- Email: [email protected]
Intestinal microbiota in short bowel syndrome
Accepted Manuscript
Intestinal Microbiota in Short Bowel Syndrome Hannah G. Piper MD PII: DOI: Reference:
S1055-8586(18)30058-1 10.1053/j.sempedsurg.2018.07.007 YSPSU 50759
To appear in:
Seminars in Pediatric Surgery
Please cite this article as: Hannah G. Piper MD , Intestinal Microbiota in Short Bowel Syndrome, Seminars in Pediatric Surgery (2018), doi: 10.1053/j.sempedsurg.2018.07.007
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Intestinal Microbiota in Short Bowel Syndrome Hannah G. Piper, MD
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Division of Pediatric Surgery, University of British Columbia/BC Children’s Hospital, 4480 Oak Street, Vancouver, BC, Canada V6H 3V4
Address correspondence to: Hannah G. Piper, MD, FRCSC, FACS
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University of British Columbia Division of Pediatric Surgery
4480 Oak Street, Ambulatory Care Building K0-134, Vancouver, BC V6H 3V4
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Email: [email protected]
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Keywords: short bowel syndrome, intestinal microbiota, prebiotics, probiotics, dysbiosis
Intestinal Microbiota in Short Bowel Syndrome
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Abstract
Children with short bowel syndrome have significant changes to their intestinal
microbiota after intestinal loss. The purpose of this article is to understand the potential implications of these changes on gut function, hepatic cholestasis and overall nutrition.
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Possible therapies to restore the commensal bacterial community in these patients will also be reviewed.
Introduction
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The management of pediatric short bowel syndrome (SBS) has evolved
considerably over the past several decades. Previously, survival through the neonatal period was the main objective and certainly not a guarantee. More recently, with most babies surviving into childhood, the focus has shifted towards improving residual
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intestinal function, weaning from parenteral nutrition (PN) and providing the best quality of life possible. It is becoming increasingly apparent that the amount of residual small bowel is not the only variable that will determine if a child will thrive and eventually
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become independent of PN. Although the type and length of the remaining intestine is very important, there continue to be children who have what seems to be sufficient
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length, where the intestine never regains enough function to support enteral independence. Similarly, occasionally there is a patient whose remaining small bowel
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adaptation exceeds expectations. Because of these observations there is increased
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interest in understanding the factors that contribute to gut function. The intestinal microbiota, which includes all of the microorganisms in the gut, and
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the microbiome, which includes all of the genes of the microbiota as well as their byproducts [1], are now recognized to play an important role in gut health and function, and are known to be disrupted after intestinal resection. Although the implications of the dysbiosis are not completely understood they are likely to be both far reaching and challenging to correct in the setting of SBS. The small bowel itself usually contains only
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a few species of bacteria, however the entire gastrointestinal tract has between 300-500 different species, predominantly anaerobes, in high density with 1011 – 1012 microbes/mL of luminal content in the colon [2]. With non-culture based, next-generation sequencing techniques more detailed analyses of the gut microbiota at different time
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points can be obtained, providing information about changes to the microbiota
throughout adaptation. Most commonly bacterial genomic DNA is extracted from a fecal sample and phylogenetic relationships are determined by comparing variable regions of the gene coding for 16S rRNA. This gene is used because it codes for a critical
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component of cell function and is universal in all bacteria [2]. With this and newer
techniques the importance of the microbiota in both the pathology of and recovery from SBS is becoming more clear, and new interventions to restore the commensal gut
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bacteria are possible.
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Establishing the intestinal microbiota
Colonization of the intestine begins at birth and is ultimately influenced by mode
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of delivery, diet, antibiotic exposure, and the living environment. The diversity and
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richness of the microbiota increases significantly in the first 2 years of life and continues to evolve until early childhood at which point the composition becomes relatively stable
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and resistant to stress [2]. Interestingly, early in life the initial microbial populations are often heavily dominated by a single taxonomic group, which is seldom the case later in adulthood. Then with the introduction of solid food there is a significant transition to a microbiota profile that more closely resemble that of an adult [3]. However, until at least
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one year of age the microbes remain somewhat unstable where large shifts can still occur in the setting of illness or antibiotic exposure. Early colonizers of the gut include aerobes (Staphylococcus, Streptococcus and Enterobacteriaceae) whereas later, strict anaerobes (Eubacterium and Clostridia)
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dominate [3], The major phyla present in the human gut are the Firmicutes,
Bacteroidetes and Actinobacteria. However, babies tend to have more Proteobacteria and Actinobacteria (specifically the genus Bifidobacterium) in the gut microbiota
compared to adults and Bifidobacteria continue to be more abundant in childhood [4]
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(Figure 1). Many of the most abundant bacteria are not found elsewhere in the body suggesting that they are specifically suited for the intestinal environment. Additionally, these bacteria can influence gene expression by the host, promoting this favorable
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environment and preventing other bacteria from thriving. For example Escherichia coli, Enterococcus and Lactobacillus all achieve very high densities and metabolic activity in
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the human cecum [5]. Many patients with SBS undergo their initial small bowel resection as newborns which is clearly a time of significant intestinal microbial transition
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and vulnerability. Not only do they undergo anatomic rearrangements, they are also
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frequently PN dependent for long periods of time with variable enteral intake and often receive antibiotics. All of these factors increase the risk of significant intestinal microbial
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disturbances of which the long-term consequences are not completely understood. Dysbiosis or derangement to the gut microbiota is associated with numerous
chronic diseases including obesity, inflammatory bowel disease, and diabetes. Specifically, inflammatory bowel diseases have been associated with an increase in the abundance of gram negative Enterobacteriaceae which belong to the phylum
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Proteobacteria and are known to be pro-inflammatory, and a decrease in antiinflammatory Clostridia bacteria, belonging to the phylum Firmicutes. Anti-inflammatory Clostridia are important for the induction of colonic regulatory T cells (Treg) that dampen inflammation in the gut [6, 7], and promote intestinal motility. Intestinal bacteria are also
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thought to be critical in the development of necrotizing enterocolitis. Toll-like receptor 4 (TLR4), an intestinal receptor that recognizes bacterial cell components, is required for disease development in the mouse model. Additionally, increased TLR4 expression has been seen in intestine resected from babies with necrotizing enterocolitis [8].
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However, whether there are specific classes of bacteria or bacterial metabolic byproducts that are ultimately responsible for the disease is not yet known. Not
surprisingly there is emerging evidence that persistent derangements to the microbiota
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occur in the setting of SBS. In a piglet model dysbiosis was seen at both two and six weeks post small bowel resection, particularly in the phylum Firmicutes [9]. A
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subsequent study in children with intestinal failure found an increase in the abundance of Proteobacteria, known to be pro-inflammatory [10] and another study in adults with
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SBS, found a predominance of Lactobacillus after intestinal loss, whereas Clostridium
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and Bacteroides were reduced [11]. The microbiota also tends to be simpler and less diverse after intestinal resection which likely also has a role in overall diminished gut
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health [10, 12]. In general, there is a trend towards an increased abundance of proinflammatory bacteria and a deficiency in anti-inflammatory bacteria in the setting of intestinal disease, including SBS.
The Intestinal Microbiota and Bacterial Overgrowth
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One of the presumed consequences of intestinal microbiota dysbiosis in patients with SBS is small intestinal bacterial overgrowth (SIBO). Part of the difficulty with studying and treating this problem is the lack of consensus regarding the definition of SIBO. Traditionally SIBO is defined as having >105 CFU/mL of bacteria in the small
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bowel or >103 CFU/mL of bacterial species that normally are found in the colon [13]. Usually bacterial counts in the small bowel are 104 or less/mL and are primarily aerobic and facultative anaerobes, but once across the ICV counts increase to between 1010 and 1012 CFU/mL and are dominated by Bacteroides, Bifidobacteria and Clostridia.
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However, in order to make this diagnosis a small bowel, usually jejunal, aspirate is
required which can be difficult to obtain in children, frequently requiring endoscopy. Alternatively, a hydrogen breath test can be used where the patient ingests a
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carbohydrate (glucose, lactulose or xylose) and then the exhaled H2 is measured. A double peak is seen on a hydrogen expiration graph where the first peak is from gas
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produced by bacteria in the small bowel and the second peak is from bacteria in the colon. The test is considered positive for SIBO if H2 is increased by more than 10-20
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parts per million compared to baseline for two consecutive samples. [14, 15]. Breath
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tests can unfortunately be difficult to interpret in the setting of SBS where transit times through the gut are less predictable. More practically, bacterial overgrowth tends to be
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defined based on clinical symptoms that seem to improve with a trial of antibiotics. Common symptoms include increased stool output, poor weight gain, abdominal pain, foul-smelling stools, and bloating. Generally speaking SIBO is attributed to increased aerobic and anaerobic gram negative bacteria usually found in the colon which ferment carbohydrates into gas (Escherichia coli, Enterococcus, Klebsiella pneumonia and
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Proteus mirabilis) [14]. More recently however, it is felt that SIBO is not necessarily due to the overgrowth of any particular species of bacteria, but rather occurs when there is a divergent ratio between the major phyla [16]. Risk factors for bacterial overgrowth are thought to include gastric achlorhydria
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potentially from extended use of proton pump inhibitors, impaired intestinal motility, and increased levels of unabsorbed substances within the intestinal lumen. In a study in adults there was a correlation between decreased ileocecal junctional pressures, as measured by a wireless motility capsule, and a positive lactulose breath test providing
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support for the idea that the loss of the ileocecal valve does predispose to an increased bacterial load in the small bowel [17]. In another study in children with intestinal failure, 70% of patients with refractory symptoms including bloating, emesis or diarrhea, had
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duodenal aspirates that grew > 105 CFU/mL of bacteria. This included 60% of patients on PN compared to 40% of patients who were receiving full enteral nutrition.
