Gut flora and bacterial translocation in chronic liver disease

Gut fl ora and bacterial translocation in chronic liver disease

Abstract
Increasing evidence suggests that derangement of gut
fl ora is of substantial clinical relevance to patients with
cirrhosis. Intestinal bacterial overgrowth and increased
bacterial translocation of gut flora from the intestinal
lumen, in particular, predispose to an increased potential
for bacterial infection in this group. Recent studies
suggest that, in addition to their role in the pathogenesis
of overt infective episodes and the clinical consequences
of sepsis, gut fl ora contributes to the pro-infl ammatory
state of cirrhosis even in the absence of overt infection.
Furthermore, manipulation of gut fl ora to augment the
intestinal content of lactic acid-type bacteria at the
expense of other gut fl ora species with more pathogenic
potential may favourably influence liver function in
cirrhotic patients. Here we review current concepts of the
various inter-relationships between gut flora, bacterial
translocation, bacterial infection, pro-inflammatory
cytokine production and liver function in this group.

http://www.wjgnet.com/1007-9327/12/1493.pdf

Gut Flora based Theraphy in Liver Disease? The Liver Cares about the Gut

http://onlinelibrary.wiley.com/doi/10.1002/hep.20220/pdf

After 30 days of treatment, 50 percent of patients treated with either the synbiotic preparation or fermentable fiber showed a reversal of MHE, compared to a 13 percent reversal rate in the placebo group. Furthermore, patients in both treatment groups had a lower fecal pH at day 30, along with significantly reduced levels of ammonia in their veins, and significantly reduced serum endotoxin levels.

Both treatments appeared to have significantly altered the cirrhotic patients' gut flora. At the outset of the study, the cirrhotic patients with MHE were found to have significant fecal overgrowths of E. Coli and Staphylococcus. Treatment with the synbiotic preparation reduced these levels to those of the healthy controls, while counts of non-urease producing Lactobacillus were significantly increased. Treatment with fermentable fiber alone increased non-urease producing Bifidobacterium spp and significantly reduced overgrowths of E. Coli and Fusobacterium spp. Treatment with the placebo did not alter the counts of any of the gut flora assessed.

"Our study is the first to examine the impact of synbiotics and fermentable fiber alone on MHE and other aspects of hepatic function in patients with cirrhosis," the authors report. "We conclude that treatment with synbiotics or fermentable fiber alone is an alternative to use of non-absorbable disaccharides, such as lactulose, for the management of MHE in patients with cirrhosis. Significant reductions in viable counts of potentially pathogenic gut flora occur with both treatments."

In an accompanying editorial in the same issue of Hepatology, Drs. Steven F. Solga and Anna Mae Diehl of Johns Hopkins University discuss the "impressive and exciting improvements in HE with both synbiotic therapy and fiber alone." They note that it is even more exciting that altering the gut flora may improve not only HE but also liver disease.

The researchers "have made a major contribution to the application to gut flora therapy to humans with liver disease," they write. "We expect this research to stimulate further interest in the study of gut flora therapy and the 'gut-liver' axis, because the liver does, indeed, care about the gut."

Beside digestive conditions, these bugs induce more severe problems, like obesity and now they were found to influence how fat is digested and deposited in the liver.

An imbalanced gut flora can affect this metabolic path and trigger diseases. Our gut has up to 100 trillion bacteria, about 10% of the number of the human body's cells.

In 2006, one team revealed that obese people carry a somewhat different bacterial species load than normal weighed people. Other approaches showed that gut microbes can induce insulin resistance, determining type 2 diabetes and fatty liver disease, a severe condition.

To see how microbes impair metabolism, a team at the Nestl� Research Center in Lausanne, Switzerland, led by biochemist Jeremy Nicholson of Imperial College London studied the health of seven mice whose gut flora was substituted with that of a 3-week old human infant. These results were compared with those achieved from mice with normal gut flora. After four weeks, the team determined levels of 12 bile acids in each mouse's urine, blood, liver and small intestine.


