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Correspondence Address correspondence to: Arthur J. Kastl Jr, MD, Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, 3401 Civic Center Boulevard, 7NW, Philadelphia, Pennsylvania 19104. fax: (215) 590-3606.
Despite growing literature characterizing the fecal microbiome and its association with health and disease, few studies have analyzed the microbiome of the small intestine. Here, we examine what is known about the human small intestinal microbiota in terms of community structure and functional properties. We examine temporal dynamics of select bacterial populations in the small intestine, and the effects of dietary carbohydrates and fats on shaping these populations. We then evaluate dysbiosis in the small intestine in several human disease models, including small intestinal bacterial overgrowth, short-bowel syndrome, pouchitis, environmental enteric dysfunction, and irritable bowel syndrome. What is clear is that the bacterial biology, and mechanisms of bacteria-induced pathophysiology, are enormously broad and elegant in the small intestine. Studying the small intestinal microbiota is challenged by rapidly fluctuating environmental conditions in these intestinal segments, as well as the complexity of sample collection and bioinformatic analysis. Because the functionality of the digestive tract is determined primarily by the small intestine, efforts must be made to better characterize this unique and important microbial ecosystem.
There is limited information about the small intestinal microbiota, an ecosystem that is relevant to many physiologic mechanisms and pathologic states. Here, we highlight human and animal studies to advance understanding of microbe-influenced human conditions, and the fundamental distinctions of this population relative to the large intestine.
The communities of microorganisms in the human digestive tract are a complex ecosystem that is both essential for health and also a potential driver of a variety of pathologies. The adult human intestine is colonized by more than 1000 microbial species encompassing all domains of life: archaea, bacteria, and eukarya. The large intestine harbors approximately 1010–1011 colony-forming units (CFU)/mL, the composition and dynamics of which have been described previously.
The properties of the microbiota in the human small intestine are less well characterized, primarily because of challenges in sampling this segment of the digestive tract.
Studying the small intestine ecosystem is principally relevant to digestive health, because the duodenum and jejunum are tasked with facilitating the majority of nutrient assimilation and absorption.
In addition, there is significant contact between food substrate and commensal bacteria in the small intestine, creating an environment rich in microbe–microbe and host–microbe interactions.
Studying these concepts is challenged by rapidly fluctuating environmental conditions in these intestinal segments, as well as the complexity of sample collection and bioinformatic analysis.
Here, we examine what is known about the human small intestinal microbiota in terms of community structure and functional properties, methodologic challenges, and the roles of this community in select human pathologic conditions.
Methodologic Challenges in Studying the Small Intestinal Microbiota
A distinguishing feature of the small intestine compared with the colon is its relative inaccessibility, which poses challenges to sampling and experimental design. Although fecal samples most commonly are collected in studies of the gut microbiota, stool more accurately represents the distal portions of the gut,
leaving the small intestinal microbiota communities hidden from view. Studies of the human small intestinal microbiota have involved invasive sampling procedures including esophagoduodenogastroscopy and nasoduodenal catheters, while other studies have sampled ileal mucosa obtained during colonoscopy, intestinal resection, small-bowel transplantation, or from sudden death victims.
Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum.
Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
These methodologies are subject to contamination from the oropharyngeal cavity or colon, and also limit the ability to study microbial dynamics as a function of time or environmental change (eg, diet). Some studies have enrolled participants with ileostomies, which affords longitudinal effluent sampling directly from the small intestine.
Although this may be methodologically advantageous, it is important to recognize that ostomy samples are exposed to the skin and external environment, which may impact the microbial community.
An additional methodologic challenge of microbiome investigations is moving beyond correlations and associations, toward better pinpointing microbe–phenotype relationships and causality.
Thus, animal models of germ-free (GF), gnotobiotic, and conventionalized mice continue to be valuable for mechanistic exploration, although major differences to human beings in terms of intestinal size, metabolic rate, dietary habits, and spatiotemporal microbial structures need to be considered carefully when extrapolating data.
The term dysbiosis is used pervasively in microbiota literature to refer to microbial imbalance, and serves as a broad communication tool without clear establishment of cause and effect.
The challenge moving forward is to establish when and how dysbiosis contributes to a disease state as opposed to its presence alone.