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Escherichia coli and Klebsiella were the most common gram-negative organisms and Streptococcus viridans and Enterococcus were the most common gram positives. No
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correlation was seen between acid blockade, previous lengthening procedures or
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primary motility disorders [18]. Regardless of the cause, SIBO can result in several problems including
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malabsorption, bacterial translocation and D-lactic acidosis. In one study looking at stool samples from adults with SBS and jejuno-colic anastomoses, fat and protein absorption were significantly reduced at approximately 40% of intake in those with presumed overgrowth [16]. Additionally, increased carbohydrate breakdown by bacteria can lead to excess carbon dioxide, hydrogen and methane production causing bloating,
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distension and pain. D-lactic acidosis occurs in some patients when non-absorbed carbohydrates are delivered to intestinal bacteria that make lactic acid as a by-product. Normally the L isomer of lactic acid produced by most human bacteria is absorbed and metabolized by the liver, but some bacteria produce both D and L isomers or only D
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isomers which are difficult to metabolize in some people, resulting in toxic levels of the isomer [15].
The goals of treatment for confirmed or presumed SIBO are not to achieve
intestinal sterilization but to reduce the number of pathogenic bacteria and restore
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commensal bacteria. This is usually done with a 7-14 day course of antibiotics that aims to target anaerobes and aerobes, with an improvement in symptoms expected in 1-2 weeks. Metronidazole is standard fist line therapy, other options include
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Amoxicillin/clavulonic which is bactericidal, and has prokinetic properties and rifaximin (non-absorbable analog of rifampin) which is bacteriostatic [19]. However, the efficacy
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of antibiotics is largely unknown and they may have unpredictable long-term effects. When our group looked at the microbiota in children with SBS and symptoms of
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bacterial overgrowth both before and after antibiotic therapy, we found that there was
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actually a decrease in the abundance of beneficial anti-inflammatory Clostridia and an increase in inflammatory Proteobacteria after completing a week of antibiotics [20]. It is
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possible that combining antibiotic therapy with a probiotic or prebiotic might allow for a more durable reconstitution of the commensal microbiota, however more research in this area is needed. Alternatively, the institution of a low FODMAP diet (fermentable, oligosaccharides, disaccharides, monosaccharides and polyols) has been advocated by some to treat SIBO in other patient populations such as those with irritable bowel
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syndrome, because it minimizes short-chain carbohydrates that are poorly absorbed by the small bowel and are metabolized by intestinal bacteria resulting in excess gas production. However there has been little research looking at its use in short bowel syndrome. One of the potential downsides of such a restrictive diet is that many of these
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children struggle to ingest sufficient calories enterally even with a fairly liberal diet. This approach to treatment deserves further study. Ultimately management of SIBO should focus on correcting the underlying cause, addressing nutritional deficiencies and trying
tailored for individual patients.
Dysbiosis and Hepatic Cholestasis
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to restore a healthy microbiota. Treatment in the setting of SBS likely needs to be
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Over half of infants and children with SBS develop hepatic cholestasis at some point during intestinal adaptation. The etiology is felt to be multifactorial with factors
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such as prematurity, prolonged PN exposure, intravenous lipid emulsions and episodes of sepsis all believed to contribute to inflammation and cholestasis in the liver.
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Interestingly, small bowel resection has been shown to be an independent risk factor for
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the development of liver disease in children and adults with intestinal failure [21]. Changes to the intestinal microbiota seen in SBS can also result in increased
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inflammation in the gut and potentially the liver. The link between the intestinal microbiota and cholestasis has not been completely elucidated, but compelling evidence is accumulating. In a study by Korpela et al. the composition of the intestinal microbiota in patients with SBS was associated with liver steatosis and was a better predictor of the degree of steatosis than ether the duration of PN support required or the
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length of the remaining intestine. They found three predominant microbiota signatures. Patients with prolonged PN support had an increased abundance of Proteobacteria (known to be pro-inflammatory) and tended to have the most severe liver injury. Those with the least amount of small bowel had an overabundance of Lactobacillus and
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reduced microbial richness, and those with a high abundance of Clostridium cluster XIVa (known to be anti-inflammatory) were the least severe cases of intestinal failure. However, many of these patients (56%) were also receiving antibiotics during sample collection and therefore it is somewhat difficult to interpret these results [22].
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In addition to intestinal inflammation, one of the problems associated with gut microbial dysbiosis is an alteration in bile acid (BA) metabolism, which is also a known risk factor for hepatic cholestasis. Bile acids are important for the solubilization of
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cholesterol, lipids and vitamins in the intestine, and bile acid dysmetabolism is associated with fat malabsorption, diarrhea, inflammation and liver injury [23]. Primary
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BAs are synthesized from cholesterol in the liver and then conjugated with either glycine or taurine. The bacteria in the large intestine deconjugate the bile acids, converting
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them into secondary and tertiary bile acids where they diffuse passively through the
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intestinal epithelium and are transported back to the liver [24]. After small intestinal resection there is a switch to a dominance of primary BAs, likely secondary to changes
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in the intestinal bacteria [25]. This can result in hepatic cholestasis because BAs also have metabolic functions in the body through nuclear receptors, one of which is the farsenoid X receptor (FXR). FXR is activated by BAs and is a key regulatory step in their synthesis, inducing target genes within the liver and small intestine. Bacterial dysbiosis has been strongly linked to perturbations in FXR signaling and subsequently
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hepatic cholestasis. Pereira-Fantini et al. reported a novel piglet model of SBS associated liver disease that is independent of PN. Using this model they were able to demonstrate a decrease in the abundance of bacteria that are able to deconjugate primary BAs including both Clostridium and Bacteroides. This resulted in an increase in
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primary BAs returning to the liver and abnormal FXR signaling within the intestine and liver in those animals that developed cholestasis [23]. Another study by Jain et al.
looked at the utility of giving enteral BAs in piglets receiving PN to prevent dysbiosis associated cholestasis. Oleanolic acid (OA), an agonist to a bile acid receptor located
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in the small bowel crypts, was given to a strictly PN fed cohort to see if this improved cholestasis. Significant clonal proliferation of Bacteroidetes, specifically the Porphyromonadaceae family, was noted in animals receiving parenteral compared to
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enteral nutrition and this was prevented by giving OA. Animals receiving PN and OA also had a more diverse microbial population compared to those getting PN alone.
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There was an elevation in serum bilirubin level in animals treated with PN and this decreased in those animals getting OA [26]. Although there does appear to be a direct
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link between the gut microbiota, bile acid metabolism and hepatic cholestasis, there
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may be variability in the changes to the microbiota depending on the patient’s anatomy and diet (enteral vs. parenteral). This gut-liver communication via bacteria and bile acids
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does however suggest a potential for additional therapeutic interventions.
The Role of Bacteria in Energy Harvest and Metabolism Growth failure is seen in many chronic pediatric illnesses due to a variety of contributing factors. For babies and children with SBS, difficulties with growth are most
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commonly related to increased nutritional needs from malabsorption, metabolic alterations and inflammation. Growth failure before two years of age has been linked to problems with both physical and cognitive development later in life [27] and children with SBS continue to be at high risk [28], making this an important issue to address in
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the long term care of these patients. Although traditionally the focus has been on macro and micronutrient provision as the main intervention, there is mounting evidence that the intestinal microbiota plays an important role in both metabolism and how efficiently the gut is able to harvest energy from enteral nutrition. Interestingly, in 1978 a study
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was published suggesting an association between commensal bacteria and
metabolism. In this study germ free rats were noted to have a fasting metabolic rate approximately 20% lower than conventional rats. The same group found that in the
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setting of starvation, germ-free rats died significantly faster than conventional rats who survived over a week longer, despite a similar rate of weight loss [29]. Almost 40 years
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later consistent findings have been reported where germ free mice are both shorter and gain less weight compared to wild type litter mates fed a common diet [30]. Similarly, in
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a recent study, germ free mice who received a fecal transplant from healthy babies
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gained more lean body mass and overall weight than mice transplanted from undernourished babies [31] even though both groups of mice were receiving the same
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enteral diet. These findings are felt to be due primarily to microbial fermentation of polysaccharides that cannot otherwise be digested by the host, and microbial regulation of host genes that promote lipid storage [32]. In fact, there is data to suggest that obesity may be associated with a distinct intestinal microbiota signature with a lower proportion of Bacteroidetes and a higher proportion of Firmicutes [33].
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With this in mind, it is important to consider how the microbial composition could potentially be optimized to promote healthy growth and metabolism in the setting of SBS. The main functions of the intestinal bacteria include the fermentation of dietary fibers, vitamin K and short chain fatty acid (SCFA) production, and absorption of
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calcium, magnesium and iron[5]. SCFAs are monocarboxylic hydrocarbons produced from non-absorbed carbohydrates and include acetate, propionate and butyrate.
