IBD

Environmental stimuli and gut inflammation via dysbiosis in mouse and man

A new study sheds further light on the interplay between environmental stimuli, the gut microbiota and intestinal inflammation. Identification of modifiable environmental triggers and the mechanisms by which they act has implications for the prevention and treatment of inflammatory bowel disease.

Refers to Lee, J.-Y. et al. High-fat diet and antibiotics cooperatively impair mitochondrial bioenergetics to trigger dysbiosis that exacerbates pre-inflammatory bowel disease. Cell Host Microbe 28, 273–284 (2020).

The cause of inflammatory bowel disease (IBD) remains unknown, but the central prevailing hypothesis is of a dysregulated mucosal immune response to a gut microbial dysbiosis in a genetically susceptible host. Two decades of gene discovery has yielded nearly 300 IBD susceptibility loci and numerous biological insights1. The elucidation of key pathways in humans and mice has demonstrated the importance of the interplay between genetic variation, the gut microbiota, host–microbial interactions and environmental stimuli including diet. Indeed, there are now several animal models where specific aspects of habitual diet, host response and genetic susceptibility have been shown to interact with the development of colitis in mice2.

A new study by Andreas Baumler and colleagues3 has further elucidated the mechanisms by which environmental factors (a high-fat diet (HFD) and oral antibiotics) contribute to intestinal inflammation in humans and in a mouse model (Fig. 1). They started with a cohort of patients with irritable bowel syndrome (IBS) and raised faecal calprotectin levels, adopting the term ‘pre-IBD’. This is an interesting, if somewhat contentious, group. Although they do not have IBD as determined by a detailed endoscopic and histopathological examination, they do exhibit a low level of mucosal inflammation. The raised faecal calprotectin levels come not from an excess of mucosal neutrophils shed into the gut lumen (as in IBD), but rather by a direct upregulation of S100A8 and S100A9 — the two proteins that heterodimerize to form calprotectin — in the colonic epithelium.

Fig. 1: Schematic putting results from Lee et al. into context.
figure1

The inflammatory effect of antibiotic use and a high-fat diet (HFD) in Lee et al.3 is mediated by impaired mitochondrial bioenergetics in the gut epithelium. This process, in turn, leads to increased oxygenation of the gut lumen, promoting an expansion of pro-inflammatory Enterobacteriaceae. Both 5-amino salicylic acid (5-ASA) and butyrate abrogate the inflammation acting via PPARγ.

What is the relevance of this patient population and how does it fit with our IBD clinical practice? Lee et al.3 argue that this subset of patients with IBS overlap with the broader spectrum of IBD; but they do not have IBD, nor is it clear whether they are at increased risk of developing IBD at a later stage. Preclinical-IBD has been described and studied in serum samples from patients who subsequently developed IBD4. I do not think that IBS with an elevated faecal calprotectin can be described as ‘pre-IBD’, as Lee et al. attest; rather, pre-IBD is a state that is at high risk of conversion to Crohn’s disease or ulcerative colitis, a state that might justify intervention. Nonetheless, the detailed examination of these patients provides some fascinating insights.

Lee et al.3 compared 19 patients with IBS with elevated faecal calprotectin levels with 30 patients with IBS with normal levels (<50 μg/g) and a further 43 adult healthy individuals. The patients with IBS with high faecal calprotectin levels were more likely to have used antibiotics in the past 12 months and had a higher reported total fat intake compared with patients with IBS with normal faecal calprotectin levels. This effect appeared additive: patients with the combination of a HFD and recent antibiotic usage were observed to have an eightfold increased risk of IBS with high faecal calprotectin levels. It would be important to know whether these patients also had a history of nonsteroidal anti-inflammatory drug use, as it is clearly documented as causing an increase in faecal calprotectin levels in IBS and is potentially a major confounder. Examination of the gut microbiota by 16S ribosomal RNA gene amplicon sequencing demonstrated decreases in Clostridia abundance and increases in Enterobacteriaceae in patients with IBS with high faecal calprotectin level compared with normal levels. However, it is unclear whether this finding was causal or a downstream effect of the inflammation. The implications here are interesting: if you are taking antibiotics while on a HFD you might be at increased risk of developing IBS with an elevated faecal calprotectin level, driven by changes in the gut microbiota. A summation of all available high-quality epidemiological data supports antibiotic exposure but not dietary fat intake as risk factors for IBD5. By contrast, in mice, a maternal HFD and maternal obesity both increase the susceptibility to colitis in offspring, and excess calorie intake weaning does the same for mice when they reach adulthood6.

