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The most abundant proteases in the GI tract are digestive enzymes which aresynthesized in the pancreas, secreted as inactive zymogens, and activated byenteropeptidases into the lumen of the duodenum.

Afterwards, digestiveproteases are inactivated by autocatalysis passing through the GI tract. 142 Dietary proteins aredigested into small peptides and amino acids by digestive proteases in thesmall intestine and then digestive proteases are deactivated during the processof digestion. Several studies provided further evidence that digestiveproteases are continuously degrading passing through the GI tract. 140, 141 In the ileum, proteasesactivity (PA) is 20~60-fold greater than in feces, 121, 142, 143 indicating thatpancreatic proteases are physically disrupted in the large intestine more thanin the small intestine.

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While high amounts of digestive proteases (1~3g trypsinanalogues and 0.5g elastase) were secreted from the pancreas in humans, 144 large amounts of theseproteases were already inactivated in the feces. Analogous to the observationin humans, cecal PA in different animals were higher than ileal PA. 145, 146 One study showed thata substantial proportion of fecal PA was still observed in patients who failedto produce digestive enzymes due to the exocrine pancreatic insufficiency, 147 suggesting thatbacterial proteases (e.g. cell-bound proteases of Bacteroides fragilis) are also part of luminal proteases.Inactivation of digestive proteases rapidly and widely occurs at the transitionbetween the ileum and cecum, indicating that the small intestine is exposed to high amounts of active pancreaticproteases, while the large intestine has a low pancreatic PA.In the large intestine, intestinal microbiota is pivotal for the regulationof proteolytic homeostasis.

147 It is well known thatcolonic PA in germfree (GF) mice was higher than colonic PA in conventionalmice, suggesting that enteric bacteria modulate host pancreatic proteases. 148 Other studies providedsimilar evidence that chickens, rats and rabbits in the gnotobiotic facilityenhanced PA in the cecum compared to the animals in conventional housing. 145, 146, 149 From this point of view, however, not every microbiota contributes tophysiological regulation of pancreatic proteases in the large intestine. 150 A disturbance ofintestinal microbiota in rats by benzylpenicillin, ampicillin, doxycycline, orclindamycin treatment increased cecal PA to the level observed in GF ratscompared to conventional rats. 151 A similar result hasbeen reported concerning clindamycin treatment influencing a long-lastingincrease in PA in rats.

152 Analogous to theanimal studies, a clinical study revealed that AB treatment elevated trypsinand elastase in the feces, resulting in altered microbiota-dependent inactivationof pancreatic proteases. 153 Additionally, aquantitative analysis of pancreatic proteases in feces showed that AB treatmentin patients strongly increased trypsin (100-fold), chymotrypsin and elastase 2(2~3-fold) concentration compared to untreated persons. 154 In this context, specific AB treatment has been reported toresult in a substantial increase of pancreatic proteases, mostly trypsin in thelarge intestine. This major increase in pancreatic PA in the largeintestine is thought to be due to the eradication of specific microbiota whichare essential for inactivation of the high load of digestive proteases in thelarge intestine under physiological conditions (Figure.

3). Regarding the specificorganism which has an anti-PA property, thecommensals that modulate pancreatic proteases in the large intestine are mostlyunknown except for Parabacteroidesdistasonis E9. 150, 155, 156 A single human-derivedP.

distasonis strain E9 has beenproven to normalize the high PA in GF rats in a monoassociation experiment,while colonization of E.coli in GFminipigs and rats did not decrease PA in the large intestine. 157 AlthoughParabacteroides distasonis E9 had been proven to normalize the PA in vivo, theunderlying anti-proteolytic mechanism of microorganisms is unknown. It isunclear whether the reduction of the high load of trypsin in the largeintestine is due to direct degradation or secretion of protease inhibitors.

Thus,the following question “what kinds of ABdisturb the proteolytic balance” still has to be addressed.

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