Although all three types are easily absorbed by intestinal epithelial cells, butyrate is preferentially oxidized accounting for 80% of energy used by the colon [34]. SCFAs
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have a trophic effect on the intestinal epithelium, stimulating cell proliferation and differentiation in both the small and large bowel. Certain bacteria, particularly
Firmicutes from the class Clostridia, are known producers of SCFAs and have anti-
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inflammatory properties. These anti-inflammatory Clostridia lack toxins and virulence factors and have been shown to increase colonic SCFA levels in mice [6, 7]. As
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previously noted, several studies have found a decrease in in the abundance of antiinflammatory Clostridia in SBS. When our group profiled the gut microbiota in a series
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of children with SBS, we found that compared to healthy children there was a deficiency
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in anaerobic Firmicutes including several species thought to play a beneficial role in gut health. In addition, a subset with poor growth had a deficiency of six species of bacteria
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compared to children with SBS who were growing well, five of which were from the phylum Firmicutes [20]. All of this suggest that the proportion of Firmicutes and potentially the SCFA levels in the gut may prove to be important in the evaluation of a child with SBS who is not growing well.
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Treatment strategies to target the microbiota Although the implications of disturbances to the commensal intestinal microbiota after major intestinal resection are becoming well recognized, there is no consensus regarding the ultimate treatment strategy. Options for restoring balance to the bacteria
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in the gut include treatment with antibiotics to reduce the abundance of pro-
inflammatory pathogens, supplementing the diet with either probiotics, prebiotics or a combined synbiotic, or a more broad approach at repopulating the gut microbiota with fecal microbial transplant. As previously discussed, antibiotics in isolation are likely not
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an effective strategy although there may be a role for short term gut decontamination followed by probiotics. Probiotics are live organisms that provide a health benefit to the host and can be used to repopulate the gut by competing with pathogens for nutrients
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and mucosal adherence. Commonly available probiotics include Lactobacillus, Bifidobacterium and the yeast Saccharomyces (Table 1). Clinical studies have
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demonstrated that Lactobacillus rhamnosus shortens the duration of diarrhea secondary to rotavirus in infants by modifying the immune system [35]. Additionally, in animal
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models of SBS Lactobacillus stimulated intestinal growth and decreased bacterial Lactobacillus and
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translocation in both peripheral and portal blood [36, 37].
Bifidobacterium have also been safely used in very low birth weight infants to prevent
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necrotizing enterocolitis and shorten the duration of PN support [38, 39]. Lactobacillus is primarily thought to exert its effect by fermenting carbohydrates into lactic acid which then inhibits growth of certain pathogenic bacteria and provides substrate for other SCFA-producing commensal bacteria [40]. In a study where newborn piglets received Enterococcus faecium, from the order Lactobacillales, there was increased body weight
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and higher levels of Lactobacillales in the stool compared to those not receiving the probiotic [41]. All of these studies provide evidence that probiotics could potentially be very useful for children with SBS, however there remain few commercially available products to choose from and the efficacy in children with poor intestinal absorption and
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rapid transit is unknown.
Another potentially helpful treatment to consider is prebiotics. Prebiotics are nondigestible food ingredients that beneficially affect the host by stimulating growth or activity of certain bacteria. Examples include oligosaccharides and fructo-
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oligosaccharides (Table 2). Interestingly, breast fed babies already receive
considerable probiotics from breast milk. Human breast milk contains over 200 types of oligosaccharides (human milk oligosaccharides or HMOs) making them the third most
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plentiful ingredient in the milk after lactose and fats. Babies themselves cannot digest the HMOs and they therefore serve as nutrition for the intestinal bacteria. They pass
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through the stomach and small intestine into the colon where Bifidiobacterium, specifically Bifidiobacterium longum and infantis, break them down. As they use the
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HMOs they create SCFAs and other anti-inflammatory molecules including sialic acid
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which is needed for brain development in the first year of life [42]. The two main types of commercially available prebiotics are inulin-type fructans and galacto-oligosaccharides
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both of which are fermented into SCFAs and lactate by Lactobacillus and Bifidobacterium, and ultimately decrease the abundance of pathogenic bacteria [43] (Table 2). This type of synbiotic relationship between bacteria and host could potentially be very useful in SBS. It is generally felt that by combining probiotics and prebiotics (as a synbiotic), the gut can be repopulated with both the beneficial bacteria and the food
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they need to thrive and outcompete more pathogenic bacteria. In fact, there is evidence to suggest that this strategy can improve intestinal adaptation after significant resection. In a piglet model of SBS where 80% of proximal small bowel was resected, treatment groups who received either a prebiotic or a combined prebiotic and probiotic had
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increased jejunal and ileal mass as well as increased ileal villus height after one week of therapy compared to both the probiotic alone and control groups[44]. Additionally, in a study where patients with SBS received both Bifidiobacterium and Lactobacillus along with galactooligosaccharides, fecal SCFA levels increased and growth improved [45].
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Further trials with synbiotics would be helpful to determine the best combination and dosage for children with short bowel syndrome.
A final therapeutic consideration is fecal microbial transplant (FMT). FMT is a
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process in which healthy gut bacteria from a screened donor is directly infused into the diseased gut. Currently this is used primarily for adult patients with recurrent
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Clostridium difficile infections as an alternative to antibiotics. The success rate of FMT in the treatment of recurrent C.difficile is about 90% [46]. FMT has also been used for
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children with refractory ulcerative colitis where dysbiosis of the gut microbiota is known
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to play an important role with a link to deficiencies in Lactobacillus and Fecalibacterium. In a recent study, 12 children with ulcerative colitis were randomized to receive FMT or
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placebo transplant with their own stool. The study found that FMT was safe and was associated with an improvement in symptoms in most patients. None of the transplanted patients required an escalation in therapy, compared to 70% of the placebo group [47]. There is also evidence in adults that FMT results in an increase in microbial diversity and is associated with clinical remission from ulcerative colitis [48].
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Currently fecal microbial transplant has not been well studied in SBS, however similar to patients with inflammatory bowel disease there are known perturbations to the commensal bacterial and therefore there may be benefits to this approach.
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References 1. Khanna S: Microbiota Replacement Therapies: Innovation in Gastrointestinal Care. Clinical pharmacology and therapeutics 2018, 103(1):102-111. 2. Spor A, Koren O, Ley R: Unravelling the effects of the environment and host genotype on the gut microbiome. Nature reviews Microbiology 2011, 9(4):279290. 3. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO: Development of the human infant intestinal microbiota. PLoS Biol 2007, 5(7):e177. 4. Ringel-Kulka T, Cheng J, Ringel Y, Salojarvi J, Carroll I, Palva A, de Vos WM, Satokari R: Intestinal microbiota in healthy u.s. Young children and adults-a high throughput microarray analysis. PLoS One 2013, 8(5):e64315. 5. Guarner F, Malagelada JR: Gut flora in health and disease. Lancet 2003, 361(9356):512-519. 6. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K et al: Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013, 500(7461):232-236. 7. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y et al: Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011, 331(6015):337-341. 8. Carlisle EM, Morowitz MJ: The intestinal microbiome and necrotizing enterocolitis. Curr Opin Pediatr 2013, 25(3):382-387. 9. Lapthorne S, Pereira-Fantini PM, Fouhy F, Wilson G, Thomas SL, Dellios NL, Scurr M, O'Sullivan O, Ross RP, Stanton C et al: Gut microbial diversity is reduced and is associated with colonic inflammation in a piglet model of short bowel syndrome. Gut Microbes 2013, 4(3):212-221. 10. Engstrand Lilja H, Wefer H, Nystrom N, Finkel Y, Engstrand L: Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome. Microbiome 2015, 3:18. 11. Joly F, Mayeur C, Bruneau A, Noordine ML, Meylheuc T, Langella P, Messing B, Duee PH, Cherbuy C, Thomas M: Drastic changes in fecal and mucosaassociated microbiota in adult patients with short bowel syndrome. Biochimie 2010, 92(7):753-761. 12. Korpela K, Mutanen A, Salonen A, Savilahti E, de Vos WM, Pakarinen MP: Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric-Onset Intestinal Failure. JPEN J Parenter Enteral Nutr 2015.