The Diversity and Temporal Dynamics of the Small Intestinal Microbiota
The small intestine is a harsh environment for microbial life owing to short transit time, the influx of digestive enzymes and bile, and intermittent food substrate delivery. As a result, the bacterial populations in this region of the intestinal tract have a lower biomass, are less diverse, but are more dynamic, given the need to respond to rapidly changing luminal conditions. Generally speaking, bacterial populations increase from approximately 104–5 CFU/mL in the duodenum to 107–8 CFU/mL in the distal ileum, where transit slows (Figure 1).
Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
In addition, the proportion of gram-positive to gram-negative, as well as facultative anaerobic and strict anaerobic, species increases from proximal to distal segments of the small intestine and colon.
Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
Bacterial genera commonly found in the small intestine include Lactobacillus, Clostridium, Staphylococcus, Streptococcus, and Bacteroides, among others,
Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
owing to differences in sample collection and analytic methodologies (Figure 2).
Figure 1Overview of bacterial colony density throughout the digestive tract, factors from the proximal tract that shape small intestinal communities, and distinguishing characteristics of the small intestine and colon.
Figure 2Commonly found bacteria genera in the small intestine and a brief overview of community properties. A specific metabolic interaction between Streptococcus, Veillonella, and Clostridiales is highlighted to show an example of host–microbe and bacterial interactions.
A major concept that has been shown across studies is that the small intestinal microbiota is phylogenetically less diverse than the colon, but more dynamic. Booijink et al
highlighted this concept in their study of 7 patients with inflammatory bowel disease (IBD), all of whom had ileostomies. There, the ileal effluent had a higher relative abundance of species within the orders Lactobacillales and Clostridiales, mainly Streptococcus bovis–related species, and the Veillonella group.
There were significant interindividual differences, and intraindividual temporal fluxes, between morning and afternoon profiles over a period of 9–28 days,
A separate study looking specifically at Streptococcus and Veillonella species from ileostomies highlighted that there is incredible strain-level richness in the small intestine.
There, 16S ribosomal RNA gene sequencing showed a total of 160 Streptococcus and 37 Veillonella isolates, with temporal variance in 7 predominant isolates within a 72-hour time frame. The theme of temporal variation in the small intestinal microbiota is a stark contrast to the relatively stable composition in the colon,
and dietary influences may drive some of these findings.
Dietary Influences on Community Structures and Functions
Carbohydrates and the Small Intestinal Microbiota
A major contributor to the luminal environment is the host diet, and studies have examined the effects of isolated macronutrients on the structure of small intestinal microbial communities and resulting metabolic profiles. Carbohydrate fermentation is a core function of the gut microbiota. Zoetendal et al
collected ileostomy effluent samples to show that the small intestinal metagenome, compared with the fecal metagenome, is significantly more enriched with genes related to carbohydrate metabolism. Processes such as sugar phosphotransferase systems, the pentose phosphate pathway, lactate and propionate fermentation, as well as cofactors such as cobalamin and biotin, were encoded across many taxa from ileal effluent, and in particular Streptococcus, arguing that carbohydrate metabolism is a central function of the collective small intestinal microbiota.
Metatranscriptomic analysis showed that the earlier-mentioned metabolic processes are highly active, and that the small intestinal microbiota adapt rapidly to fluctuating nutrient availability in the lumen, rapidly metabolizing simple carbohydrates for community maintenance.
Streptococci are enriched with genes for energy generation, and are suggested to make a considerable contribution to primary digestion of food components in the small bowel,
with fermentation products that support the growth of secondary fermenters (eg, Veillonella, Clostridium) (Figure 2). Indeed, cohabitation of Streptococcus and Veillonella occurs not only in the intestine, but also in the stomach, esophagus, throat, and oral cavity,
positing that the microbiota modulates lipid digestive physiology. Furthermore, the small intestinal microbiota differ when comparing mice on low-fat and high-fat (HF) diets.
A HF diet induces an abundance of Clostridia, while decreasing Bifidobacteria and Bacteroides, creating a microbial genetic profile with an enhanced capacity for inducing genes involved in small intestine epithelial lipid transport and pancreatic cholecystokinin signaling.
