High-fat diet with antibiotic use linked to gut inflammation

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A small University of California – Davis study found that combining a Western-style high-fat diet with antibiotic use significantly increases the risk of developing pre-inflammatory bowel disease (pre-IBD). The study suggests that this combination shuts down the energy factories (mitochondria) in cells of the colon lining, leading to gut inflammation.

Irritable bowel syndrome (IBS) affects approximately 11% of people worldwide. It is characterised by recurring episodes of abdominal pain, bloating and changes in bowel habits. IBS patients with mucosal inflammation and changes in the gut's microbial composition are considered pre-IBD.

The study included 43 healthy adults and 49 adult patients diagnosed with IBS. The researchers measured faecal calprotectin, a biomarker for intestinal inflammation, of participants. Elevated levels of faecal calprotectin indicated a pre-IBD condition. The study identified 19 patients with IBS as pre-IBD.

The researchers found that all participants who consumed high-fat diet and used antibiotics were at 8.6 times higher risk for having pre-IBD than those on low-fat diet and no recent history of antibiotic use. Participants with the highest fat consumption were about 2.8 times more likely to have pre-IBD than those with the lowest fat intake. A history of recent antibiotic usage alone was associated with 3.9 times higher likelihood of having pre-IBD.

"Our study found that a history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD," said Andreas Bäumler, professor of medical microbiology and immunology and lead author on the study. "Until now, we didn't appreciate how different environmental risk factors can synergise to drive the disease."

Using mouse models, the study also tested the effect of high-fat diet and antibiotics use on the cells in the intestinal lining. It found that high-fat diet and antibiotics cooperate to disrupt the work of the cell's mitochondria, shutting its ability to burn oxygen. This disruption causes reduction in cell's oxygen consumption and leads to oxygen leakage into the gut.

The body's beneficial bacteria thrive in environments lacking oxygen such as the large intestine. Higher oxygen levels in the gut promote bacterial imbalances and inflammation. With the disruption in the gut environment, a vicious cycle of replacing the good bacteria with potentially harmful proinflammatory microbes that are more oxygen tolerant begins. This in turn leads to mucosal inflammation linked to pre-IBD conditions.

The study also identified 5-aminosalicylate (mesalazine), a drug that restarts the energy factories in the intestinal lining, as a potential treatment for pre-IBD. "The best approach to a healthy gut is to get rid of the preferred sustenance of harmful microbes," Lee said. "Our study emphasized the importance of avoiding high fat food and abuse of antibiotics to avoid gut inflammation."

This work was supported by the National Research Foundation of Korea grant

Abstract
The clinical spectra of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) intersect to form a scantily defined overlap syndrome, termed pre-IBD. We show that increased Enterobacteriaceae and reduced Clostridia abundance distinguish the fecal microbiota of pre-IBD patients from IBS patients. A history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD. Exposing mice to these risk factors resulted in conditions resembling pre-IBD and impaired mitochondrial bioenergetics in the colonic epithelium, which triggered dysbiosis. Restoring mitochondrial bioenergetics in the colonic epithelium with 5-amino salicylic acid, a PPAR-γ (peroxisome proliferator–activated receptor gamma) agonist that stimulates mitochondrial activity, ameliorated pre-IBD symptoms. As with patients, mice with pre-IBD exhibited notable expansions of Enterobacteriaceae that exacerbated low-grade mucosal inflammation, suggesting that remediating dysbiosis can alleviate inflammation. Thus, environmental risk factors cooperate to impair epithelial mitochondrial bioenergetics, thereby triggering microbiota disruptions that exacerbate inflammation and distinguish pre-IBD from IBS.

Authors
Jee-Yon Lee, Stephanie A Cevallos, Mariana X Byndloss, Connor R Tiffany, Erin E Olsan, Brian P Butler, Briana M Young, Andrew WL Rogers, Henry Nguyen, Kyongchol Kim, Sang-Woon Choi, Eunsoo Bae, Je Hee Lee, Ui-Gi Min, Duk-Chul Lee, Andreas J Bäumler

 

University of California – Davis Health material

 

Cell Host and Microbe abstract

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