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Khoshini R, Dai SC, Lezcano S, Pimentel M: A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Digestive diseases and sciences 2008, 53(6):1443-1454. Sachdev AH, Pimentel M: Gastrointestinal bacterial overgrowth: pathogenesis and clinical significance. Therapeutic advances in chronic disease 2013, 4(5):223-231. Dibaise JK, Young RJ, Vanderhoof JA: Enteric microbial flora, bacterial overgrowth, and short-bowel syndrome. Clin Gastroenterol Hepatol 2006, 4(1):11-20. Mayeur C, Gratadoux JJ, Bridonneau C, Chegdani F, Larroque B, Kapel N, Corcos O, Thomas M, Joly F: Faecal D/L lactate ratio is a metabolic signature of microbiota imbalance in patients with short bowel syndrome. PLoS One 2013, 8(1):e54335. Roland BC, Ciarleglio MM, Clarke JO, Semler JR, Tomakin E, Mullin GE, Pasricha PJ: Low ileocecal valve pressure is significantly associated with small intestinal bacterial overgrowth (SIBO). Digestive diseases and sciences 2014, 59(6):1269-1277. Gutierrez IM, Kang KH, Calvert CE, Johnson VM, Zurakowski D, Kamin D, Jaksic T, Duggan C: Risk factors for small bowel bacterial overgrowth and diagnostic yield of duodenal aspirates in children with intestinal failure: a retrospective review. J Pediatr Surg 2012, 47(6):1150-1154. Bohm M, Siwiec RM, Wo JM: Diagnosis and management of small intestinal bacterial overgrowth. Nutr Clin Pract 2013, 28(3):289-299. Piper HG, Fan D, Coughlin LA, Ho EX, McDaniel MM, Channabasappa N, Kim J, Kim M, Zhan X, Xie Y et al: Severe Gut Microbiota Dysbiosis Is Associated With Poor Growth in Patients With Short Bowel Syndrome. JPEN J Parenter Enteral Nutr 2016. Pichler J, Horn V, Macdonald S, Hill S: Intestinal failure-associated liver disease in hospitalised children. Archives of disease in childhood 2012, 97(3):211-214. Korpela K, Mutanen A, Salonen A, Savilahti E, de Vos WM, Pakarinen MP: Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric-Onset Intestinal Failure. JPEN J Parenter Enteral Nutr 2017, 41(2):238-248. Pereira-Fantini PM, Lapthorne S, Joyce SA, Dellios NL, Wilson G, Fouhy F, Thomas SL, Scurr M, Hill C, Gahan CG et al: Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndromeassociated liver disease. Journal of hepatology 2014, 61(5):1115-1125. Yang H, Duan Z: Bile Acids and the Potential Role in Primary Biliary Cirrhosis. Digestion 2016, 94(3):145-153. Ohkohchi N, Andoh T, Izumi U, Igarashi Y, Ohi R: Disorder of bile acid metabolism in children with short bowel syndrome. Journal of gastroenterology 1997, 32(4):472-479. Jain AK, Sharma A, Arora S, Blomenkamp K, Jun IC, Luong R, Westrich DJ, Mittal A, Buchanan PM, Guzman MA et al: Preserved Gut Microbial Diversity Accompanies Upregulation of TGR5 and Hepatobiliary Transporters in Bile
CE
13.
24. 25.
26.
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32.
33. 34.
35.
36.
37.
CR IP T
AC
38.
AN US
31.
M
30.
ED
29.
PT
28.
CE
27.
Acid-Treated Animals Receiving Parenteral Nutrition. JPEN J Parenter Enteral Nutr 2017, 41(2):198-207. Kyle UG, Shekerdemian LS, Coss-Bu JA: Growth failure and nutrition considerations in chronic childhood wasting diseases. Nutr Clin Pract 2015, 30(2):227-238. McLaughlin CM, Channabasappa N, Pace J, Nguyen H, Piper HG: Growth Trajectory in Children With Short Bowel Syndrome During the First 2 Years of Life. J Pediatr Gastroenterol Nutr 2018, 66(3):484-488. Levenson SM: The influence of the indigenous microflora on mammalian metabolism and nutrition. JPEN J Parenter Enteral Nutr 1978, 2(2):78-107. Schwarzer M, Makki K, Storelli G, Machuca-Gayet I, Srutkova D, Hermanova P, Martino ME, Balmand S, Hudcovic T, Heddi A et al: Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science 2016, 351(6275):854-857. Blanton LV, Charbonneau MR, Salih T, Barratt MJ, Venkatesh S, Ilkaveya O, Subramanian S, Manary MJ, Trehan I, Jorgensen JM et al: Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science 2016, 351(6275). Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006, 444(7122):1027-1031. Ley RE, Turnbaugh PJ, Klein S, Gordon JI: Microbial ecology: human gut microbes associated with obesity. Nature 2006, 444(7122):1022-1023. Kles KA, Chang EB: Short-chain fatty acids impact on intestinal adaptation, inflammation, carcinoma, and failure. Gastroenterology 2006, 130(2 Suppl 1):S100-105. Salminen MK, Tynkkynen S, Rautelin H, Saxelin M, Vaara M, Ruutu P, Sarna S, Valtonen V, Jarvinen A: Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis 2002, 35(10):1155-1160. Mogilner JG, Srugo I, Lurie M, Shaoul R, Coran AG, Shiloni E, Sukhotnik I: Effect of probiotics on intestinal regrowth and bacterial translocation after massive small bowel resection in a rat. J Pediatr Surg 2007, 42(8):1365-1371. Tolga Muftuoglu MA, Civak T, Cetin S, Civak L, Gungor O, Saglam A: Effects of probiotics on experimental short-bowel syndrome. Am J Surg 2011, 202(4):461-468. Saengtawesin V, Tangpolkaiwalsak R, Kanjanapattankul W: Effect of oral probiotics supplementation in the prevention of necrotizing enterocolitis among very low birth weight preterm infants. J Med Assoc Thai 2014, 97 Suppl 6:S20-25. Rouge C, Piloquet H, Butel MJ, Berger B, Rochat F, Ferraris L, Des Robert C, Legrand A, de la Cochetiere MF, N'Guyen JM et al: Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, doubleblind, placebo-controlled trial. Am J Clin Nutr 2009, 89(6):1828-1835.
39.
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44.
45.
46.
47.
PT
ED
48.
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42. 43.
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41.
Antonissen G, Eeckhaut V, Van Driessche K, Onrust L, Haesebrouck F, Ducatelle R, Moore RJ, Van Immerseel F: Microbial shifts associated with necrotic enteritis. Avian Pathol 2016, 45(3):308-312. Wang YB, Du W, Fu AK, Zhang XP, Huang Y, Lee KH, Yu K, Li WF, Li YL: Intestinal microbiota and oral administration of Enterococcus faecium associated with the growth performance of new-born piglets. Benef Microbes 2016:1-10. Yong E: Breast-feeding the microbiome. The New Yorker 2016:1-15. Viladomiu M, Hontecillas R, Yuan L, Lu P, Bassaganya-Riera J: Nutritional protective mechanisms against gut inflammation. J Nutr Biochem 2013, 24(6):929-939. Barnes JL, Hartmann B, Holst JJ, Tappenden KA: Intestinal adaptation is stimulated by partial enteral nutrition supplemented with the prebiotic short-chain fructooligosaccharide in a neonatal intestinal failure piglet model. JPEN J Parenter Enteral Nutr 2012, 36(5):524-537. Kanamori Y, Sugiyama M, Hashizume K, Yuki N, Morotomi M, Tanaka R: Experience of long-term synbiotic therapy in seven short bowel patients with refractory enterocolitis. J Pediatr Surg 2004, 39(11):1686-1692. Gough E, Shaikh H, Manges AR: Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011, 53(10):994-1002. Michail S: Fecal Microbial Transplant In Children With Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study. J Pediatr Gastroenterol Nutr 2017. Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, Leong RWL, Connor S, Ng W, Paramsothy R et al: Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017, 389(10075):1218-1228.
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Relative Abundance of the Major Bacterial Phyla in Adults and Children
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(b)
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Figure 1 Typical relative abundance of the major bacterial phyla in the GI tract of adults (a) and children (b). Firmicutes dominate in both groups whereas children have expansion of Actinobacteria and Proteobacteria. Table 1. Examples of commonly used probiotics for children Name Culturelle
Composition Lactobacillus rhamnosus
Ultimate Flora
Bifidobacterium bifidum Bifidobacterium infantis Bifidobacterium breve Bifidobacterium longum
Proposed Benefit Used for antibiotic associated diarrhea Supports gut immune health, used to treat diarrhea
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Lactobacillus acidophilus Lactobacillus fermentum Lactobacillus rhamnosus Lactobacillus salvarius Lactobacillus casei
Mutaflor
Escherichia coli Nissle
Florastor
Saccharomyces Boulardii
Has been used to treat diarrhea, constipation and eczema, and for the prevention of necrotizing enterocolitis in very low birth weight babies Has been used to treat pouchitis in inflammatory bowel disease and pseudomembranous colitis Used for antibiotic associated diarrhea and chronic diarrhea in children
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Bifidobacterium breve Bifidobacterium bifidum Bifidobacterium infantis Bifidobacterium longum Lactobacillus rhamnosus
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FloraBABY
Table 2. Examples of prebiotics for children
Composition Naturally occurring polysaccharide (fructose polymer), storage carbohydrate found in many plants Produced by degrading inulin or polyfructose, found in blue Agave and Jerusaleum artichokes Chain of galactose units with a terminal glucose unit
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Fructo-oligosaccharide (FOS)
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Name Inulin
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Galacto-oligosaccharide (GOS)
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Human milk oligosaccharide (HMO)
Family of unconjugated glycans found in human breast milk
Proposed Benefit May be used for acute diarrheal illness, stimulates growth of Bifidobacterium
Promotes calcium absorption, stimulates growth of Bifidobacterium Stimulates growth of Bifidobacterium and Lactobacillus Stimulates growth of Bifidobacterium longum and acts as anti-adhesive to prevent attachment of pathogenic bacteria to mucosal surfaces
Intestinal Microbiota in Short Bowel Syndrome Hannah G. Piper MD PII: DOI: Reference:
S1055-8586(18)30058-1 10.1053/j.sempedsurg.2018.07.007 YSPSU 50759
To appear in:
Seminars in Pediatric Surgery
Please cite this article as: Hannah G. Piper MD , Intestinal Microbiota in Short Bowel Syndrome, Seminars in Pediatric Surgery (2018), doi: 10.1053/j.sempedsurg.2018.07.007
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Intestinal Microbiota in Short Bowel Syndrome Hannah G. Piper, MD
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Division of Pediatric Surgery, University of British Columbia/BC Children’s Hospital, 4480 Oak Street, Vancouver, BC, Canada V6H 3V4
Address correspondence to: Hannah G. Piper, MD, FRCSC, FACS
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University of British Columbia Division of Pediatric Surgery
4480 Oak Street, Ambulatory Care Building K0-134, Vancouver, BC V6H 3V4
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Email: [email protected]
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Keywords: short bowel syndrome, intestinal microbiota, prebiotics, probiotics, dysbiosis
Intestinal Microbiota in Short Bowel Syndrome
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Abstract
Children with short bowel syndrome have significant changes to their intestinal
microbiota after intestinal loss. The purpose of this article is to understand the potential implications of these changes on gut function, hepatic cholestasis and overall nutrition.