We know from fecal-based human studies that diet can alter the colonic microbiota and metabolites within 48 hours, as well as lead to long-term reductions in diversity and taxonomic changes such as increases in Firmicutes and Proteobacteria.
Future investigations should consider the small intestinal microbiota’s response to factors such as fat saturation status and varying fatty acid composition, and dietary intervention studies are needed.
Of particular relevance to studying microbial–fat digestion interplay is the influence of bile acids (BAs) both on digestive physiology and community structure (Table 1). Primary BAs are synthesized in the liver, secreted into the small intestine, and are central to emulsification and absorption of dietary lipids and fat-soluble vitamins.
and exert wide-ranging physiologic effects through activation of the nuclear hormone receptor farnesoid X receptor (FXR) and the G-protein–coupled receptor Takeda G-protein coupled Receptor 5.
Suppression of bile acid synthesis via obeticholic acid (a semisynthetic primary bile acid and activator of FXR) causes induction of small intestinal gram-positive bacteria in human fecal samples.
As part of the enterohepatic circulation, primary BAs are conjugated to glycine or taurine, and are reabsorbed in the distal ileum. Bacteria in the ileum express bile salt hydrolases, which induce deconjugation of primary BAs, and subsequent conversion to secondary BAs through bacteria-mediated 7-α-dihydroxylation.
which antagonizes intestinal FXR. Tempol is an antioxidant that preferentially reduces Lactobacillus and its bile salt hydrolases, causing accumulation of tauro-β-muricholic acid, and subsequent FXR antagonism.
increased taurine-conjugated BAs, facilitated an abundance of sulfite-reducing Bilophila wadsworthia, which in turn was correlated with colitis in genetically susceptible interleukin 10 knockout mice.
Because sulfate-reducing organisms preferentially transport their nutrients from sites of inflammation, they have relevance in IBD and are found in abundance in mucosal biopsy specimens from patients with ileal Crohn’s disease.
Taken together, these studies are beginning to show that small intestinal microbial communities depend on the capacity to quickly metabolize temporarily available macronutrients, and the resulting metabolites are integrated into an enormously complex network of microbe–microbe and microbe–host interactions. Certainly, more mechanistic investigation is needed, and there are clues from human disease processes that can serve as models to help guide future research.
Table 1Small Intestinal Microbiota, Select Roles, and Physiologic Effects
Nutrient
Mechanism
Carbohydrate digestion
Degradation and fermentation of diet-derived simple carbohydrates into organic acids, aldehydes, alcohols, and gases Impaired brush-border disaccharidase activity Hydrogen sulfide and hydrogen gas contribute to intestinal motility regulation through effects on smooth muscle
Fat digestion and bile acid physiology
Bile acid deconjugation, decreased bile acid pool for fat solubilization lead to steatorrhea Bile acid (eg, lithocholic acid) may directly inhibit absorption, leading to steatorrhea Induce intestinal peristalsis and contractions mediated by Takeda G-protein coupled Receptor 5 on enteric neurons and enteroendocrine cells (deoxycholic acid) Secondary bile acid pools stimulate chloride and water secretion
Micronutrient stores
Vitamin K stores may be increased owing to bacterial synthesis Direct bacterial consumption for vitamin B12 and modification for use as own cofactor Anaerobe-induced inhibition of vitamin B12 absorption in terminal ileum Fat-soluble vitamin deficiency from deconjugated bile acids, decreased fat absorption
Micronutrients and the Small Intestinal Microbiota
Beyond their roles in the digestive physiology of dietary macronutrients, the small intestinal microbiota also contributes to synthesis and assimilation of several important micronutrients (Table 1). Proper fat absorption is crucial for maintaining fat-soluble vitamin stores, and all but vitamin K are absorbed via passive diffusion in the small intestine.
Although human vitamin K1 (phytomenadione) stores are derived primarily from dietary plant sources, the majority of vitamin K2 (menaquinone) is generated by intestinal bacterial biosynthesis.
Veillonella, Enterobacteriaceae, Bacteroides, and Prevotella all have been shown to synthesize this nutrient. Small intestinal bacterial overgrowth (SIBO), a condition discussed later in this review, is associated with impaired vitamin K metabolism in human beings.
