Dietary fiber consumption is suggested to favorably impact immune function, but the mechanisms mediating this effect remain under explored. In a recent study in Nature, Arifuzzaman et al. unveil that murine consumption of a specific dietary fiber, inulin, induces type 2 inflammatory responses, through discrete microbiome-mediated mechanisms; these dietary-induced immune responses, in turn, modulate context-dependent detrimental or beneficial inflammatory consequences in the mammalian host.

Dietary fiber (DF) consumption is suggested to drive beneficial effects on the mammalian host, including the shaping of its gut microbiome composition and function towards a favorable metabolic configuration. DFs are also suggested to modulate various aspects of immune function, though these interactions remain less mechanistically defined.1,2 For example, increased consumption of DF was recently shown to favorably contribute to immunotherapy efficacy in melanoma patients, potentially through effects exerted on the gut microbiome and its secreted metabolites.3 Many DF-derived benefits are enabled by DF fermentation by gut commensals, which, in turn, result in enhanced microbial replication and modulation of bioactive metabolites such as secondary bile acids and short chain fatty acids (SCFAs).4 Indeed, SCFAs, central microbiome-derived metabolites, have been shown to influence multiple cellular subsets and functions in promotion of immunoregulatory effects.5 Of note, unique commensals and their respective metabolic machineries differentially degrade different DFs. As a result, variations in DF consumption, coupled with differences in microbiome degradation capacities, often lead to heterogeneous clinical outcomes in different physiological contexts.

Type 2 inflammatory responses are characterized by upregulation of the cytokines interleukin (IL)-4, IL-5, IL-13 produced by Th2 cells and group 2 innate lymphoid cells (ILC2), coupled with upregulation of IL-25 and IL-33, and resultant eosinophil expansion. This hallmark response is often invoked by helminth infection, asthma, and discrete responses to a variety of allergens.6 Previously, mice fed pectin-rich diet and induced with allergic airway inflammation were suggested to develop an attenuated type 2 inflammatory response, manifesting as reduced pulmonary IL-4, IL-5, IL-13 and IL-17A in comparison to mice fed a control diet.7 These changes were suggested to be driven by degradation of pectin into the SCFA propionate7 and butyrate,8 suppressing ILC2 cytokine production and associated type 2 inflammation through yet undiscovered mechanisms.

In a recent work, Arifuzzaman et al.9 demonstrate that supplementation of the DF inulin to mice induces eosinophilia and upregulates type 2 inflammatory response, by a microbiome-dependent mechanism. The authors demonstrate that inulin supplementation induces compositional changes in the gut microbiome hallmarked by Bacteroides expansion, coupled with marked changes observed in hundreds of significantly altered serum metabolites. Molecular networking analyses further unraveled that inulin consumption was associated with a reduction in serum phenols, coupled with upregulation of indoles and primary unconjugated bile acids, including cholic acid (CA). These changes were accompanied by enhanced colon and pulmonary eosinophilic infiltration in inulin-fed mice. To decode the upstream innate immune cellular subsets regulating this type 2 inflammatory response, the researchers utilized Rag2–/– mice, deficient in adaptive B and T cells, and Rag2–/–Il2rg–/– mice, which are also deficient in ILCs. Remarkably upon inulin supplementation, eosinophilia normally developed in Rag2–/– mice but was absent in Rag2–/–Il2rg–/– mice, indicating an essential role of ILCs in mediating inulin-induced eosinophilia. Indeed, RNA-sequencing of sorted colonic ILC2 cells from inulin-fed mice demonstrated a significant upregulation of type 2 inflammatory genes and pathways, including IL-5. Quantitative PCR and immunofluorescence further featured an inulin feeding-mediated upregulation of IL-33 in colonic stromal cells. Inulin-fed IL-33- and IL-33 receptor-deficient mice did not develop eosinophilia, thereby establishing a likely role of IL-33 in this process.

To determine the inulin-dependent metabolites driving this type 2 inflammatory response, Arifuzzaman et al. surveyed some of the differentially abundant metabolites discovered in their untargeted metabolomics analysis. CA, alone or in combination with indolepropionic acid (IPA), sufficiently induced a type 2 inflammatory response, even in the absence of inulin supplementation. Spatial transcriptomics further implicated bile acid signaling in this type 2 inflammatory response, with the Nr1h4 gene, encoding the bile acid nuclear receptor farnesoid X receptor (FXR)  in the process. Indeed, the FXR receptor was highly expressed in colonic epithelial and muscularis regions in inulin-fed mice, while constitutive Nr1h4 deletion abolished the inulin-induced eosinophilia and IL-33 expression. From the commensal end, a bacterial Bacteroides ovatus bile salt hydrolase (bsh) was involved in promotion of inulin-driventype 2 inflammation. Monocolonization of inulin-fed germ-free mice with wild-type Bacteroides ovatus, but not with bsh-deficient Bacteroides ovatus, induced CA elevation and a downstream type 2 inflammatory response.

To highlight the clinical consequences of the newly discovered fiber-microbiome-immunity axis, Arifuzzaman et al. further induced allergic airway inflammation in mice, demonstrating aggravated eosinophil responses and pulmonary inflammation upon inulin feeding, as compared to feeding with a control diet. Furthermore, the researchers demonstrated that inulin-fed, Nippostrongylus brasiliensis-inoculated mice featured a potentiated type 2 inflammatory response, resulting in improved parasitic clearance, as compared to parasite-inoculated, normal chow-fed mice.

The work by Arifuzzaman et al. is significant in several facets. It highlights a novel mechanism by which inulin promotes type 2 inflammation, via a microbiome-mediated modulation of primary bile acid conversion into CA, which, in turn, induces IL-33 and IL-5 expression by stromal cells and ILC2s, respectively (Fig. 1). Importantly, it demonstrates that distinct fibers may differentially impact the microbiome and host. As such, the inulin-related impacts reported by Arifuzzaman et al. are divergent from the ones previously reported by others with respect to the DF pectin. Decoding the unique effects of other fiber formulations, and their combinations, on host metabolism and immunity will likely constitute fascinating directions of future research. Likewise, translating these findings into the human setting may enable the development of rationalized fiber consumption recommendations tailored to the individual.10 Collectively, the impressive study by Arifuzzaman et al. sheds new light on the unique and pleotropic DF impacts on mammalian physiology and immunity.

Fig. 1: Inulin promotes type 2 inflammation.
figure 1

An inulin-rich diet results in intestinal Bacteroides expansion, which drives a bacterial bsh-dependent elevation of serum CA. CA signals on stromal cell and ILC2 to induce expression of IL-33 and IL-5, respectively. These cytokines, in turn, drive a type 2 inflammatory response and associated hyper-eosinophilic infiltration, leading to exacerbated asthma but improved intestinal parasitic clearance.