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Possible therapies to restore the commensal bacterial community in these patients will also be reviewed.
Introduction
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The management of pediatric short bowel syndrome (SBS) has evolved
considerably over the past several decades. Previously, survival through the neonatal period was the main objective and certainly not a guarantee. More recently, with most babies surviving into childhood, the focus has shifted towards improving residual
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intestinal function, weaning from parenteral nutrition (PN) and providing the best quality of life possible. It is becoming increasingly apparent that the amount of residual small bowel is not the only variable that will determine if a child will thrive and eventually
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become independent of PN. Although the type and length of the remaining intestine is very important, there continue to be children who have what seems to be sufficient
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length, where the intestine never regains enough function to support enteral independence. Similarly, occasionally there is a patient whose remaining small bowel
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adaptation exceeds expectations. Because of these observations there is increased
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interest in understanding the factors that contribute to gut function. The intestinal microbiota, which includes all of the microorganisms in the gut, and
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the microbiome, which includes all of the genes of the microbiota as well as their byproducts [1], are now recognized to play an important role in gut health and function, and are known to be disrupted after intestinal resection. Although the implications of the dysbiosis are not completely understood they are likely to be both far reaching and challenging to correct in the setting of SBS. The small bowel itself usually contains only
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a few species of bacteria, however the entire gastrointestinal tract has between 300-500 different species, predominantly anaerobes, in high density with 1011 – 1012 microbes/mL of luminal content in the colon [2]. With non-culture based, next-generation sequencing techniques more detailed analyses of the gut microbiota at different time
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points can be obtained, providing information about changes to the microbiota
throughout adaptation. Most commonly bacterial genomic DNA is extracted from a fecal sample and phylogenetic relationships are determined by comparing variable regions of the gene coding for 16S rRNA. This gene is used because it codes for a critical
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component of cell function and is universal in all bacteria [2]. With this and newer
techniques the importance of the microbiota in both the pathology of and recovery from SBS is becoming more clear, and new interventions to restore the commensal gut
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bacteria are possible.
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Establishing the intestinal microbiota
Colonization of the intestine begins at birth and is ultimately influenced by mode
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of delivery, diet, antibiotic exposure, and the living environment. The diversity and
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richness of the microbiota increases significantly in the first 2 years of life and continues to evolve until early childhood at which point the composition becomes relatively stable
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and resistant to stress [2]. Interestingly, early in life the initial microbial populations are often heavily dominated by a single taxonomic group, which is seldom the case later in adulthood. Then with the introduction of solid food there is a significant transition to a microbiota profile that more closely resemble that of an adult [3]. However, until at least
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one year of age the microbes remain somewhat unstable where large shifts can still occur in the setting of illness or antibiotic exposure. Early colonizers of the gut include aerobes (Staphylococcus, Streptococcus and Enterobacteriaceae) whereas later, strict anaerobes (Eubacterium and Clostridia)
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dominate [3], The major phyla present in the human gut are the Firmicutes,
Bacteroidetes and Actinobacteria. However, babies tend to have more Proteobacteria and Actinobacteria (specifically the genus Bifidobacterium) in the gut microbiota
compared to adults and Bifidobacteria continue to be more abundant in childhood [4]
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(Figure 1). Many of the most abundant bacteria are not found elsewhere in the body suggesting that they are specifically suited for the intestinal environment. Additionally, these bacteria can influence gene expression by the host, promoting this favorable
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environment and preventing other bacteria from thriving. For example Escherichia coli, Enterococcus and Lactobacillus all achieve very high densities and metabolic activity in
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the human cecum [5]. Many patients with SBS undergo their initial small bowel resection as newborns which is clearly a time of significant intestinal microbial transition
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and vulnerability. Not only do they undergo anatomic rearrangements, they are also
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frequently PN dependent for long periods of time with variable enteral intake and often receive antibiotics. All of these factors increase the risk of significant intestinal microbial
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disturbances of which the long-term consequences are not completely understood. Dysbiosis or derangement to the gut microbiota is associated with numerous
chronic diseases including obesity, inflammatory bowel disease, and diabetes. Specifically, inflammatory bowel diseases have been associated with an increase in the abundance of gram negative Enterobacteriaceae which belong to the phylum
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Proteobacteria and are known to be pro-inflammatory, and a decrease in antiinflammatory Clostridia bacteria, belonging to the phylum Firmicutes. Anti-inflammatory Clostridia are important for the induction of colonic regulatory T cells (Treg) that dampen inflammation in the gut [6, 7], and promote intestinal motility. Intestinal bacteria are also
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thought to be critical in the development of necrotizing enterocolitis. Toll-like receptor 4 (TLR4), an intestinal receptor that recognizes bacterial cell components, is required for disease development in the mouse model. Additionally, increased TLR4 expression has been seen in intestine resected from babies with necrotizing enterocolitis [8].
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However, whether there are specific classes of bacteria or bacterial metabolic byproducts that are ultimately responsible for the disease is not yet known. Not
surprisingly there is emerging evidence that persistent derangements to the microbiota
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occur in the setting of SBS. In a piglet model dysbiosis was seen at both two and six weeks post small bowel resection, particularly in the phylum Firmicutes [9]. A
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subsequent study in children with intestinal failure found an increase in the abundance of Proteobacteria, known to be pro-inflammatory [10] and another study in adults with
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SBS, found a predominance of Lactobacillus after intestinal loss, whereas Clostridium
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and Bacteroides were reduced [11]. The microbiota also tends to be simpler and less diverse after intestinal resection which likely also has a role in overall diminished gut
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health [10, 12]. In general, there is a trend towards an increased abundance of proinflammatory bacteria and a deficiency in anti-inflammatory bacteria in the setting of intestinal disease, including SBS.
The Intestinal Microbiota and Bacterial Overgrowth
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One of the presumed consequences of intestinal microbiota dysbiosis in patients with SBS is small intestinal bacterial overgrowth (SIBO). Part of the difficulty with studying and treating this problem is the lack of consensus regarding the definition of SIBO. Traditionally SIBO is defined as having >105 CFU/mL of bacteria in the small
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bowel or >103 CFU/mL of bacterial species that normally are found in the colon [13]. Usually bacterial counts in the small bowel are 104 or less/mL and are primarily aerobic and facultative anaerobes, but once across the ICV counts increase to between 1010 and 1012 CFU/mL and are dominated by Bacteroides, Bifidobacteria and Clostridia.
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However, in order to make this diagnosis a small bowel, usually jejunal, aspirate is
required which can be difficult to obtain in children, frequently requiring endoscopy. Alternatively, a hydrogen breath test can be used where the patient ingests a
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carbohydrate (glucose, lactulose or xylose) and then the exhaled H2 is measured. A double peak is seen on a hydrogen expiration graph where the first peak is from gas
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produced by bacteria in the small bowel and the second peak is from bacteria in the colon. The test is considered positive for SIBO if H2 is increased by more than 10-20
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parts per million compared to baseline for two consecutive samples. [14, 15]. Breath
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tests can unfortunately be difficult to interpret in the setting of SBS where transit times through the gut are less predictable. More practically, bacterial overgrowth tends to be
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defined based on clinical symptoms that seem to improve with a trial of antibiotics. Common symptoms include increased stool output, poor weight gain, abdominal pain, foul-smelling stools, and bloating. Generally speaking SIBO is attributed to increased aerobic and anaerobic gram negative bacteria usually found in the colon which ferment carbohydrates into gas (Escherichia coli, Enterococcus, Klebsiella pneumonia and
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Proteus mirabilis) [14]. More recently however, it is felt that SIBO is not necessarily due to the overgrowth of any particular species of bacteria, but rather occurs when there is a divergent ratio between the major phyla [16]. Risk factors for bacterial overgrowth are thought to include gastric achlorhydria
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potentially from extended use of proton pump inhibitors, impaired intestinal motility, and increased levels of unabsorbed substances within the intestinal lumen. In a study in adults there was a correlation between decreased ileocecal junctional pressures, as measured by a wireless motility capsule, and a positive lactulose breath test providing
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support for the idea that the loss of the ileocecal valve does predispose to an increased bacterial load in the small bowel [17]. In another study in children with intestinal failure, 70% of patients with refractory symptoms including bloating, emesis or diarrhea, had
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duodenal aspirates that grew > 105 CFU/mL of bacteria. This included 60% of patients on PN compared to 40% of patients who were receiving full enteral nutrition.