Lee et al.3 then fed mice without endogenous Enterobacteriaceae a HFD and gave them oral antibiotics. These mice developed low-grade intestinal inflammation, a high faecal calprotectin level and symptoms including the mouse equivalent of diarrhoea and abdominal pain. After antibiotic treatment, Escherichia coli — a member of the Enterobacteriaceae — increased in stool in all animals, but failed to return to baseline levels in mice fed a HFD. This increase was facilitated by an increase in oxygen bioavailability following HFD and antibiotics. Mitochondrial activity is important to maintain the colonic epithelium in relative hypoxia, which in turn limits the amount of oxygen available for the aerobic growth of facultative anaerobic bacteria such as E. coli. In Lee et al., increased epithelial oxygenation was seen in response to a shift to a glycolytic metabolism. Reduced mitochondrial activity, as occurs in response to a HFD and antibiotic exposure, means lower epithelial oxygen consumption and, in turn, high epithelial oxygenation and increased Enterobacteriaceae. This dysbiosis further exacerbated the low-level mucosal inflammation.

A final intriguing piece of this complex jigsaw is the role of PPARγ and 5-amino salicylic acids (5-ASAs), the mainstay of therapy for mild to moderate ulcerative colitis. It was shown more than 10 years ago that 5-ASAs act as PPARγ agonists7. Notably, butyrate is also a known PPARγ agonist8 and Baumler’s team show that antibiotics and HFD together in mice result in a sustained reduction in PPARγ-regulated genes (Angptl4), an effect not seen by either on their own. This effect was ameliorated with endogenous 5-ASA administration. Antibiotics reduced microbial-derived butyrate, which, via a reduction in PPARγ signalling, impaired mitochondrial bioenergetics. A diet rich in saturated fatty acids led to increased mitochondrial hydrogen peroxide. Both antibiotics and diet therefore impair the same host cell function but by different mechanisms. 5-ASA via PPARγ inhibition can at least partly restore normal function and might further explain the clear clinical benefit in ulcerative colitis.

What does all this mean and why is it important? These experiments provide tantalizing evidence for a role of a HFD and antibiotic-driven gut dysbiosis in causing low-level gut inflammation with an elevated faecal calprotectin level. Arguments about definitions of pre-IBD aside, it is intriguing to think about this finding as one potential mechanism leading to the development of IBD, and it is therefore worth putting into the context of global IBD trends and the treatment landscape for IBD. Epidemiological trends clearly show the global emergence of IBD with urbanization and adoption of a Western lifestyle5. Multiple putative priming and triggering events are described, including early-life antibiotic exposure, low breast-feeding rates, cigarette smoking and vitamin D deficiency. The recent rapid emergence in East and South East Asia, the Indian subcontinent and South America has sharpened the focus on dietary patterns.

Furthermore, there is a very clear unmet therapeutic need in IBD. Current therapies are limited by lack of efficacy, with nearly all biologic therapies hitting a ceiling of about 40% mucosal healing at 12 months9. Strategies that complement existing medical therapies by modifying diet and the gut microbiome could help achieve deeper and longer lasting remission for more patients. Of direct relevance here, one study has shown that using a low-fat, high-fibre diet as an intervention in a small group of patients with ulcerative colitis improved quality of life and reduced some markers of inflammation and dysbiosis10.

There is a huge amount of work still to do to translate the observations and mechanistic insights of Lee et al. However, these data provide insights suggesting that reduced dietary fat intake and limited antibiotic exposure are worthy of further investigation for IBD. Could this understanding translate into preventative strategies for high-risk individuals? This possibility might be some way off, but the triggers for the development of IBD might be the same as the triggers for flare and disease progression and are therefore worthy of deeper exploration.

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Correspondence to Charlie W. Lees.

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C.L. is funded by a UKRI Future Leaders Fellowship and has received additional research support from AbbVie, Chief Scientist’s Office, Cure Crohn’s Colitis and Gilead. He has received consultancy fees from AbbVie, Dr Falk, Gilead, Hospira, Iterative Scopes, Janssen, Oshi Health, Pfizer, Takeda, Trellus Health and Vifor Pharma. He has received speaking fees and travel support from AbbVie, Dr. Falk, Ferring, Gilead, Hospira, Janssen, Pfizer and Takeda.

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Lees, C.W. Environmental stimuli and gut inflammation via dysbiosis in mouse and man. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-00373-6

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