In the Journals

Gut microbiota amino acids linked to disease severity in Crohn’s

Fecal samples from patients with Crohn’s disease showed as association between severity of the disease, gut dysbiosis and free amino acids while others showed the impact of antibiotics on the dysbiosis, leading researchers to suggest that nitrogen flux may be a potential target for inflammatory bowel disease.

“It’s early days right now but we have a certain level of confidence that changing the environment in the gut will be a good opportunity to move forward in novel therapeutics and the reason is we already have a signal based on physician experiences in the field,” Gary D. Wu, MD, associate chief for research in the division of gastroenterology at the Perelman School of Medicine at the University of Pennsylvania, told Healio Gastroenterology and Liver Disease. “We already know antibiotics sort of work. We have a little bit of a signal for [fecal microbiota transfer] and ulcerative colitis and there are certain defined diets that are effective in the treatment of inflammatory bowel disease. Our notion is simply to use our best science to make these things work better. That’s why we have a level of optimism that ultimately, we are going to be able to find better solutions.”

Disease severity

Wu, with Josephine Ni, MD, and colleagues performed metabolomic analysis on fecal samples obtained from pediatric patients from the PLEASE study. They used liquid chromatography-mass spectrometry to identify 341 known small molecules and classified almost all of them as “amino acids and their derivatives,” which were associated with CD (false discovery rate-adjusted P < .05) and occur as a result of bacterial nitrogen metabolism, according to a press release. Diet did not account for the amino acids, the researchers wrote.

The fecal amino acids from the pediatric patients correlated with intestinal inflammation activity measured by fecal calprotectin, they wrote.

“The results showed that fecal amino acids were associated with Crohn’s disease and positively correlated with increasing disease activity,” the researchers wrote. “Fecal amino acids and their derivatives were also positively associated with taxa in the Proteobacteria phylum, such as Escherichia, Klebsiella, Haemophilus and Proteus, all of which have been associated with gut microbiota dysbiosis in patients with IBD.”

“There is this nitrogen signal: Amino acids associated with IBD,” Wu said. “Part of the way to engineer the microbiota in patients with IBD for treatment might be to target nitrogen flux or nitrogen metabolism in bacteria. This is not something that has been previously explored and we showed in a mouse model that this might be important.”

Alteration of gut microbiota

To look at alteration of the gut microbiota by antibiotics, Wu and colleagues also observed five adults treated with three antibiotics (Xifaxan [rifaximin, Salix Pharmaceuticals], trimethoprim-sulfamethoxazole and metronidazole) for 3 days.

“There was a surprisingly small effect on the composition of the human gut microbiota, with the dominant effect being inter-subject variability,” they wrote.

But when vancomycin and neomycin were administered for 3 days with MiraLAX (polyethylene glycol 3350 [PEG], Bayer) given on the second day, subjects showed a reduction in both culturable bacteria and 16S rRNA gene copy number of approximately four to five logs after 72 hours (P < .01).

“We’d like to engineer the environment of the gut for the treatment of inflammatory bowel disease because current therapeutic modalities really focus on the host,” Wu said. “The first step we believe is to clean the slate and reduce bacterial load very significantly. If you just put in a group of microbes without opening up the niche and allow the organisms to take hold, they just pass through. We provide evidence that you can meaningfully reduce the bacterial load in humans.”

Wu and colleagues also performed mouse studies to targeting bacterial nitrogen flux as a therapeutic modality for hyperammonemia and suggests that this could be a future target for human treatment of hepatic encephalopathy. In ongoing studies, Lindsey Albenberg, DO, is looking at altering the microbiome of patients with refractory Crohn’s, Wu said.  – by Katrina Altersitz

 

Disclosures: Wu reports he is a co-inventor on a patent on relevant concepts; has consulting agreements with Chr. Hansen, Janssen and Pfizer; and receives research funding from Takeda, Nestle, Seres Therapeutics and Intercept Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures.