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Escherichia coli and Klebsiella were the most common gram-negative organisms and Streptococcus viridans and Enterococcus were the most common gram positives. No
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correlation was seen between acid blockade, previous lengthening procedures or
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primary motility disorders [18]. Regardless of the cause, SIBO can result in several problems including
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malabsorption, bacterial translocation and D-lactic acidosis. In one study looking at stool samples from adults with SBS and jejuno-colic anastomoses, fat and protein absorption were significantly reduced at approximately 40% of intake in those with presumed overgrowth [16]. Additionally, increased carbohydrate breakdown by bacteria can lead to excess carbon dioxide, hydrogen and methane production causing bloating,
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distension and pain. D-lactic acidosis occurs in some patients when non-absorbed carbohydrates are delivered to intestinal bacteria that make lactic acid as a by-product. Normally the L isomer of lactic acid produced by most human bacteria is absorbed and metabolized by the liver, but some bacteria produce both D and L isomers or only D
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isomers which are difficult to metabolize in some people, resulting in toxic levels of the isomer [15].
The goals of treatment for confirmed or presumed SIBO are not to achieve
intestinal sterilization but to reduce the number of pathogenic bacteria and restore
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commensal bacteria. This is usually done with a 7-14 day course of antibiotics that aims to target anaerobes and aerobes, with an improvement in symptoms expected in 1-2 weeks. Metronidazole is standard fist line therapy, other options include
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Amoxicillin/clavulonic which is bactericidal, and has prokinetic properties and rifaximin (non-absorbable analog of rifampin) which is bacteriostatic [19]. However, the efficacy
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of antibiotics is largely unknown and they may have unpredictable long-term effects. When our group looked at the microbiota in children with SBS and symptoms of
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bacterial overgrowth both before and after antibiotic therapy, we found that there was
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actually a decrease in the abundance of beneficial anti-inflammatory Clostridia and an increase in inflammatory Proteobacteria after completing a week of antibiotics [20]. It is
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possible that combining antibiotic therapy with a probiotic or prebiotic might allow for a more durable reconstitution of the commensal microbiota, however more research in this area is needed. Alternatively, the institution of a low FODMAP diet (fermentable, oligosaccharides, disaccharides, monosaccharides and polyols) has been advocated by some to treat SIBO in other patient populations such as those with irritable bowel
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syndrome, because it minimizes short-chain carbohydrates that are poorly absorbed by the small bowel and are metabolized by intestinal bacteria resulting in excess gas production. However there has been little research looking at its use in short bowel syndrome. One of the potential downsides of such a restrictive diet is that many of these
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children struggle to ingest sufficient calories enterally even with a fairly liberal diet. This approach to treatment deserves further study. Ultimately management of SIBO should focus on correcting the underlying cause, addressing nutritional deficiencies and trying
tailored for individual patients.
Dysbiosis and Hepatic Cholestasis
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to restore a healthy microbiota. Treatment in the setting of SBS likely needs to be
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Over half of infants and children with SBS develop hepatic cholestasis at some point during intestinal adaptation. The etiology is felt to be multifactorial with factors
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such as prematurity, prolonged PN exposure, intravenous lipid emulsions and episodes of sepsis all believed to contribute to inflammation and cholestasis in the liver.
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Interestingly, small bowel resection has been shown to be an independent risk factor for
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the development of liver disease in children and adults with intestinal failure [21]. Changes to the intestinal microbiota seen in SBS can also result in increased
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inflammation in the gut and potentially the liver. The link between the intestinal microbiota and cholestasis has not been completely elucidated, but compelling evidence is accumulating. In a study by Korpela et al. the composition of the intestinal microbiota in patients with SBS was associated with liver steatosis and was a better predictor of the degree of steatosis than ether the duration of PN support required or the
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length of the remaining intestine. They found three predominant microbiota signatures. Patients with prolonged PN support had an increased abundance of Proteobacteria (known to be pro-inflammatory) and tended to have the most severe liver injury. Those with the least amount of small bowel had an overabundance of Lactobacillus and
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reduced microbial richness, and those with a high abundance of Clostridium cluster XIVa (known to be anti-inflammatory) were the least severe cases of intestinal failure. However, many of these patients (56%) were also receiving antibiotics during sample collection and therefore it is somewhat difficult to interpret these results [22].
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In addition to intestinal inflammation, one of the problems associated with gut microbial dysbiosis is an alteration in bile acid (BA) metabolism, which is also a known risk factor for hepatic cholestasis. Bile acids are important for the solubilization of
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cholesterol, lipids and vitamins in the intestine, and bile acid dysmetabolism is associated with fat malabsorption, diarrhea, inflammation and liver injury [23]. Primary
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BAs are synthesized from cholesterol in the liver and then conjugated with either glycine or taurine. The bacteria in the large intestine deconjugate the bile acids, converting
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them into secondary and tertiary bile acids where they diffuse passively through the
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intestinal epithelium and are transported back to the liver [24]. After small intestinal resection there is a switch to a dominance of primary BAs, likely secondary to changes
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in the intestinal bacteria [25]. This can result in hepatic cholestasis because BAs also have metabolic functions in the body through nuclear receptors, one of which is the farsenoid X receptor (FXR). FXR is activated by BAs and is a key regulatory step in their synthesis, inducing target genes within the liver and small intestine. Bacterial dysbiosis has been strongly linked to perturbations in FXR signaling and subsequently
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hepatic cholestasis. Pereira-Fantini et al. reported a novel piglet model of SBS associated liver disease that is independent of PN. Using this model they were able to demonstrate a decrease in the abundance of bacteria that are able to deconjugate primary BAs including both Clostridium and Bacteroides. This resulted in an increase in
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primary BAs returning to the liver and abnormal FXR signaling within the intestine and liver in those animals that developed cholestasis [23]. Another study by Jain et al.
looked at the utility of giving enteral BAs in piglets receiving PN to prevent dysbiosis associated cholestasis. Oleanolic acid (OA), an agonist to a bile acid receptor located
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in the small bowel crypts, was given to a strictly PN fed cohort to see if this improved cholestasis. Significant clonal proliferation of Bacteroidetes, specifically the Porphyromonadaceae family, was noted in animals receiving parenteral compared to
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enteral nutrition and this was prevented by giving OA. Animals receiving PN and OA also had a more diverse microbial population compared to those getting PN alone.
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There was an elevation in serum bilirubin level in animals treated with PN and this decreased in those animals getting OA [26]. Although there does appear to be a direct
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link between the gut microbiota, bile acid metabolism and hepatic cholestasis, there
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may be variability in the changes to the microbiota depending on the patient’s anatomy and diet (enteral vs. parenteral). This gut-liver communication via bacteria and bile acids
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does however suggest a potential for additional therapeutic interventions.
The Role of Bacteria in Energy Harvest and Metabolism Growth failure is seen in many chronic pediatric illnesses due to a variety of contributing factors. For babies and children with SBS, difficulties with growth are most
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commonly related to increased nutritional needs from malabsorption, metabolic alterations and inflammation. Growth failure before two years of age has been linked to problems with both physical and cognitive development later in life [27] and children with SBS continue to be at high risk [28], making this an important issue to address in
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the long term care of these patients. Although traditionally the focus has been on macro and micronutrient provision as the main intervention, there is mounting evidence that the intestinal microbiota plays an important role in both metabolism and how efficiently the gut is able to harvest energy from enteral nutrition. Interestingly, in 1978 a study
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was published suggesting an association between commensal bacteria and
metabolism. In this study germ free rats were noted to have a fasting metabolic rate approximately 20% lower than conventional rats. The same group found that in the
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setting of starvation, germ-free rats died significantly faster than conventional rats who survived over a week longer, despite a similar rate of weight loss [29]. Almost 40 years
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later consistent findings have been reported where germ free mice are both shorter and gain less weight compared to wild type litter mates fed a common diet [30]. Similarly, in
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a recent study, germ free mice who received a fecal transplant from healthy babies
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gained more lean body mass and overall weight than mice transplanted from undernourished babies [31] even though both groups of mice were receiving the same
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enteral diet. These findings are felt to be due primarily to microbial fermentation of polysaccharides that cannot otherwise be digested by the host, and microbial regulation of host genes that promote lipid storage [32]. In fact, there is data to suggest that obesity may be associated with a distinct intestinal microbiota signature with a lower proportion of Bacteroidetes and a higher proportion of Firmicutes [33].
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With this in mind, it is important to consider how the microbial composition could potentially be optimized to promote healthy growth and metabolism in the setting of SBS. The main functions of the intestinal bacteria include the fermentation of dietary fibers, vitamin K and short chain fatty acid (SCFA) production, and absorption of
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calcium, magnesium and iron[5]. SCFAs are monocarboxylic hydrocarbons produced from non-absorbed carbohydrates and include acetate, propionate and butyrate.