The liver synthesizes about 6 types of bile acids, which are released into the small intestine to help digest fats. From the gut, the bile acids reach again the liver and control cholesterol metabolism and other endocrine processes.

"But different gut microbes can modify the structure of bile acids in different ways, adding or snipping off various parts of the molecules, which would presumably alter their fat-dissolving abilities," said Nicholson.

17 variants of bile acid were detected in the gut, assigned into two chemical classes.

The mice with the human bacterial flora had more of one class of bile acid and less of the other, translated into significantly different metabolites levels in the urine, blood and liver compared to mice type bacterial flora.

"The results are the first to provide a detailed analysis how gut bugs shift the balance of metabolites present," said medical microbiologist David Relman of Stanford University.

"They also mean that altering gut microflora has far-reaching physiological consequences for the host animal."

Mice with the human bacteria also presented more LDL (bad cholesterol), in the liver and less glutathione, a natural antioxidant that impedes tissue damage.

"Major changes to gut flora like this could predispose the body toward disease." said Nicholson.

[_] 1: World J Gastroenterol. 2007 Sep 21;13(35):4737-45.

Liver-gut axis in the regulation of iron homeostasis.

The human body requires about 1-2 mg of iron per day for its
normal functioning, and dietary iron is the only source for
this essential metal. Since humans do not possess a mechanism
for the active excretion of iron, the amount of iron in the
body is determined by the amount absorbed across the proximal
small intestine and, consequently, intestinal iron absorption
is a highly regulated process. In recent years, the liver has
emerged as a central regulator of both iron absorption and iron
release from other tissues. It achieves this by secreting a
peptide hormone called hepcidin that acts on the small
intestinal epithelium and other cells to limit iron delivery to
the plasma. Hepcidin itself is regulated in response to various
systemic stimuli including variations in body iron stores, the
rate of erythropoiesis, inflammation and hypoxia, the same
stimuli that have been known for many years to modulate iron
absorption. This review will summarize recent findings on the
role played by the liver and hepcidin in the regulation of body
iron absorption.

Specific populations of gut bacteria linked to fatty liver
January 31, 2011



The more we learn about biology, the closer we get to being able to treat disease – and the more complicated our understanding of disease itself becomes.


A new research finding showing a strong relationship between complex microbial ecologies in human intestines and the common but serious medical condition known as fatty liver illustrates this paradox.

From past genomic studies, we have learned that a mind-boggling multitude of different kinds of benign bacteria inhabit our intestines and that these populations can vary almost infinitely from one human being to the next. We know that the kind of food we eat is important to our health and we know that having the right bacteria in our intestines is important in digesting our food properly, but we still do not know how our individual variations in gut bacteria might influence more specific health issues. In particular, we do not know how these bacteria influence how the substances we eat affect our organ systems.

In the condition known as fatty liver, fat deposits build up in the liver, with potentially serious health consequences for nearly a third of the American population. Fatty liver can be caused by alcohol abuse, obesity, hormonal changes and/or diabetes. Recent work has suggested that diet is also important with strong indications that deficiencies in the essential nutrient choline might be partially involved in some incidences of the condition. Choline deficiency also implicates genetics, since many people lack the genes to efficiently make choline internally.

Now, a new bioinformatics finding shows that the abundance or scarcity of certain types of bacteria in the gut may also help predict susceptibility to non-alcoholic fatty liver. The implication of the finding is that these groups of bacteria may be influencing the body's ability to properly use the choline available in food, though the study does not examine the specific metabolic activity of the bacteria involved.

In a metagenomic analysis of the microbial communities living in the intestinal tracts of 15 female patients participating in a study of the effects on liver condition from a choline-depleted diet, bioinformatics researchers at the University of North Carolina at Charlotte found a strong correlation between the relative abundances of two specific classes of bacteria and the development of fatty liver. A report on the finding appears in the current issue of the journal Gastroenterology.

