Antibiotics affect the mouth and gut differently

When we discuss antibiotic resistance, it’s not always clear where the resistance is developing or how exactly the resistance develops. A study out of the UK and Sweden looked at two niches, the gut and the mouth, to understand the difference between how the different parts of the body react to antibiotics.

The scientists discovered that these two parts of the body reacted and recovered very differently after a one-week course of antibiotics. They took fecal and saliva samples prior to the antibiotic regime and then gave the study participants a weeklong course of clindamycin, ciprofloxacin, minocycline, amoxicillin, or a placebo and continued taking fecal and saliva samples for a year.

They found that the oral microbiome recovered much faster than the gut microbiome back to its normal state. It took much longer for the gut microbiome to recover and for participants taking ciprofloxacin, diversity was changed even after 12 months. They also found that while participants largely had genes associated with antibiotic resistance in their gut prior to the trial, the amount of antibiotic resistant genes increased after taking the antibiotic. Antibiotic resistant genes in the mouth remained largely stable before and after treatment.  It was also observed that butyrate production, a health associated short-chain fatty acid, was severely affected by ciprofloxacin and clindamycin.

This raises a number of questions like why does the oral microbiome recover so much faster than the gut microbiome? And why isn’t there a similar increase in antibiotic resistant genes in the mouth like we see in the gut? While this study raises many questions, it provides an opportunity to look at the mouth and better understand what is unique about that environment in comparison to the gut. 

Short chain fatty acid composition in the gut is associated with Hirschsprung associated enterocolitis

Ball and stick representation of an acetate molecule, CH3COO-

Hirschsprung disease is a disorder in which a baby is born without nerves in part or all of the large intestines, rendering them functionless. Hirschsprung-associated enterocolitis (HAEC) is a complication of Hirschsprung disease (HD), in which the intestines become inflamed due to infection. HAEC is a common cause of death in children with Hirschsprung disease, but the real cause of infection in not very well understood yet. Poor immunity, poor intestinal wall function, and an altered gut microbiome are thought to contribute to the issue. An important role of the gut microbiome is to produce short chain fatty acids (SCFAs) from complex and indigestible fiber. The short chain fatty acids contribute to bacterial homeostasis of the gut, and so they may be associated with intestinal issues observed in HAEC. Scientists from California, Michigan, and Sweden set out to test this possible connection by measuring the SCFA, and SCFA-producing bacterial composition in HD children who have HAEC.  The study was published by the Journal of Pediatric Surgery. 

The study population consisted of 18 children with HD, with ages ranging from 3 months to 8 years, and a median age of 2.7 years. Nine participants had a history of HAEC, while nine did not. Fecal samples were collected from the children and analyzed for SCFAs and bacterial composition. Among the children involved in the study, there were no significant differences in early feeding type, probiotic use, complications unrelated to HAEC, and length of HD diagnosis. One patient in the HD group and two in the HAEC group had trisomy 21, better known as Down Syndrome.

Total fecal SCFA composition in children with a history of HAEC was four-fold lower than that of HD patients who did not have a history of HAEC.  When broken into individual SCFAs, the children with HAEC had substantially less acetate in their stools, but actually slightly higher butyrate levels compared to non-HAEC.  Interestingly, the HAEC patients actually had higher levels of butyrate and acetate producing bacteria, despite the dramatically lower acetate levels.  The authors suggest that perhaps the butyrate producing bacteria are actually converting acetate to butyrate, resulting in higher levels of both butyrate and butyrate producing bacteria, along with lower levels of acetate.

While we still don’t know a cause for Hirschsprung-associated enterocolitis, this study does provide an association between HAEC episodes and alteration of short chain fatty acid composition of the large intestines. This study is limited by its small sample size and other factors that are difficult to account for, but the results still do help scientists identify possible causes of the disease.

Atopic dermatitis associated gut microbe identified

A moderate case of hand dermatitis

Atopic dermatitis, otherwise known as eczema, is an inflammatory autoimmune response of the skin.  Today in the United States it affects around 25% of children, and as many as 3% of adults, with its incidences increasing each year.  Like many other allergies, the microbiome is now being implicated in the cause of this disease.  A few months back evidence was published linking atopic dermatitis to the skin bacteria Staphylococcus aureus.  Other work, however, has shown that the gut microbiome may be critically important to this disease as well, especially because gut bacteria are more likely to control and elicit certain inflammatory responses seen in dermatitis, such as the release of specific cytokines.  A group of Korea recently compared the gut bacteria in atopic dermatitis patients and healthy controls and identified a specific organism that may be important to the disease.  They published their results last week in the Journal of Allergy and Clinical Immunology.