 

 

 

 

 

 

 

Fecal samples from patients with Crohn’s disease showed as association between severity of the disease, gut dysbiosis and free amino acids while others showed the impact of antibiotics on the dysbiosis, leading researchers to suggest that nitrogen flux may be a potential target for inflammatory bowel disease.

“It’s early days right now but we have a certain level of confidence that changing the environment in the gut will be a good opportunity to move forward in novel therapeutics and the reason is we already have a signal based on physician experiences in the field,” Gary D. Wu, MD, associate chief for research in the division of gastroenterology at the Perelman School of Medicine at the University of Pennsylvania, told Healio Gastroenterology and Liver Disease. “We already know antibiotics sort of work. We have a little bit of a signal for [fecal microbiota transfer] and ulcerative colitis and there are certain defined diets that are effective in the treatment of inflammatory bowel disease. Our notion is simply to use our best science to make these things work better. That’s why we have a level of optimism that ultimately, we are going to be able to find better solutions.”

Disease severity

Wu, with Josephine Ni, MD, and colleagues performed metabolomic analysis on fecal samples obtained from pediatric patients from the PLEASE study. They used liquid chromatography-mass spectrometry to identify 341 known small molecules and classified almost all of them as “amino acids and their derivatives,” which were associated with CD (false discovery rate-adjusted P < .05) and occur as a result of bacterial nitrogen metabolism, according to a press release. Diet did not account for the amino acids, the researchers wrote.

The fecal amino acids from the pediatric patients correlated with intestinal inflammation activity measured by fecal calprotectin, they wrote.

“The results showed that fecal amino acids were associated with Crohn’s disease and positively correlated with increasing disease activity,” the researchers wrote. “Fecal amino acids and their derivatives were also positively associated with taxa in the Proteobacteria phylum, such as Escherichia, Klebsiella, Haemophilus and Proteus, all of which have been associated with gut microbiota dysbiosis in patients with IBD.”

“There is this nitrogen signal: Amino acids associated with IBD,” Wu said. “Part of the way to engineer the microbiota in patients with IBD for treatment might be to target nitrogen flux or nitrogen metabolism in bacteria. This is not something that has been previously explored and we showed in a mouse model that this might be important.”

Alteration of gut microbiota

To look at alteration of the gut microbiota by antibiotics, Wu and colleagues also observed five adults treated with three antibiotics (Xifaxan [rifaximin, Salix Pharmaceuticals], trimethoprim-sulfamethoxazole and metronidazole) for 3 days.

“There was a surprisingly small effect on the composition of the human gut microbiota, with the dominant effect being inter-subject variability,” they wrote.

But when vancomycin and neomycin were administered for 3 days with MiraLAX (polyethylene glycol 3350 [PEG], Bayer) given on the second day, subjects showed a reduction in both culturable bacteria and 16S rRNA gene copy number of approximately four to five logs after 72 hours (P < .01).

“We’d like to engineer the environment of the gut for the treatment of inflammatory bowel disease because current therapeutic modalities really focus on the host,” Wu said. “The first step we believe is to clean the slate and reduce bacterial load very significantly. If you just put in a group of microbes without opening up the niche and allow the organisms to take hold, they just pass through. We provide evidence that you can meaningfully reduce the bacterial load in humans.”

Wu and colleagues also performed mouse studies to targeting bacterial nitrogen flux as a therapeutic modality for hyperammonemia and suggests that this could be a future target for human treatment of hepatic encephalopathy. In ongoing studies, Lindsey Albenberg, DO, is looking at altering the microbiome of patients with refractory Crohn’s, Wu said.  – by Katrina Altersitz

 

Disclosures: Wu reports he is a co-inventor on a patent on relevant concepts; has consulting agreements with Chr. Hansen, Janssen and Pfizer; and receives research funding from Takeda, Nestle, Seres Therapeutics and Intercept Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures.

 

 

 

 

 

 

 

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