Researchers have discovered how our choice of diet can weaken our gut immune system and lead to the development of diabetes.
A growing body of research supports that during obesity, our immune system is often responding to components of bacteria that “leak” through the intestinal tissue and results in inflammation.
In turn, inflammation can drive insulin resistance, which predisposes people to diabetes.
In new research published in Nature Communications this week, Dr. Dan Winer, Scientist, Toronto General Hospital Research Institute and the Department of Pathology at University Health Network (UHN), and his team, including graduate students Helen Luck and Saad Khan, and co-lead author, Dr. Shawn Winer at St. Michael’s Hospital, highlight how a high fat diet influences one component of the gut immune system called B cells, specifically those that produce a protein called IgA.
“We discovered that during obesity, there are lower levels of a type of B cell in the gut that make an antibody called IgA,” says lead author Helen Luck.
“IgA is naturally produced by our bodies and is crucial to regulating the bacteria that live in our gut.
It acts as a defense mechanism that helps neutralize potentially dangerous bacteria that take advantage of changes to the environment, such as when we consume an imbalanced or fatty diet.”
In their experiments, they also observed that IgA deficient pre-clinical models, which lack protective IgA, had worsened blood sugar levels when fed a high fat diet.
As well, transplantation of gut bacteria from these IgA deficient models into models that had no gut bacteria was able to transfer the disease, demonstrating that IgA can regulate the amounts of harmful bacteria in the gut during diet-related obesity.
In collaboration with a bariatric surgery research team at UHN led by Dr. Johane Allard and Dr. Herbert Gaisano, the team saw increased levels of IgA within the stool of patients soon after bariatric surgery, supporting the importance of IgA and the gut immune system in humans with obesity.
Overall, the research highlights a robust connection between high fat diets, obesity and the lack of gut IgA in promoting inflammation and insulin resistance.
The knowledge that this class of antibodies regulate pathogenic bacteria, and protects against a “leaky gut,” and additional complications of obesity, is a powerful tool in the fight against diabetes.
“If we can boost these IgA B cells or their products, then we may be able to control the type of bacteria in the gut,” says Dr. Dan Winer.
“Especially the ones that are more likely to be linked to inflammation and ultimately insulin resistance. Going forward, this work could form the basis for new gut immune biomarkers or therapies for obesity and its complications, like insulin resistance and type 2 diabetes.”
Excessive consumption of dietary fat alters the composition of gut microbiota.
High-fat diet (HFD) consumption increases the ratio of Firmicutes:Bacteroidetes, the dominant phyla in the human and mouse gut .
Family-level changes in gut microbiota have also been reported, including increases in Enterobacteriaceae, Enterococcaceae, and Bifidobacteriaceae, as well as decreases in Lactobacillaceae and Prevotellaceae [2,3,4].
In addition, HFD consumption has been associated with decreased microbial diversity . Several factors, such as bile acid, dietary fat, and short-chain fatty acids (SCFAs), may induce shifts in microbial composition as a result of HFD feeding.
Firstly, elevated fat consumption triggers increased bile acid synthesis, a process required in lipid digestion and absorption.
Unabsorbed bile acids are hydrolyzed into secondary bile acids by gut microbial bile salt hydrolase .
The antimicrobial nature of the resultant secondary bile acids has been suggested to favor the growth of bile-tolerant microbiota .
Secondly, movement of unabsorbed dietary fat into the distal intestine after HFD consumption has been shown to cause an increase in the Firmicutes:Bacteroidetes ratio due to the bacteriostatic properties of saturated fatty acids [8, 9].
Further, prolonged consumption of a diet rich in saturated fats is associated with ER stress-mediated reduction in colonic mucin production, resulting in changes in gut microbiota composition .
These HFD-related changes in gut microbiota result in lower SCFA production in the intestinal lumen .
The subsequent increase in luminal pH inhibits the growth of pH-sensitive bacteria, further modulating the gut microbiota composition .
In addition to these factors, we hypothesized that the secretory immunoglobulin A (SIgA) coating of gut microbiota is related to changes in microbial composition upon HFD consumption.
This is because SIgA plays an important role in maintaining a stable gut microbial composition .
SIgA is the predominant antibody isotype secreted into the intestinal lumen .
While it is evident that the SIgA coating of gut microbiota modulates the gut microbial composition, the relationship between the SIgA coating of gut microbiota and HFD-induced changes in gut microbiota remains unclear.
To investigate this relationship, we evaluated the level of IgA coating of gut microbiota and the gut microbial composition in NFD- and HFD-fed mice and explored the correlation between them.
In the present study, we investigated the relationship between SIgA coating of gut microbiota and HFD-induced changes in gut microbiota.
Our study demonstrates that the level of SIgA coating fecal bacteria greatly decreased in HFD-fed mice compared with NFD-fed mice, which suggests that SIgA coating of gut microbiota may be suppressed by HFD feeding.
Furthermore, we observed that the suppression of SIgA coating of gut microbiota induced by HFD is completely reversed by substitution of HFD with NFD.
It was reconfirmed that excessive fat intake is a major cause of suppression of SIgA coating of gut microbiota.
Although the exact underlying mechanism remains unclear, we showed the possibility that fat content in diet is one of the determinant factors modulating the adaptive mucosal immune response associated with SIgA against gut microbiota.
There are two possible causes for the decrease of SIgA coating of gut microbiota induced by HFD: one is the fecal IgA concentration, and the other is SIgA specificity against gut microbiota.
Although no significant difference was found, the fecal IgA concentration was decreased by HFD ingestion. Furthermore,
it was positively correlated with the average level of SIgA coating per fecal bacterium.