Although all three types are easily absorbed by intestinal epithelial cells, butyrate is preferentially oxidized accounting for 80% of energy used by the colon [34]. SCFAs
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have a trophic effect on the intestinal epithelium, stimulating cell proliferation and differentiation in both the small and large bowel. Certain bacteria, particularly
Firmicutes from the class Clostridia, are known producers of SCFAs and have anti-
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inflammatory properties. These anti-inflammatory Clostridia lack toxins and virulence factors and have been shown to increase colonic SCFA levels in mice [6, 7]. As
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previously noted, several studies have found a decrease in in the abundance of antiinflammatory Clostridia in SBS. When our group profiled the gut microbiota in a series
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of children with SBS, we found that compared to healthy children there was a deficiency
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in anaerobic Firmicutes including several species thought to play a beneficial role in gut health. In addition, a subset with poor growth had a deficiency of six species of bacteria
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compared to children with SBS who were growing well, five of which were from the phylum Firmicutes [20]. All of this suggest that the proportion of Firmicutes and potentially the SCFA levels in the gut may prove to be important in the evaluation of a child with SBS who is not growing well.
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Treatment strategies to target the microbiota Although the implications of disturbances to the commensal intestinal microbiota after major intestinal resection are becoming well recognized, there is no consensus regarding the ultimate treatment strategy. Options for restoring balance to the bacteria
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in the gut include treatment with antibiotics to reduce the abundance of pro-
inflammatory pathogens, supplementing the diet with either probiotics, prebiotics or a combined synbiotic, or a more broad approach at repopulating the gut microbiota with fecal microbial transplant. As previously discussed, antibiotics in isolation are likely not
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an effective strategy although there may be a role for short term gut decontamination followed by probiotics. Probiotics are live organisms that provide a health benefit to the host and can be used to repopulate the gut by competing with pathogens for nutrients
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and mucosal adherence. Commonly available probiotics include Lactobacillus, Bifidobacterium and the yeast Saccharomyces (Table 1). Clinical studies have
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demonstrated that Lactobacillus rhamnosus shortens the duration of diarrhea secondary to rotavirus in infants by modifying the immune system [35]. Additionally, in animal
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models of SBS Lactobacillus stimulated intestinal growth and decreased bacterial Lactobacillus and
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translocation in both peripheral and portal blood [36, 37].
Bifidobacterium have also been safely used in very low birth weight infants to prevent
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necrotizing enterocolitis and shorten the duration of PN support [38, 39]. Lactobacillus is primarily thought to exert its effect by fermenting carbohydrates into lactic acid which then inhibits growth of certain pathogenic bacteria and provides substrate for other SCFA-producing commensal bacteria [40]. In a study where newborn piglets received Enterococcus faecium, from the order Lactobacillales, there was increased body weight
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and higher levels of Lactobacillales in the stool compared to those not receiving the probiotic [41]. All of these studies provide evidence that probiotics could potentially be very useful for children with SBS, however there remain few commercially available products to choose from and the efficacy in children with poor intestinal absorption and
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rapid transit is unknown.
Another potentially helpful treatment to consider is prebiotics. Prebiotics are nondigestible food ingredients that beneficially affect the host by stimulating growth or activity of certain bacteria. Examples include oligosaccharides and fructo-
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oligosaccharides (Table 2). Interestingly, breast fed babies already receive
considerable probiotics from breast milk. Human breast milk contains over 200 types of oligosaccharides (human milk oligosaccharides or HMOs) making them the third most
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plentiful ingredient in the milk after lactose and fats. Babies themselves cannot digest the HMOs and they therefore serve as nutrition for the intestinal bacteria. They pass
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through the stomach and small intestine into the colon where Bifidiobacterium, specifically Bifidiobacterium longum and infantis, break them down. As they use the
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HMOs they create SCFAs and other anti-inflammatory molecules including sialic acid
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which is needed for brain development in the first year of life [42]. The two main types of commercially available prebiotics are inulin-type fructans and galacto-oligosaccharides
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both of which are fermented into SCFAs and lactate by Lactobacillus and Bifidobacterium, and ultimately decrease the abundance of pathogenic bacteria [43] (Table 2). This type of synbiotic relationship between bacteria and host could potentially be very useful in SBS. It is generally felt that by combining probiotics and prebiotics (as a synbiotic), the gut can be repopulated with both the beneficial bacteria and the food
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they need to thrive and outcompete more pathogenic bacteria. In fact, there is evidence to suggest that this strategy can improve intestinal adaptation after significant resection. In a piglet model of SBS where 80% of proximal small bowel was resected, treatment groups who received either a prebiotic or a combined prebiotic and probiotic had
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increased jejunal and ileal mass as well as increased ileal villus height after one week of therapy compared to both the probiotic alone and control groups[44]. Additionally, in a study where patients with SBS received both Bifidiobacterium and Lactobacillus along with galactooligosaccharides, fecal SCFA levels increased and growth improved [45].
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Further trials with synbiotics would be helpful to determine the best combination and dosage for children with short bowel syndrome.
A final therapeutic consideration is fecal microbial transplant (FMT). FMT is a
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process in which healthy gut bacteria from a screened donor is directly infused into the diseased gut. Currently this is used primarily for adult patients with recurrent
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Clostridium difficile infections as an alternative to antibiotics. The success rate of FMT in the treatment of recurrent C.difficile is about 90% [46]. FMT has also been used for
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children with refractory ulcerative colitis where dysbiosis of the gut microbiota is known
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to play an important role with a link to deficiencies in Lactobacillus and Fecalibacterium. In a recent study, 12 children with ulcerative colitis were randomized to receive FMT or
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placebo transplant with their own stool. The study found that FMT was safe and was associated with an improvement in symptoms in most patients. None of the transplanted patients required an escalation in therapy, compared to 70% of the placebo group [47]. There is also evidence in adults that FMT results in an increase in microbial diversity and is associated with clinical remission from ulcerative colitis [48].
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Currently fecal microbial transplant has not been well studied in SBS, however similar to patients with inflammatory bowel disease there are known perturbations to the commensal bacterial and therefore there may be benefits to this approach.
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References 1. Khanna S: Microbiota Replacement Therapies: Innovation in Gastrointestinal Care. Clinical pharmacology and therapeutics 2018, 103(1):102-111. 2. Spor A, Koren O, Ley R: Unravelling the effects of the environment and host genotype on the gut microbiome. Nature reviews Microbiology 2011, 9(4):279290. 3. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO: Development of the human infant intestinal microbiota. PLoS Biol 2007, 5(7):e177. 4. Ringel-Kulka T, Cheng J, Ringel Y, Salojarvi J, Carroll I, Palva A, de Vos WM, Satokari R: Intestinal microbiota in healthy u.s. Young children and adults-a high throughput microarray analysis. PLoS One 2013, 8(5):e64315. 5. Guarner F, Malagelada JR: Gut flora in health and disease. Lancet 2003, 361(9356):512-519. 6. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K et al: Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013, 500(7461):232-236. 7. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y et al: Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011, 331(6015):337-341. 8. Carlisle EM, Morowitz MJ: The intestinal microbiome and necrotizing enterocolitis. Curr Opin Pediatr 2013, 25(3):382-387. 9. Lapthorne S, Pereira-Fantini PM, Fouhy F, Wilson G, Thomas SL, Dellios NL, Scurr M, O'Sullivan O, Ross RP, Stanton C et al: Gut microbial diversity is reduced and is associated with colonic inflammation in a piglet model of short bowel syndrome. Gut Microbes 2013, 4(3):212-221. 10. Engstrand Lilja H, Wefer H, Nystrom N, Finkel Y, Engstrand L: Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome. Microbiome 2015, 3:18. 11. Joly F, Mayeur C, Bruneau A, Noordine ML, Meylheuc T, Langella P, Messing B, Duee PH, Cherbuy C, Thomas M: Drastic changes in fecal and mucosaassociated microbiota in adult patients with short bowel syndrome. Biochimie 2010, 92(7):753-761. 12. Korpela K, Mutanen A, Salonen A, Savilahti E, de Vos WM, Pakarinen MP: Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric-Onset Intestinal Failure. JPEN J Parenter Enteral Nutr 2015.
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18.
19. 20.
21.
22.
CR IP T
AC
23.
AN US
17.
M
16.
ED
15.
PT
14.