Vitamin B12, whose digestive physiology is intimately linked to the small intestine, also is impacted by bacterial biology. Facultative gram-negative aerobes and anaerobes are capable of competitively using cobalamin as a cofactor for their own metabolic processes.
Indeed, in vitro models have shown that members of the genus Bacteroides outcompete intrinsic factor for binding to cobalamin, interfering with absorption in vivo.
Disease Models of Dysbiosis in the Small Intestine
Although SIBO has been investigated for decades, it remains diagnostically challenging owing to difficulty characterizing and analyzing the small intestinal microbiota. SIBO is often a consequence of gut stasis, and has been studied in the context of anatomic abnormalities in the small intestine including diverticulae,
When excessive fermentation occurs in the small intestine, metabolic byproducts contribute to bloating, nausea, abdominal pain, distention, and acidic stools. Rarely, encephalopathy from D-lactic acidosis
is a metabolic complication of SIBO that results from excessive fermentation by Lactobacilli species, Enterococci, and Streptococci, and, interestingly, has been described only in patients with short-bowel syndrome (SBS).
With bacterial overgrowth, however, steatorrhea and fat-soluble vitamin deficiency can result from premature bacterial deconjugation of primary bile salts.
At present, the most commonly used tests to diagnose SIBO in clinical practice are hydrogen and methane breath tests, and small-bowel aspirate for culture. Both of these modalities have significant diagnostic and practical limitations.
Through scavenging hydrogen produced by neighboring microbes, termed the sink effect, methanogenic bacteria allow increased polysaccharide fermentation by neighboring microbes.
This normal physiology predominates in the colon, but also can be altered in SIBO, leading to depleted methanogenic species, and subsequently positive hydrogen breath tests.
However, both sensitivity and specificity are variable, and, as a consequence, the symptomatic response of a trial of antibiotics often is substituted for objective testing in clinical practice. Despite the risk for contamination and its invasive nature, small-bowel aspiration for culture has the advantage of potentially identifying the organisms involved in SIBO, and the antimicrobial sensitivities thereof. A wide variety of oropharyngeal and colonic commensal bacteria have predominated duodenal and proximal jejunal cultures in patients with SIBO-induced diarrhea and malabsorption, including Streptococcus, Escherichia, Staphylococcus, Klebsiella, Proteus, Lactobacillus, Bacteroides, Clostridium, Veillonella, Fusobacterium, and Peptostreptococcus, among others,
meaning that SIBO, as a heterogeneous entity, is unlikely to be caused by a single bacterial strain. A deeper understanding of SIBO is needed to better understand the host–microbe relationships in the small intestine, and to develop improved diagnostic and treatment modalities.
Short-Bowel Syndrome
SBS occurs when a significant amount of small intestine is surgically removed, resulting in malabsorption that disrupts protein–energy, fluid, electrolyte, and micronutrient balances.
Patients with SBS have disrupted microbiota related not only to the anatomic change, but superimposed parenteral nutrition (PN), variable enteral intake, and potentially recurrent antibiotic exposure. Small studies analyzing fecal samples have shown that the diversity of the colonic bacteria is reduced, with a higher proportion of the proinflammatory Proteobacteria phylum.
Patients with SBS have a higher abundance of Lactobacillus in fecal samples, bacteria that are efficient fermenters, but also may induce encephalopathy and acidosis through D-lactate production.
However, the excess D-lactate production was not transferred, indicating that the host small intestine may be protective against this systemic acidosis.
In addition to disruption of the colonic bacteria in patients with SBS, small intestinal bacteria also is disrupted such that patients with SBS have a high incidence of SIBO as diagnosed by a glucose breath test
The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses.
Risk factors for small bowel bacterial overgrowth and diagnostic yield of duodenal aspirates in children with intestinal failure: a retrospective review.
where gas production can lead to severe abdominal distension, and in turn limit the ability to tolerate food. One study showed that 70% of children who had refractory bloating, diarrhea, or emesis had duodenal aspirates consistent with SIBO, with Escherichia coli, Klebsiella, Streptococcus viridans, and Enterococcus being the most common organisms.
Risk factors for small bowel bacterial overgrowth and diagnostic yield of duodenal aspirates in children with intestinal failure: a retrospective review.
