Bacteroides thetaiotaomicron Ameliorates Experimental Allergic Airway Inflammation via Activation of ICOS+Tregs and Inhibition of Th2 Response

Abstract

Inhibition of allergic airway diseases (AAD) by immunomodulation of the adaptive immune system through restoration of the enteric dysbiosis is an emerging therapeutic strategy. Patients with allergic rhinitis (n = 6) and healthy controls (n = 6) were enrolled, and gut microbiome composition analysis was performed by 16S rDNA sequencing. We also established an ovalbumin (OVA)-induced allergic airway inflammation murine model. Dysbiosis of the gut flora was observed in both AAD patients and the mice, with the decrease of the biodiversity and the quantity of the Bacteroidetes phylum. Oral application of Bacteroides (B.) thetaiotaomicron ameliorated the symptoms of OVA-induced airway hyperresponsiveness (AHR) and attenuated the airway inflammation in mice. In addition, nasal lavage fluid (NALF) and bronchoalveolar lavage fluid (BALF) from AAD mice orally administered with B. thetaiotaomicron showed reduced numbers of immune cells, and diminished secretion of T helper (Th)-2 cytokines (IL-4, IL-5, and IL-13) compared with the corresponding control mice, whereas the levels of Th1 cytokineIFN-γ was not changed in both the groups. When B. thetaiotaomicron was co-administered with metronidazole in AAD mice, the immunomodulatory effect was weakened and the allergic inflammatory response was aggravated. The ratios of CD4+Foxp3+ cells, CD4+ICOS+ T cells, CD4+ICOS+ Foxp3+ regulatory T cells, and IL-10-expressing CD4+Foxp3+ cells were increased in lymphocytes of spleen, mesenteric, and cervical lymph nodes of AAD mice administrated with B. thetaiotaomicron. Therefore, our data indicate that oral administration of B. thetaiotaomicron effectively inhibited the development of AAD in murine model; inhibition was mediated by the activation of Tregs and inhibition of Th2 response without promoting a Th1 response.

CD103 integrin identifies a high IL‐10‐producing FoxP3+regulatory T‐cell population suppressing allergic airway inflammation

“…IRF4 has been previously reported to drive a regulatory T‐cell suppressor program for specifically controlling Th2 responses, 15 while IRF4‐deficient Tregs have been shown to express reduced amounts of suppressive molecules such as ICOS, CTLA‐4 and IL‐10 51 . ICOS and KLRG1 have been demonstrated, in turn, to be involved in the suppressive function of FoxP3 + Tregs on Th2 responses and allergic inflammation in mice 52–54 . It is therefore reasonable to speculate that CD103 + Treg‐mediated suppression of Th2 responses is due to the high presence of IRF4 and the costimulatory molecules ICOS and KLRG1.…”

The Changes in Bacterial Microbiome Associated with Immune Disorder in Allergic Respiratory Disease

“…A pooled analysis of multiple studies confirms that there are various bacterial changes in the gut of patients with allergic respiratory disease [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. For this review, we mainly considered changes in gut bacteria in patients with AR and asthma, as only a few 16srRNA gene sequence analyses have been performed on gut bacteria of patients with CRS ( Figures S1B and S2 ), and these findings in CRS show increased levels of Enterobacter and a decline in Bifidobacterium [ 31 ].…”

Extracellular Vesicle-Derived Protein File from Peripheral Blood Predicts Immune-Related Adverse Events in Gastric Cancer Patients Receiving Immunotherapy

“…ICOS and IDO1 are proteins related to immunotherapy; relevant target drugs have been produced [ 30 , 31 ], and several studies support that they were associated with allergic diseases [ 32 ]. It has been reported that activation of ICOS + Tregs mediates allergic airway diseases, and targeting the ICOS/ICOS-L pathway may disrupt T follicular helper cell responses and ameliorate allergic asthma by disrupting the disease [ 33 , 34 ]. In addition, IDO1, as an immunosuppressive tolerogenic enzyme, has been reported as biomarkers of immune system activation and childhood allergic diseases [ 35 , 36 ].…”