The researchers measured the gut microbiomes of 132 people, including 90 of which had atopic dermatitis and were seeking medical treatment.  They also measured gene expression by bacteria in the gut, and short chained fatty acids (SCFAs) in the guts of all the individuals.  They discovered that one particular bacterial species was much more abundant in dermatitis patients compared to controls, Faecalibacterium prausnitzii.  After, they measured SCFA production, and noted that a decrease in butyrate and propionate was directly linked with the presence of F. prausnitzii, suggesting an important link between this bug, SCFAs, and the disease state. In addition, they noted that the overall diversity of bacteria was similar in all microbiomes measured.  Finally, the scientists investigated the gene expression, and observed an increase in bacteria that are capable of breaking down gut mucins, or mucous, in the guts of atopic dermatitis individuals.  For example, these bugs were expressing proteins that break down fucose and N-acetylgalactosamine (GalNAc), two monosaccharides that are normally derived from mucins rather than food.

This study presents a number of differences in the gut microbiomes of individuals with an without atopic dermatitis.  The scientists suggest that an important species associated with this disease may be F. prausnitzii, and perhaps it may even be influencing the disease through a lack of SCFA production, and the breakdown of gut mucins.  Atopic dermatitis is a complex disease, and certainly cannot be explained by the presence of an individual bug.  However, this paper does support the notion that diseased individuals, who present rashes on their skin, may have disruptions to gut, and that changes in the gut microenvironment create a niche for specific bacteria to grow.  This, in turn, may inform new therapeutic strategies that target the gut microbiome, rather than topical treatments.

Fish oil may be important to altering the microbiome, reducing anxiety

Last week we published a blog on the gut-brain axis, and the various associations between brain health and the gut microbiome.  One of the ailments we discussed was depression, which is often studied in mice by inducing early life stress on the mice.  One way to do this is by separating mice from their mothers for hours at a time at a young age.  The Maternal Separation model, as it is known, causes stress and anxiety in these mice, but more importantly, research has shown that it creates a dysbiosis of their gut microbiomes as well.  Many scientists believe the dysbiosis may be implicated in causing some of the stress phenotypes, and so reversing this dysbiosis could have therapeutic value.  Researchers from the University College Cork, in Cork Ireland, experimented with N-3 polyunsaturated fatty acids (PUFAs), like those found in fish oil, in these maternally separated mice, and found they may be important to preventing the dysbiosis.  They published their findings in the journal PLoS ONE.

In the study, the researchers separated mice into two groups, one underwent maternal separation, and the other had a normal upbringing.  Within each group the mice were separated into two more groups, one that received fish oil supplements and the other that didn’t.  Over the course of 17 weeks each groups’ feces were sampled for their microbiomes.  The Maternal separation tended to decrease the bacteroidetes to firmicutes ratio of the mice’s microbiome, which has previously been linked to depression in humans.  Interestingly, supplementation with the fish oil increased this ratio in those maternally separated mice.  In addition, the fish oil also increased the concentration of bacteria that were higher in non-separated mice, such as populations of Rikenella.  Finally, the fish oil increased the amount of butyrate producing bacteria, and as we have seen many times before, butyrate and other short chained fatty acids (SCFAs) are often associated with health.

Overall this study showed that fish oil shifted stressed mice’s microbiome to a more natural state, presumably helping them in the process.  While the scientists did not directly measure stress levels in these mice to support the microbiome connection, hopefully that will be part of a follow up study.  The scientists noted that fish oil is clinically shown to reduce inflammation, and made it a point to connect the stress in the mice to systemic inflammation.  Systemic inflammation is also mediated by the microbiome.  Indeed, people that have inflammation from IBD, for example, do tend to have more stress and anxiety.  In the end, fish oil could make for an interesting prebiotic to shift the microbiome, counteract inflammation, and improve mental health. 

Microbiome differences between healthy people and those with IBS

Methane (above) is produced by Methanogens, which are increased in the guts of healthy individuals compared to those with diarrheal IBS.