Although PN can be life-saving in this population, children with SBS who need PN, particularly those with SIBO, have a high incidence of gram-negative and enteric bacteremia
The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses.
The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses.
Proteobacteria were associated with prolonged PN and hepatitis, and Lactobacilli were associated with advanced steatosis and fibrosis, mostly after weaning off PN.
This may suggest that steatosis begins during PN in response to, for example, proinflammatory lipopolysaccharide produced by Proteobacteria, and progresses after weaning off PN because Lactobacilli become dominant and affect lipid metabolism through altered BA signaling.
Ongoing insult may lead to the need for liver and/or intestinal transplantation, an important cause of significant morbidity and mortality in SBS patients.
Indeed, more investigation into the small bowel specifically is needed to develop improved diagnostics and therapeutic targets.
Pouchitis
The etiology of IBD is a complex interplay of factors including genetic susceptibility, interaction of mucosal immunity with environmental triggers, and the intestinal microbiota.
An alternative to an ileostomy for patients with IBD whose colon has been removed is an ileal pouch–anal anastomosis (IPAA), in which an ileal reservoir, or pouch, is surgically created and anastomosed to the anal canal. This surgery also may be indicated for patients with familial adenomatous polyposis (FAP), in whom a colectomy often is performed to remove innumerable precancerous or transformed polyps.
and frequently is treated with antibiotics. Interestingly, pouchitis occurs in approximately half of patients with IBD pouches, but seldom in FAP patients,
In patients with multiple-stage IPAA surgery, biopsy specimens upstream from the ileostomy at the time of stoma closure harbor predominantly facultative anaerobes (eg, Lactobacilli, Enterococci, and coliforms), a paucity of sulfate-reducing bacteria, and low levels of Clostridium perfringens.
After ileostomy closure, the bacterial biomass increases in the ileal pouch, and populations shift with decreased facultative anaerobes and increased obligate anaerobes, sulfate-reducing bacteria, and Clostridia species,
which is much more prominent in ulcerative colitis (UC) pouches compared with FAP. Mucosal adaptation occurs in maturing ileal pouches, and the presence of feces has been associated with colonic metaplasia and transformed mucin glycosylation.
arguing that fecal stasis may be a contributing factor in the metaplasia process. Sulfomucin provides a metabolic substrate for sulfate-reducing bacteria such as Bacteroides fragilis,
which promote colonization and expansion of these bacteria, and explains the high prevalence of sulfate-reducing bacteria in UC, compared with minimal or no colonization in FAP pouches.
What has yet to be well characterized are the microbiota differences between UC and FAP ileostomies, before IPAA occurs, which may help elucidate why metaplasia and pouchitis occur to a greater extent in UC patients.
Environmental Enteric Dysfunction
Childhood malnutrition is a global health challenge, and there are new insights about the roles of microbiota maturation and enteropathogen burden as perpetuators of malnutrition. Malnourished children have an impaired microbiota maturation index, and stool transplantation from malnourished children into GF mice transmit an impaired growth phenotype.
Adding routine antibiotic agents to nutritional interventions has been shown to decrease mortality in children with uncomplicated severe acute malnutrition,
providing additional evidence for the relevance of studying microbial-based interventions in this condition. Environmental enteric dysfunction (EED) is the intersection of dietary macronutrient insufficiency with small intestinal dysfunction and is a significant contributor to global malnutrition in children.
MAL-ED Network Age and sex normalization of intestinal permeability measures for the improved assessment of enteropathy in infancy and early childhood: results from the MAL-ED study.
Growth faltering in rural Gambian infants is associated with impaired small intestinal barrier function, leading to endotoxemia and systemic inflammation.
Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli.
Enteropathogens commonly isolated in fecal samples from stunted children, including Campylobacter species, Cryptosporidium, E coli pathotypes, and Giardia, normally reside in the small intestine
Although sampling the small intestinal microbiota in patients with EED has not been reported, there is evidence from mouse models that protein malnutrition predisposes the small intestine to persistent pathogen colonization and mucosal injury.
It already is known that malnutrition itself can significantly alter the microbiome in the duodenum, with a shift toward Bacteroidetes and Proteobacteria, and changes in bile acid and vitamin pools.
