Diet, microbiota, and the immune system acting together in metabolic syndrome

We now know that a diet rich in sugar and fat contributes to increased gut inflammation, and that the gut’s immune system plays a key role in metabolic homeostasis. We also know that the gut microbiota is an important modulator of gut immunity and that it influences metabolic functions as well. Lastly, we know that cells such as type 3 innate lymphoid cells (ILC3) and T helper 17 cells (Th17) may be involved, depending on the context, in protecting against metabolic syndrome. However, the series of molecular mechanisms linking the high-fat diet (HFD) to its metabolic effects remains poorly understood.

To shed some light on the matter, researchers fed mice on an HFD diet or a normal diet for four weeks. Unlike the second group, the HFD group developed a typical metabolic syndrome, involving weight gain, insulin resistance, and glucose intolerance. Analyses of the gut mucosa and feces of the HFD mice revealed that the HFD diet induced a rapid loss of segmented filamentous bacteria (SFB) in the gut microbiota, which in turn led to the loss of Th17, and ultimately the onset of metabolic syndrome.

Probiotics restore protection against metabolic syndrome

Investigations on the involvement of other immune cells such as ILC3 or CD4 T cells allowed the researchers to affirm that the gut microbiota needs Th17 cells to protect against metabolic syndrome. These additional investigations also showed that the loss of Th17 cell homeostasis via the elimination of SFBs was indeed involved in the adverse effects of the HFD diet. 

Next, the mice were fed SFBs by oral gavage for four weeks, which resulted in: 

• Significant recovery in Th17 cells and their expression in the gut 
• Decrease in gut inflammation
• Weight loss
• Protection against insulin resistance 

A microbial diet that stimulates Th17 cells may therefore improve metabolic syndrome and diabetic obesity by recalibrating gut immunity homeostasis.

Is sugar the main culprit in the Western diet’s harmful effects?

However, knowing that in addition to fat, the Western diet is also rich in sugar, the researchers compared the effects on mice of the HFD diet (25% sugar, including sucrose and maltodextrin, common in candy and soda) with the effects of another diet very low in sugar (3%-6%). They found that sugar indirectly reduced Th17 cells by increasing gut microbiota levels of bacteria such as Faecalibaculum rodentium at the expense of SFBs that promote Th17.

A diet that treats metabolic syndrome? Not so fast...

While sugar has been shown to be enough to cause the concomitant loss of SFBs and Th17 cells, the elimination of dietary sugar only has a therapeutic benefit where the appropriate immune cells are present in the gut. A simple change of diet may not be sufficient in some people. The researchers believe their work shows that metabolic syndrome, obesity, and type 2 diabetes mellitus are regulated by a complex network of interactions between diet, the gut microbiota, and immune cells. The management of these diseases cannot therefore be identical for each patient. Accordingly, in the future, precision therapeutic approaches should take into account differences between individuals in terms of the gut microbiota’s immunomodulatory system.