrageenan,xanthan gum,and xylan hardly relieved colitis.(2)The important role of gut microbiota in alleviating colitis by β-glucan was identified first in the mechanistic study.It was demonstrated that β-glucan improved the dysbiosis and diversity of gut microbiota and increased the abundance of Lactobacillus in the gut of colitis mice.Further correlation analysis showed that the abundance of Lactobacillus was significantly and negatively correlated with the severity of colitis.The results of animal experiments showed that β-glucan did not ameliorate colitis in antibiotic-treated mice.In addition,transplantation of fecal bacteria from mice following β-glucan intervention to recipient mice revealed that the colonization of this fecal bacteria could effectively alleviate colitis in mice.The above results suggest that gut microbiota is an important target for β-glucan to alleviate colitis.(3)It was confirmed that β-glucan mainly caused the enrichment of L.johnsonii by in vitro culture and bacterial genome sequencing,and a strain of L.johnsonii with ameliorating effect on colitis was screened.The results of in vitro fermentation showed that β-glucan could be degraded by the gut microbiota from mice with colitis,and caused changes in the structure of the gut microbiota,as well as significantly boosting the proliferation of Lactobacillus(consistent with the in vivo results).Further cultureomics studies showed that β-glucan was mainly enriched Lactobacillus johnsonii,and a promising strain of L.johnsonii,named L.johnsonii NSP009,was screened.It was revealed that this bacterium could effectively alleviate DSS-induced colitis in mice,while the heat-killed bacterium failed to protect against colitis.This result suggests that the metabolites produced by L.johnsonii are essential for the relief of colitis.(4)The mechanism of β-glucan to alleviate colitis in mice was elucidated based on the transcriptomic and metabolomic analysis.Colonic transcriptome analysis demonstrated that L.johnsonii significantly activated the aryl hydrocarbon receptor(Ah R)signaling pathway,which ameliorated colitis mainly by promoting the secretion of IL-22 and Muc2 that are downstream of this pathway.Metabolomic analysis showed that L.johnsonii produces a certain level of indole-3-lactic acid(ILA),an Ah R agonist.ILA has been shown to have a good effect in relieving colitis in mice.We further used CH223191 to inhibit the activation of Ah R in mice and found that neither ILA nor L.johnsonii could significantly improve colitis in mice.This result confirms that the activation of Ah R signaling pathway plays an important role in the alleviation of colitis by L.johnsonii and ILA.Through reviewing the results of β-glucan-related in vivo studies,this same increase in ILA and activation of the Ah R signaling pathway was found in mice with colitis after β-glucan administration.Taken together,we identified and confirmed the important mechanism of β-glucan in alleviating colitis through the L.johnsonii-ILA-Ah R axis.(5)The causes of β-glucan-induced enrichment in L.johnsonii were investigated using a combined multi-omics analysis.In vitro studies indicated that L.johnsonii could not directly degrade β-glucan,and also that β-glucan could not directly promote the proliferation of L.johnsonii.However,β-glucan caused enrichment of L.johnsonii both in vivo and in vitro.This leads us to propose a hypothesis that “the proliferation of L.johnsonii is associated with β-glucan-degrading bacteria”.Retrospective analysis of in vivo and in vitro bacterial sequencing data revealed that the abundance of L.johnsonii was significantly and positively correlated with that of Bacteroides uniformis.It was demonstrated that B.uniformis has the ability to degrade β-glucan and promote the proliferation of L.johnsonii.Further studies revealed that B.uniformis promotes L.johnsonii proliferation mainly through the glucose produced from the degradation ofβ-glucan as well as through the niacinamide produced by B.uniformis during the metabolism.(6)An exploratory study conducted on a healthy population confirmed that β-glucan was effective in increasing the abundance of L.johnsonii and the concentration of ILA in the stool of subjects.Specifically,the administration of 5 g β-glucan for 2weeks increased the abundance of B.uniformis,L.johnsonii and ILA concentrations in the feces of healthy adults,which strongly corroborates the results in animal studies.The development of colitis is often accompanied by a decrease in Lactobacillus and a deficiency of Ah R agonists in the intestine.Based on the concept of “treating disease before it occurs”,β-glucan can cause an enrichment of L.johnsonii,which maintains the level of ILA in the intestine,and the related dietary interventions may prevent or control the development of colitis.In summary,this paper systematically evaluated the effectiveness of ten different polysaccharides against colitis and confirmed the promising intervention of β-glucan.Further investigation revealed that the gut microbiota is the important target of β-glucan in alleviating colitis,and the important role of the L.johnsonii-ILA-Ah R axis was identified and confirmed.Furthermore,this paper elucidates the reasons for the proliferation of L.johnsonii caused by β-glucan from the perspective of bacterial crossfeeding.These findings provide certain guidelines for the dietary management of patients with colitis,and theoretical support for the development of healthy foods withβ-glucan,as well as new insights and evidence for the interactions of gut microbiota. |