Khoshini R, Dai SC, Lezcano S, Pimentel M: A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Digestive diseases and sciences 2008, 53(6):1443-1454. Sachdev AH, Pimentel M: Gastrointestinal bacterial overgrowth: pathogenesis and clinical significance. Therapeutic advances in chronic disease 2013, 4(5):223-231. Dibaise JK, Young RJ, Vanderhoof JA: Enteric microbial flora, bacterial overgrowth, and short-bowel syndrome. Clin Gastroenterol Hepatol 2006, 4(1):11-20. Mayeur C, Gratadoux JJ, Bridonneau C, Chegdani F, Larroque B, Kapel N, Corcos O, Thomas M, Joly F: Faecal D/L lactate ratio is a metabolic signature of microbiota imbalance in patients with short bowel syndrome. PLoS One 2013, 8(1):e54335. Roland BC, Ciarleglio MM, Clarke JO, Semler JR, Tomakin E, Mullin GE, Pasricha PJ: Low ileocecal valve pressure is significantly associated with small intestinal bacterial overgrowth (SIBO). Digestive diseases and sciences 2014, 59(6):1269-1277. Gutierrez IM, Kang KH, Calvert CE, Johnson VM, Zurakowski D, Kamin D, Jaksic T, Duggan C: Risk factors for small bowel bacterial overgrowth and diagnostic yield of duodenal aspirates in children with intestinal failure: a retrospective review. J Pediatr Surg 2012, 47(6):1150-1154. Bohm M, Siwiec RM, Wo JM: Diagnosis and management of small intestinal bacterial overgrowth. Nutr Clin Pract 2013, 28(3):289-299. Piper HG, Fan D, Coughlin LA, Ho EX, McDaniel MM, Channabasappa N, Kim J, Kim M, Zhan X, Xie Y et al: Severe Gut Microbiota Dysbiosis Is Associated With Poor Growth in Patients With Short Bowel Syndrome. JPEN J Parenter Enteral Nutr 2016. Pichler J, Horn V, Macdonald S, Hill S: Intestinal failure-associated liver disease in hospitalised children. Archives of disease in childhood 2012, 97(3):211-214. Korpela K, Mutanen A, Salonen A, Savilahti E, de Vos WM, Pakarinen MP: Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric-Onset Intestinal Failure. JPEN J Parenter Enteral Nutr 2017, 41(2):238-248. Pereira-Fantini PM, Lapthorne S, Joyce SA, Dellios NL, Wilson G, Fouhy F, Thomas SL, Scurr M, Hill C, Gahan CG et al: Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndromeassociated liver disease. Journal of hepatology 2014, 61(5):1115-1125. Yang H, Duan Z: Bile Acids and the Potential Role in Primary Biliary Cirrhosis. Digestion 2016, 94(3):145-153. Ohkohchi N, Andoh T, Izumi U, Igarashi Y, Ohi R: Disorder of bile acid metabolism in children with short bowel syndrome. Journal of gastroenterology 1997, 32(4):472-479. Jain AK, Sharma A, Arora S, Blomenkamp K, Jun IC, Luong R, Westrich DJ, Mittal A, Buchanan PM, Guzman MA et al: Preserved Gut Microbial Diversity Accompanies Upregulation of TGR5 and Hepatobiliary Transporters in Bile
CE
13.
24. 25.
26.
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32.
33. 34.
35.
36.
37.
CR IP T
AC
38.
AN US
31.
M
30.
ED
29.
PT
28.
CE
27.
Acid-Treated Animals Receiving Parenteral Nutrition. JPEN J Parenter Enteral Nutr 2017, 41(2):198-207. Kyle UG, Shekerdemian LS, Coss-Bu JA: Growth failure and nutrition considerations in chronic childhood wasting diseases. Nutr Clin Pract 2015, 30(2):227-238. McLaughlin CM, Channabasappa N, Pace J, Nguyen H, Piper HG: Growth Trajectory in Children With Short Bowel Syndrome During the First 2 Years of Life. J Pediatr Gastroenterol Nutr 2018, 66(3):484-488. Levenson SM: The influence of the indigenous microflora on mammalian metabolism and nutrition. JPEN J Parenter Enteral Nutr 1978, 2(2):78-107. Schwarzer M, Makki K, Storelli G, Machuca-Gayet I, Srutkova D, Hermanova P, Martino ME, Balmand S, Hudcovic T, Heddi A et al: Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science 2016, 351(6275):854-857. Blanton LV, Charbonneau MR, Salih T, Barratt MJ, Venkatesh S, Ilkaveya O, Subramanian S, Manary MJ, Trehan I, Jorgensen JM et al: Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science 2016, 351(6275). Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006, 444(7122):1027-1031. Ley RE, Turnbaugh PJ, Klein S, Gordon JI: Microbial ecology: human gut microbes associated with obesity. Nature 2006, 444(7122):1022-1023. Kles KA, Chang EB: Short-chain fatty acids impact on intestinal adaptation, inflammation, carcinoma, and failure. Gastroenterology 2006, 130(2 Suppl 1):S100-105. Salminen MK, Tynkkynen S, Rautelin H, Saxelin M, Vaara M, Ruutu P, Sarna S, Valtonen V, Jarvinen A: Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis 2002, 35(10):1155-1160. Mogilner JG, Srugo I, Lurie M, Shaoul R, Coran AG, Shiloni E, Sukhotnik I: Effect of probiotics on intestinal regrowth and bacterial translocation after massive small bowel resection in a rat. J Pediatr Surg 2007, 42(8):1365-1371. Tolga Muftuoglu MA, Civak T, Cetin S, Civak L, Gungor O, Saglam A: Effects of probiotics on experimental short-bowel syndrome. Am J Surg 2011, 202(4):461-468. Saengtawesin V, Tangpolkaiwalsak R, Kanjanapattankul W: Effect of oral probiotics supplementation in the prevention of necrotizing enterocolitis among very low birth weight preterm infants. J Med Assoc Thai 2014, 97 Suppl 6:S20-25. Rouge C, Piloquet H, Butel MJ, Berger B, Rochat F, Ferraris L, Des Robert C, Legrand A, de la Cochetiere MF, N'Guyen JM et al: Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, doubleblind, placebo-controlled trial. Am J Clin Nutr 2009, 89(6):1828-1835.
39.
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44.
45.
46.
47.
PT
ED
48.
CR IP T
42. 43.
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41.
Antonissen G, Eeckhaut V, Van Driessche K, Onrust L, Haesebrouck F, Ducatelle R, Moore RJ, Van Immerseel F: Microbial shifts associated with necrotic enteritis. Avian Pathol 2016, 45(3):308-312. Wang YB, Du W, Fu AK, Zhang XP, Huang Y, Lee KH, Yu K, Li WF, Li YL: Intestinal microbiota and oral administration of Enterococcus faecium associated with the growth performance of new-born piglets. Benef Microbes 2016:1-10. Yong E: Breast-feeding the microbiome. The New Yorker 2016:1-15. Viladomiu M, Hontecillas R, Yuan L, Lu P, Bassaganya-Riera J: Nutritional protective mechanisms against gut inflammation. J Nutr Biochem 2013, 24(6):929-939. Barnes JL, Hartmann B, Holst JJ, Tappenden KA: Intestinal adaptation is stimulated by partial enteral nutrition supplemented with the prebiotic short-chain fructooligosaccharide in a neonatal intestinal failure piglet model. JPEN J Parenter Enteral Nutr 2012, 36(5):524-537. Kanamori Y, Sugiyama M, Hashizume K, Yuki N, Morotomi M, Tanaka R: Experience of long-term synbiotic therapy in seven short bowel patients with refractory enterocolitis. J Pediatr Surg 2004, 39(11):1686-1692. Gough E, Shaikh H, Manges AR: Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011, 53(10):994-1002. Michail S: Fecal Microbial Transplant In Children With Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study. J Pediatr Gastroenterol Nutr 2017. Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, Leong RWL, Connor S, Ng W, Paramsothy R et al: Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017, 389(10075):1218-1228.
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Relative Abundance of the Major Bacterial Phyla in Adults and Children
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(b)
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Figure 1 Typical relative abundance of the major bacterial phyla in the GI tract of adults (a) and children (b). Firmicutes dominate in both groups whereas children have expansion of Actinobacteria and Proteobacteria. Table 1. Examples of commonly used probiotics for children Name Culturelle
Composition Lactobacillus rhamnosus
Ultimate Flora
Bifidobacterium bifidum Bifidobacterium infantis Bifidobacterium breve Bifidobacterium longum
Proposed Benefit Used for antibiotic associated diarrhea Supports gut immune health, used to treat diarrhea
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Lactobacillus acidophilus Lactobacillus fermentum Lactobacillus rhamnosus Lactobacillus salvarius Lactobacillus casei
Mutaflor
Escherichia coli Nissle
Florastor
Saccharomyces Boulardii
Has been used to treat diarrhea, constipation and eczema, and for the prevention of necrotizing enterocolitis in very low birth weight babies Has been used to treat pouchitis in inflammatory bowel disease and pseudomembranous colitis Used for antibiotic associated diarrhea and chronic diarrhea in children
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Bifidobacterium breve Bifidobacterium bifidum Bifidobacterium infantis Bifidobacterium longum Lactobacillus rhamnosus
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FloraBABY
Table 2. Examples of prebiotics for children
Composition Naturally occurring polysaccharide (fructose polymer), storage carbohydrate found in many plants Produced by degrading inulin or polyfructose, found in blue Agave and Jerusaleum artichokes Chain of galactose units with a terminal glucose unit
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Fructo-oligosaccharide (FOS)
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Name Inulin
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Galacto-oligosaccharide (GOS)
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Human milk oligosaccharide (HMO)
Family of unconjugated glycans found in human breast milk
Proposed Benefit May be used for acute diarrheal illness, stimulates growth of Bifidobacterium
Promotes calcium absorption, stimulates growth of Bifidobacterium Stimulates growth of Bifidobacterium and Lactobacillus Stimulates growth of Bifidobacterium longum and acts as anti-adhesive to prevent attachment of pathogenic bacteria to mucosal surfaces