This implies that the decreased SIgA secretion induced by HFD feeding might decrease the level of SIgA coating the gut microbiota.
However, a previous study demonstrated that the fecal IgA concentration is not a determinant factor for the amount of SIgA coating gut microbiota, because only less than 1% of fecal IgA is used for the coating of gut microbiota .
Therefore, this possibility should be further examined in a future study.
SIgA specificity against luminal antigens is partly regulated by dendritic cells and T cells present in the Peyer’s patches .
James et al. reported that HFD feeding reduces the ability of dendritic cells to induce T cell expansion, which plays a critical role in the differentiation of antigen-specific IgA plasmablasts .
Together with these studies, our results suggest that HFD consumption might suppress the differentiation of IgA plasmablasts specific for the gut microbiota, resulting in a decrease of SIgA coating of gut microbiota.
In line with previous studies, we observed that HFD feeding induced changes in the microbial composition at the phylum level [1, 5]. HFD-fed mice had a higher abundance of Firmicutes and a lower abundance of Bacteroidetes.
At the family level, the relative abundances of Clostridiaceae and Bifidobacteriaceae were significantly increased in HFD-fed mice compared with NFD-fed mice, while those of Lactobacillaceae and S24-7 were significantly decreased as in previous studies [2, 3].
In the present study, we found a clear correlation between the level of SIgA coating gut microbiota and the relative abundance of gut microbiota in mice fed NFD or HFD for 12 weeks. There was a tendency of negative correlation between the relative abundance of Firmicutes and the level of SIgA coating gut microbiota.
Furthermore, we observed a significant negative correlation between the relative abundances of Clostridiaceae,Mogibacteriaceae, Turicibacteraceae, and Bifidobacteriaceae and the level of SIgA coating gut microbiota.
Peterson et al. demonstrated that the growth of Bacteroides thetaiotaomicron, a dominant gut bacterium, is suppressed in IgA-deficient mice transplanted with hybridoma cells secreting IgA that specifically binds to B. thetaiotaomicron, compared with IgA-deficient mice without hybridoma cells .
Furthermore, Wei et al. reported that both aerobic and anaerobic gut microbiota grow excessively in AIDG23S mice, whose intestinal IgA has low specificity against gut microbiota compared with wild-type mice .
These reports suggest that SIgA coating of gut microbiota plays a crucial role in suppressing gut microbiota coated by SIgA.
Therefore, the negative correlation between the level of SIgA coating of gut microbiota and the relative abundances of the phylum Firmicutes and the families Clostridiaceae, Mogibacteriaceae, Turicibacteraceae, and Bifidobacteriaceae indicates that the overgrowth of these microbial groups might have occurred due to a decrease in the SIgA coating against these microbial groups upon HFD feeding.
As opposed to these microbial groups, a positive correlation between the level of SIgA coating of gut microbiota and relative abundance was observed for S24-7, a major family of Bacteroidales, and for Lactobacillaceae.
A report showed that Bacteroides and Lactobacillus, major genera of Bacteroidales and Lactobacillaceae, resist the SIgA coating in NFD-fed mice .
This report and our observations suggest that S24-7 and Lactobacillaceae might show reduced levels of SIgA coating and thus be less affected by the ability of SIgA to suppress the growth of gut microbiota. Consequently, the relative abundance of these microbial families might be higher in NFD-fed mice.
However, it is unclear from our study why the relative abundances of these microbial families decrease when the level of SIgA coating gut microbiota is decreased by HFD feeding. There is the possibility that HFD feeding promotes the overgrowth of other bacteria that depress the growth of these microbial families.
Our study also showed that HFD-fed mice have a significantly lower microbial diversity compared with NFD-fed mice, which is consistent with previous reports .
Using AIDG23Smice, Wei and colleagues demonstrated that a decrease of SIgA specificity against gut microbiota results in low microbial diversity .
So, a decrease of SIgA coating of gut microbiota induced by HFD feeding might be related to reduced microbial diversity in HFD-fed mice.
Acetate, propionate, and butyrate are major SCFAs produced by intestinal fermentation of dietary fibers. These SCFA ameliorate HFD-induced obesity and insulin resistance to a similar extent when given as a dietary supplement .
In the present study, the concentration of SCFAs was decreased in HFD-fed mice, which is in line with previous reports . In fact, in the present study, SCFA-producing gut microbiota, such as Ruminococcaceae and S24-7 [31, 32], were decreased in HFD-fed mice compared with NFD-fed mice.
There is a possibility that the reduction in SCFA producers may be due to reduction in available substrate owing to the reduced starch content in the HFD. Further research needs to be conducted to clarify this.
Interestingly, there was a significant positive correlation between the concentrations of cecal acetate and butyrate and the level of SIgA coating of gut microbiota. Kim et al. reported that oral administration of an SCFA mixture containing acetate, propionate, and butyrate increases the ratio of SIgA-coated bacteria to total intestinal bacteria, suggesting that SCFAs can promote SIgA coating of gut microbiota .
Therefore, our observations suggest that reduction in the concentration of SCFAs in the gut induced by HFD consumption might be linked to a decrease of SIgA coating of gut microbiota.
In conclusion, our study clearly showed that excessive dietary-fat intake decreases the level of SIgA coating of gut microbiota. The reduced levels of SIgA coating gut microbiota after HFD consumption might be related to HFD-induced changes in microbial composition and microbial metabolites production.
More information: Gut-associated IgA+ immune cells regulate obesity-related insulin resistance, Nature Communications (2019). DOI: 10.1038/s41467-019-11370-y
Journal information: Nature Communications
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