To recapitulate the small intestinal villus blunting and inflammation characteristic of EED, infection must co-occur with malnutrition. Several models of EED with dietary restrictions and concomitant enteric pathogen exposure have been detailed, including Giardia,
Enteroaggregative Escherichia coli (EAEC) impairs growth while malnutrition worsens EAEC infection: a novel murine model of the infection malnutrition cycle.
and allows pathogens to trigger an immune response that is ongoing, even after the pathogen is cleared. In the setting of protein malnutrition, even a small inoculum of Cryptosporidium triggered increases in chemokine ligand 5, interferon y, and B- and T-cell infiltration into the lamina propria, an effect that was not seen in fully fed mice.
Taken together, the evidence suggests that in EED, protein malnutrition provides a platform for disrupted resident microbiota and propagation of intestinal pathogen colonization and small intestine injury.
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a clinical diagnosis characterized by a change in stool characteristics and associated abdominal discomfort, and has long been speculated to be associated with changes in the gut microbiome.
Although the reported prevalence of SIBO in IBS is variable based on diagnostic modality, meta-analyses have shown that more than one third of IBS patients have SIBO.
and dietary interventions including low fermentable oligo-, di-, monosaccharides and polyols are beneficial in the treatment of IBS, providing further evidence for a microbial basis. Changes in the populations of Bifidobacteria,
GF mice colonized with the stool of patients with the diarrhea type of IBS showed faster intestinal transit, increased colonic permeability, and increased CD3+ T lymphocytes compared with mice colonized by stool from healthy controls.
In addition, microbially mediated effects on small and large intestinal secretion in IBS may be linked with BA metabolism through deconjugation in the small bowel.
Deoxycholic acid, a secondary BA, has been shown to induce intestinal peristalsis and contractions mediated by Takeda G-protein coupled Receptor 5 on enteric neurons and enteroendocrine cells,
contribute to intestinal motility regulation through their effects on smooth muscle. Given the heterogeneous nature of the disease with multiple putative mechanisms, it will be important moving forward to phenotype patients based on the underlying physiological alterations to develop targeted approaches.
Conclusions
Despite increasing literature characterizing the fecal microbiome and its association with health and disease, few studies have analyzed the microbiome of the small intestine. The immense surface area, an oxygenated environment, the presence of pancreatic and biliary secretions, rapid motility, antimicrobial peptides produced by Paneth cells, and the proximity to ingested nutrients all are factors that differentiate the small intestinal luminal environment from that of the colon, thus leading to a distinctly different composition. Because the functionality of the digestive tract is determined primarily by the small intestine, efforts must be made to characterize the small intestine microbiome, which is central to understanding normal human physiologic responses to diet and nutrient absorption, the development of the mucosal immune system, bile acid biology, and a vast range of pathologic conditions. The effectiveness of antibiotic treatment in diseases such as small intestinal bacterial overgrowth, EED, pouchitis, and IBS provide clear evidence that dysregulation of the small intestinal microbiota plays a fundamentally important role in disease pathogenesis. Technological advances, such as ingested smart capsules, indwelling catheters, as well as animal model systems are needed to gather small intestinal biospecimens, which would facilitate the characterization of small intestinal microbiota dynamics to diet and other perturbations. These samples then would be analyzed using the influx of advanced sequencing and deep metabolomics profiling technologies that have allowed a larger window into the elegant and enormously complex human gut ecosystem. The identification of specific genes and metabolites, their actions, and host targets will in turn allow for novel microbial-based interventions (eg, to promote effective dietary macronutrient and micronutrient processing), genetically modified strains as bacteriotherapy, targeted antibiotic therapy, and functional foods to modulate the small intestine bacteria for specific individual needs.
Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum.
Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses.
Risk factors for small bowel bacterial overgrowth and diagnostic yield of duodenal aspirates in children with intestinal failure: a retrospective review.
Age and sex normalization of intestinal permeability measures for the improved assessment of enteropathy in infancy and early childhood: results from the MAL-ED study.
Growth faltering in rural Gambian infants is associated with impaired small intestinal barrier function, leading to endotoxemia and systemic inflammation.
Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli.
Enteroaggregative Escherichia coli (EAEC) impairs growth while malnutrition worsens EAEC infection: a novel murine model of the infection malnutrition cycle.
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