"Certain bacterial populations correlated very strongly with increased fat in the liver during a restricted choline diet," said Melanie Spencer, a doctoral student in bioinformatics at the University of North Carolina at Charlotte and the lead author on the paper. "To us, it's an amazing result because you just don't see this clear a correlation in biological experiments in humans very often."

The authors on the paper are Spencer, Anthony Fodor, Timothy Hamp and Robert Reid from the department of bioinformatics and genomics at UNC Charlotte, as well as Steven Zeisel and Leslie Fischer from the department of nutrition at the University of North Carolina at Chapel Hill.

Using a metagenomic technique that compares versions of a ribosomal RNA gene known to vary between bacterial groups, the researchers analyzed the genomes of the patients' gut bacteria before, during and after the patients were put on a choline deficient diet. Because all patients consumed identical diets during the study, the researchers predicted that the initially distinct and complex communities of microbes in the patients' intestinal tracts would react by becoming less distinct from each other. The researchers found instead that, though each of the patients' bacterial communities did change a bit, each individual's community still remained distinctive throughout the study.

"What we expected we might find would be that when we put the patients on exactly the same diets, everyone's gut microbe mixture would begin to look similar, with the microbial communities converging. It did not happen – everybody was clearly individual throughout the entire study," Spencer noted.

"So we also looked at how the patients' microbes actually changed in pattern, even though they remained distinct from each other," she said. "The patterns of change were very interesting. Some of the patterns were very distinct in themselves."

The researchers noticed that among the numerous classes of bacteria present in each patient, variations in the populations of two particular groups seemed to correspond with variations between patients in the degree to which they developed a fatty liver during the period of dietary choline depletion.

"Those patients with the highest abundance of Gammaproteobacteria at the beginning of the study seemed to have the lowest fatty liver development. The ones with the least developed the most fatty liver," Spencer noted. "Erysipeoltrichi showed exactly the opposite association, though this relationship was not quite as strong. So there seemed to be change going on in opposite directions."

When the trends of Gammaproteobacteria abundance and Erysiptoltrichi scarcity were combined and related to fatty liver development, the relationship became even stronger.

Finally, the researchers factored in individual genetic variations that affect internal production of the nutrient choline and that should explain why some patients developed fatty liver and others did not. Surprisingly, the results showed that each person's genetics did not entirely account for their fatty liver outcome. When the researchers modified the analysis to include the abundances of the two bacterial groups and each individual's genetics, the correlation between fatty liver development and these three factors was nearly perfect. Further mathematical tests were performed to show that the correlations were not likely to be an artificial result of some bias hidden in the analysis.

"There was some concern that we were 'over-fitting' the model," Spencer noted, "so we tested it out and ran a million permutations, altering the bug abundance and subject association, to see if we could identify how many actually showed a higher correlation by chance. What we found is that the p values still held up. We can have a lot of confidence in the result."

The big question that remains for the team is why the two bacterial populations correlate so strongly to the development of fatty liver. Anthony Fodor, UNC Charlotte assistant professor of bioinformatics and the project's director, sees a possible explanation, while warning against drawing specific conclusions without further study.

"We cannot yet assign cause and effect, but it implies that some bacteria are doing something that is making it easier for people to deal with a choline deficiency and for the liver to metabolize fat."

Conversely, the bacteria whose high population levels correlate with disease may be somehow removing available forms of choline from digested food. Fodor explains that further study will be needed to answer those questions.

"We're debating what the next step is," he said. "In some ways, this is a very specialized experiment because we are inducing fatty liver in a very specific way. In the general population, fatty liver is induced in many, many ways and not everyone who has fatty liver has low choline.

"It's probably like Alzheimer's or cancer, where there are many different causes for a disease that displays a common phenotype. More research will be required to determine the extent to which bacterial populations play a role in fatty liver development in the general population, but our results strongly suggest that there may be a link in some people."

