Why does gut dysbiosis always involve Enterobacteriaceae?

Source:  Why does gut dysbiosis always involve Enterobacteriaceae?    Tag:  primary immunodeficiency disease
Enterobacteriaceae are a large family of gram-negative facultative bacteria, which belong to the class Gammaproteobacteria and phylum Proteobacteria. The Enterobacteriaceae family contains gut symbionts but also many familiar pathogens (e.g. Klebsiella, E. coli, Salmonella, Citrobacter, Enterobacter, etc). Proteobacteria and Enterobacteriaceae are normally present in the gut at relatively low levels, and exist in close proximity to the mucosa, since as facultative bacteria they can tolerate oxygen diffusing from the epithelium 1 . However they are amongst the most frequently overgrown gut bacteria in many conditions, including gut infections, IBD, IBS, constipation, celiac disease, AIDS, SIRS, obesity, Parkinson’s disease and major depression.

Overgrowth of Enterobacteriaceae is commonly thought to contribute to disease by promoting inflammation; largely because they are a major source of potent inflammatory PAMPs such as lipopolysaccharide (LPS) 2 . For instance in the gut Enterobacteriaceae/LPS can increase inflammatory tone 3 , slow intestinal motility 4 , exacerbate NSAID-induced intestinal injury 5 , increase intestinal permeability in celiac disease 6 , promote intestinal hypersensitivity in IBS 7 and exacerbate inflammation in IBD; whilst translocation of LPS into blood is associated with systemic immune activation, neuroinflammation 8 and insulin resistance 9 , amongst other things.

So an overgrowth of Enterobacteriaceae is bad! But how does it occur in the first place? Below are some mechanisms which could be important.

Diet – Diets high in sugar, fat and protein, but low in plants and indigestible carbohydrate (e.g. western or weight-loss diets), favour the growth of Proteobacteria and Enterobacteriaceae 10,11 . This could be for several reasons. Diets high in protein promote a putrefactive microbial metabolism which generates harmful metabolites 12 , whilst diets high in indigestible carbohydrate (resistant starch and fibre) promote a saccharolytic metabolism which generates beneficial short-chain fatty acids (SCFAs) 10 . SCFAs acidify the colon and inhibit Enterobacteriaceae 10 . Diets high in fat, saturated fat and omega-6 promote Enterobacteriaceae growth and LPS translocation 13–16 , whilst omega-3 does the opposite 14–16 . The beneficial effects of omega-3 on the gut microbiota are due to regulation of intestinal alkaline phosphatase (IAP) 16 .

Low gastric acid – Low levels of gastric acid may promote Enterobacteriaceae growth. Suppression of gastric acid secretion by proton pump inhibitor (PPI) administration was found to induce jejunum dysbiosis, consisting of an overgrowth of aerobic bacteria and Enterobacteriaceae, and a decrease in Bifidobacteria 5 . Many other studies have found an association between PPI use and small intestinal bacterial overgrowth (SIBO) in humans 17 (note that Enterobacteriaceae can be hydrogen-producers 18 ). This may involve several mechanisms: gastric acid can inhibit the growth of many bacteria, promote protein digestion and trigger other intestinal secretions/processes.

Immunodeficiency – Some kinds of immunodeficiency may allow an overgrowth of Enterobacteriaceae. The gut barrier regulates levels of mucosal bacteria by releasing antimicrobial peptides and IgA 19,20 . Innate immune functions are impaired in inflammatory bowel disease (IBD), especially Crohn’s disease, which allows for increased growth of bacteria such as invasive E. coli  21,22 . Also genetic variations which impair function of the NOD2 gene (encodes an intracellular immune receptor) is associated with increased abundance of Enterobacteriaceae in IBD 23 .

Inflammation & oxidative stress - Gut inflammation has been shown to induce blooms in Proteobacteria and Enterobacteriaceae. This is due to the increased formation of oxidation products (e.g. nitrate) which can serve as electron acceptors in the anaerobic respiration of some facultative bacteria 24,25 . In fact nitrate reductase activity is most prevalent in the genomes of Enterobacteriaceae 26 . Therefore inflammation is thought to account particularly for the overgrowth of Enterobacteriaceae in many conditions 24 . Moreover some Enterobacteriaceae pathogens (e.g. Salmonella) may actually induce inflammation as part of an evolutionary survival strategy 25 . Notably antibiotic treatment can induce low-grade gut inflammation which enhances the growth of Enterobacteriaceae 24–26 .

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