IBS affects somewhere around 11% of all humans.  It is not known exactly what causes the disease but it is characterized by a low grade inflammation in the colon which can manifest itself as cramping, bloating, diarrhea, constipation, and overall abdominal discomfort.  Many scientists now believe this is a microbiome mediated disease that is caused by some sort of dysbiosis in the gut, unfortunately efforts to characterize exactly what differences occur in IBS individuals have not been successful.  A new article published last week in Nature Scientific Reports describes newly discovered differences in butyrate and methane producing bacteria in the guts of people with IBS.

The scientists sequenced the microbiomes of 66 healthy controls and 113 folks with IBS, at two time points 1 month apart.  They discovered that IBS patients had higher amounts of Bacteroides and lower levels of Firmicutes than healthy individuals, as well as an overall lower microbiome diversity.  In addition, there were no major changes to either group’s microbiomes over the one month measurement window.  Interestingly those people with diarrheal IBS had much lower levels of methanogens than healthy controls, and those people with constipation IBS had higher levels of methanogens than healthy controls.  Methanogens convert hydrogen gas to methane in the gut, and this study revealed a link between methane production and gastrointestinal (GI) transit time.  Finally, the researchers determined that diarrheal IBS patients also had much lower levels of known butyrate producers.  Butyrate, a short chained fatty acid (SCFA), is associated with improved GI permeability and overall GI health.

This study described a few important insights in IBS and the microbiome.  These insights, such as the metabolic differences between bacteria in healthy individuals and those with IBS may be important to future therapeutics to treat this disease.  For example, perhaps folks with IBS could eat a lot of fiber and in the hopes of increasing the amount of butyrate in their guts.  Of course, the observed difference is only an association at this point, but other studies have suggested an increase in fiber can help relieve symptoms of the disease. 

Americans swap foods with Africans and their microbiomes follow – fiber, fat and cancer risk

Phuto pap and porridge, a traditional South African, high fiber, meal.

Despite having similar genetic backgrounds, African Americans are thirteen times more likely to develop colon cancer than rural South Africans.  Indeed, environmental factors, rather than genetics, are thought to be the major factor in developing colon cancer, because recent immigrants’ children’s risk is more similar to where they are living than to their parents’ homeland.  This environmental risk could be primarily caused by a number of factors, such as antibiotic use or drug use, but many scientists believe that diet, and its influence on the microbiome, is primarily responsible.  As it turns out, rural Africans eat much more fiber (almost 5x more) and much less fat (almost 3x less) than African Americans, and these differences have drastic effects on the microbiomes of their hosts.  Not only are the most abundant bacterial species different, but the major metabolites vary greatly as well.  Scientists from the University of Pittsburgh came up with the clever idea of swapping the foods of rural South Africans and African Americans, to investigate how this dietary intervention would affect each group’s microbiomes and risk for colon cancer.  They published the results of their study in Nature Communications last week.

The researchers studied 20 middle aged African American men and 20 middle aged rural South African men.  They each had their microbiomes and colons studied for two weeks while eating their normal diets, and then again for two weeks after swapping diets.  Initially, the Americans had microbiomes dominated by Bacteroides and the Africans by Prevotella.  After the diet though, they noticed a rapid shift in these populations, and it corresponded to an increase in colonic inflammation for the Africans and decrease in the Americans.  In addition, an increase in butyrate, the short chained fatty acid (SCFA) that is thought to be beneficial to health, followed the fiber diet as well, and a decrease was associated with eating the high fat diet; this makes sense, as butyrate is produced as a metabolite of fiber fermentation by the microbiome.  Interestingly, prior to the diet change a top-level analysis of all the metabolic end products of the microbiome showed that Africans produced more of every single one studied except for choline, which is related to heart disease.  Many of the metabolites studied, including choline, followed their diet switch, and were produced according to the food eaten, rather than the person eating it.  Perhaps most importantly, secondary bile acids, which are produced by the microbiome and may be carcinogenic and an important cause of colon cancer, followed the diet as well.  Africans, who produced much fewer secondary bile acids than Americans while consuming their regular diet, had a 400% increase in production after the diet switch, and vice versa for the Americans, who had a 70% decrease.

This study really illustrates the importance of diet on the output of the microbiome.  These metabolites can directly influence our health, and may be more important to our well-being than the bacteria that produce them.  According to this study, it appears that eating more veggies and less fat, something that parents have been saying for a long time, fits in with our understanding of the microbiome.  As Erica Sonnenburg said in our podcast 3 weeks ago, “Feed your microbiome at every meal!”