The role of the gut microbiota in nonalcoholic fatty liver disease

Ahmed Abu-Shanab & Eamonn M. M. Quigley About the authors
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Abstract

Important metabolic functions have been identified for the gut microbiota in health and disease. Several lines of evidence suggest a role for the gut microbiota in both the etiology of nonalcoholic fatty liver disease (NAFLD) and progression to its more advanced state, nonalcoholic steatohepatitis (NASH). Both NAFLD and NASH are strongly linked to obesity, type 2 diabetes mellitus and the metabolic syndrome and, accordingly, have become common worldwide problems. Small intestinal bacterial overgrowth of Gram-negative organisms could promote insulin resistance, increase endogenous ethanol production and induce choline deficiency, all factors implicated in NAFLD. Among the potential mediators of this association, lipopolysaccharide (a component of Gram-negative bacterial cell walls) exerts relevant metabolic and proinflammatory effects. Although the best evidence to support a role for the gut microbiota in NAFLD and NASH comes largely from animal models, data from studies in humans (albeit at times contradictory) is accumulating and could lead to new therapeutic avenues for these highly prevalent conditions.

Gut flora and T3
Our digestive tracts host an array of bacteria that contribute to our health in a number of ways. One way is in the production of active thyroid hormones. A whopping 20 percent of thyroid function depends on a sufficient supply of healthy gut bacteria to convert T4 to T3. When diets are poor and digestion falters, dysbiosis, an overabundance of bad bacteria, crowds out the beneficial bacteria, thus hampering the production of active thyroid hormone. Studies have also shown that bacterial gut infections reduce thyroid hormone levels, dull thyroid hormone receptor sites, increase the amount of inactive T3, decrease TSH, and promote autoimmune thyroid disorders. Additionally, some studies have found connections between Yersinia enterocolitica and Hashimoto’s disease—antibodies to this bacteria are 14 times higher in people with Hashimoto’s. Maintaining healthy gut flora and addressing bacterial overgrowth is an important component of good thyroid function.

a r wrote:Was wondering when you'd put your word in Hoppi. Not only do bacteria and their toxins, by-products make it into the body and into the liver causing a burden and constant low-grade inflammation, but what really interests me the most is the modulation the flora in the gut when they're impaired, on our cytokines and Immune Signalling, I believe that's huge.

Influence of Gut Microflora on Mesenteric Lymph Cytokine Production in Rats with Hemorrhagic Shock
Guo, Weidun MD; Magnotti, Louis J. MD; Ding, Jiayi MD; Huang, Qinghong MD; Xu, Dazhong MD, PhD; Deitch, Edwin A. MD
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Abstract

Objective : The aim of the present study was to test the hypothesis that the resident gut microflora play a role in modulating gut cytokine production under normal circumstances and in response to tissue injury with or without hemorrhagic shock.

Methods : The postnodal lymph was collected from the main mesenteric lymphatic channel 1 hour before, during (1.5 hours), and hourly for 6 hours after 90 minutes of sham or actual hemorrhagic shock (30 mm Hg) in the following three groups of rats, all of which had laparotomies and vascular instrumentation: rats with a normal gut flora (NF), rats whose gut flora had been decontaminated with oral antibiotics (AD), and rats with Escherichia coli C25 intestinal overgrowth (MA). Interleukin (IL)-6 and TNF levels in the mesenteric lymph were measured using cytokine-dependent cellular assays. Endotoxin levels and endotoxin-neutralizing capacity in the lymph were also measured.

Results : Mesenteric lymph IL-6 levels in the laparotomized MA-sham animals were significantly elevated compared with NF-sham animals at 2 to 4 hours (p < 0.05) and at 5 and 6 hours after sham shock (p < 0.01). Similarly, IL-6 levels in laparotomized AD-shock animals were increased when compared with NF-shock animals 3 hours after shock (p < 0.001). Lymph tumor necrosis factor bioactivity, although present in all surgically manipulated groups, was scarcely detectable in untouched animals. Endotoxin-neutralizing capacity was significantly impaired in shocked animals compared with untouched animals.

Conclusion : Changes in the gut microflora modulate the gut cytokine production after tissue injury with or without hemorrhagic shock, with intestinal bacterial overgrowth leading to the greatest increase in mesenteric lymph IL-6 levels.