"Nature": Internet celebrity dietary fiber inulin adds new worries! Cornell's team found that inulin induces an allergy-like immune response

*For medical professionals only

Inulin is a common dietary fiber found in fruits and vegetables such as bananas, asparagus, onions, leeks, wheat, garlic, etc
.
, and can often be seen in high-fiber dietary supplements.
In addition, the chemical structure of inulin gives it a creamy texture, so it can also be used as a fat substitute [1].

Like other dietary fibers, inulin exerts potential health benefits by regulating the gut flora and its metabolites, such as improved laxative, intestinal barrier function, glucose homeostasis, and more [1].

However, there is also a lot of negative news about inulin, and studies have shown that for mice with an imbalance of intestinal flora or a high-fat diet, abnormal fermentation of inulin in the intestine can induce liver cancer [2].

Recently, an article published in the top journal Nature said that inulin can also induce an allergic immune response - type 2 inflammation
.

Guo Chunjun and his colleagues at Weill Cornell Medical College in the United States found that inulin leads to an increase in the level of bile acids in the serum by changing the structure of the intestinal flora and its metabolite composition, which can cause type 2 inflammation and eosinophilia, which can aggravate allergic reactions in mice and enhance the body's defense under helminth infection [3].

Picture: Screenshot of the front page of the paper

After dietary fiber is degraded by intestinal bacteria, a large amount of metabolite short-chain fatty acids (SCFAs)
are produced.
SCFAs play an important regulatory role in both local and systemic parts of the intestine, affecting a variety of cells, including intestinal epithelial cells, as well as immune cells such as dendritic cells and regulatory T_{(T reg}) cells
.
Therefore, dietary fiber supplementation can improve obesity, metabolic syndrome, inflammatory diseases, etc.
[3].

However, the pros and cons of dietary fiber cannot be generalized, and there is still a big fog
about how a certain type of dietary fiber will affect intestinal bacteria or the human immune system.
This time, Guo Chunjun and his colleagues set their sights on inulin
.

They randomized pathogen-free mice (C57BL/6) into control and inulin groups, fed on a regular diet (4.
7% fiber) and an inulin-based high-fiber diet (30% dietary fiber, of which 26% inulin + 4% cellulose) were fed for 2 weeks, respectively, and then compared the differences
in all aspects between the two groups.

Let's first look at the effect of
inulin on the structure of intestinal bacteria and the composition of metabolites.

Consistent with the existing clinical studies, the abundance of Bacteroides in the inulin group was increased
compared with the control group.
The results of serum metabolomics analysis showed that the serum levels of phenolic compounds and indole in the inulin group were significantly down-regulated and indole levels were significantly up-regulated, while the metabolites with the highest serum levels and the greatest differences from those in the control group were bile acid (BA) and primary bile acid, that is, cholic acid (CA).

Inulin mainly affects intestinal bacteria and intestinal metabolites, which are Bacteroides and bile acids

From this point of view, inulin breaks people's "stereotypes"
of dietary fiber.
As just mentioned, it is currently believed that the main metabolites affected by dietary fiber intake are SCFAs, and the effect of inulin on the level of bile acids in the serum suggests that the regulatory effect of dietary fiber on intestinal bacterial metabolites is more extensive
than known.

Let's take a look at what effect inulin has on
the immune system of mice.

The researchers found that compared with the control group, the number of most types of immune cells in the inulin group did not change significantly, the number of T_reg cells increased slightly, and the level of eosinophils was significantly increased
.
Not only that, the lungs of the inulin group mice were also enriched with eosinophils
.

Mice that ate inulin had significantly higher levels of eosinophils in their gut and lungs

Curiously, eosinophilia is typical of
type 2 inflammation.
Type 2 inflammation is an immune response mediated by type 2 innate lymphocytes (ILC2s) to fight helminth infection and normal wound healing, but inappropriate activation (such as allergens) can lead to allergies, asthma and other diseases
.
At the same time, the researchers confirmed that the increase in eosinophils in mice after ingesting inulin was indeed mediated
by ILC2s.
This suggests that an inulin-based high-fiber diet induced a systemic type 2 inflammatory response
in mice.

How can this eat inulin and give the mouse a whole "allergy"?

Subsequent studies have shown that inulin intake can cause eosinophilia, which is borrowed from the "hand" of intestinal bacteria, and is inseparable from metabolite bile
acids.

Specifically, when inulin is ingested, the abundant upregulated Bacteroides produce large amounts of bile acids
under the action of bile saline hydrolase (BSH).
The researchers found that bile acids or bile acids can induce epithelial cells and stromal cells to express interleukin-33 (IL-33), and ILC2 is activated by IL-33 and produces the expression of interleukin-5 (IL-5), leading to eosinophilia and type 2 inflammation
.

If bile acid nuclear receptors (Farnimate derivative X receptors, FXR) are absent in epithelial and stromal cells, inulin cannot induce eosinophilia
.

In the absence of the FXR gene (Nr1h4-/-), intake of inulin does not cause type 2 inflammation

The researchers further observed in mouse experiments what effect type 2 inflammation induced by inulin has on allergic inflammation, tissue protection and host defense
.

The results showed that inulin aggravated the allergic inflammatory response
in mice.

They exposed the mice to an allergen (papain), which induced type 2 inflammation and lung damage
in the mice.
After giving mice inulin, it was found that the inflammatory response in the lungs of the mice was aggravated, the infiltration of inflammatory cells in the pulmonary blood vessels and the area around the bronchi increased, and the level of eosinophils in the lungs and alveoli was significantly increased
.

On the other hand, in the face of worm infection, inulin strengthens the body's defenses
.

Compared with the control mice in the regular diet, the inulin group mice had a higher level of type 2 inflammatory response, increased eosinophils and goblet cells, and faster
excretion of parasites when exposed to Japanese nematodes brasilensis infection.

Figure: Because it can induce type 2 inflammation, inulin can both cause aggravated allergic reactions and can also be used to protect against helminth infection

Not only that, the researchers also transplanted human feces into mice to explore the effects of
inulin on the human intestinal flora.
The results showed that all mice colonized by human microbiota had up-regulated serum bile acid levels after ingesting inulin, and elevated levels of inflammation-related factors IL-33 and IL-5 and eosinophilia could be observed
.
This means that inulin can also induce type 2 inflammation by acting on human intestinal bacteria
.

In summary, Guo Chunjun and his colleagues found that common dietary fiber inulin can induce type 2 inflammatory response by regulating the structure of intestinal bacteria and the cholesterol level of their metabolites, which is of great significance for the regulation of allergic inflammation and host defense.

In this way, the relationship between diet, human microorganisms, and human immunity is inextricably linked, and the intake of dietary fiber such as inulin should be further measured and reasonably supplemented
.

References:

[1] Hughes RL, Alvarado DA, Swanson KS, Holscher HD.
The Prebiotic Potential of Inulin-type Fructans: A Systematic Review.
Adv Nutr.
2021 Sep 23; 13(2):492–529.
doi: 10.
1093/advances/nmab119.

[2] Singh, V.
, et al.
(2018).
Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer.
Cell, 175(3), 679–694.
e22.
https://doi.
org/10.
1016/j.
cell.
2018.
09.
004

[3] #author-information

The author of this articleZhang Eddy