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The Structure and Function of the Human Small Intestinal Microbiota: Current Understanding and Future Directions

  • Arthur J. Kastl Jr.
    Correspondence
    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.
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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  • Natalie A. Terry
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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  • Gary D Wu
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, The University of Pennsylvania, Philadelphia, Pennsylvania
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  • Lindsey G. Albenberg
    Affiliations
    Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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Open AccessPublished:July 22, 2019DOI:https://doi.org/10.1016/j.jcmgh.2019.07.006
      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.

      Keywords

      Abbreviations used in this paper:

      BA (bile acid), CFU (colony-forming units), EED (environmental enteric dysfunction), FAP (familial adenomatous polyposis), FXR (farnesoid X receptor), GF (germ-free), HF (high-fat), IBD (inflammatory bowel disease), IBS (irritable bowel syndrome), IPAA (ileal pouch–anal anastomosis), PN (parenteral nutrition), SBS (short-bowel syndrome), SIBO (small intestinal bacterial overgrowth), UC (ulcerative colitis)
      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.
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      Methodologic Challenges in Studying the Small Intestinal Microbiota

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      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).
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      Bacterial genera commonly found in the small intestine include Lactobacillus, Clostridium, Staphylococcus, Streptococcus, and Bacteroides, among others,
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      • Ahmed S.
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      • Fite A.
      • McBain A.J.
      • Gilbert P.
      • Macfarlane S.
      Mucosa-associated bacterial diversity in relation to human terminal ileum and colonic biopsy samples.
      • Hayashi H.
      • Takahashi R.
      • Nishi T.
      • Sakamoto M.
      • Benno Y.
      Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
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      Mucosa-associated bacterial diversity in relation to human terminal ileum and colonic biopsy samples.
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      Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.
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      Figure thumbnail gr1
      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 thumbnail gr2
      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
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      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.
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      A separate study looking specifically at Streptococcus and Veillonella species from ileostomies highlighted that there is incredible strain-level richness in the small intestine.
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      Diversity of human small intestinal Streptococcus and Veillonella populations.
      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,
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      High temporal and inter-individual variation detected in the human ileal microbiota.
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      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
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      The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates.
      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.
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      The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates.
      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.
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      The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates.
      This contrasts with colon communities, which are more equipped to degrade complex carbohydrates.
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      The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates.
      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,
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      • Engstrand L.
      Comparative analysis of human gut microbiota by barcoded pyrosequencing.
      • Bik E.M.
      • Eckburg P.B.
      • Gill S.R.
      • Nelson K.E.
      • Purdom E.A.
      • Francois F.
      • Perez-Perez G.
      • Blaser M.J.
      • Relman D.A.
      Molecular analysis of the bacterial microbiota in the human stomach.
      and is likely attributed to their metabolic interaction surrounding lactic acid production and utilization, respectively.
      • Egland P.G.
      • Palmer Jr., R.J.
      • Kolenbrander P.E.
      Interspecies communication in Streptococcus gordonii-Veillonella atypica biofilms: signaling in flow conditions requires juxtaposition.

      Dietary Fat and the Small Intestinal Microbiota

      Lipid digestion and absorption are complex physiologic processes that are central to the duodenum and jejunum.
      • Volk N.
      • Lacy B.
      Anatomy and physiology of the small bowel.
      GF mice have increased fecal lipid levels compared with mice in conventional housing,
      • Rabot S.
      • Membrez M.
      • Bruneau A.
      • Gerard P.
      • Harach T.
      • Moser M.
      • Raymond F.
      • Mansourian R.
      • Chou C.J.
      Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism.
      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.
      • Martinez-Guryn K.
      • Hubert N.
      • Frazier K.
      • Urlass S.
      • Musch M.W.
      • Ojeda P.
      • Pierre J.F.
      • Miyoshi J.
      • Sontag T.J.
      • Cham C.M.
      • Reardon C.A.
      • Leone V.
      • Chang E.B.
      Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids.
      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.
      • Martinez-Guryn K.
      • Hubert N.
      • Frazier K.
      • Urlass S.
      • Musch M.W.
      • Ojeda P.
      • Pierre J.F.
      • Miyoshi J.
      • Sontag T.J.
      • Cham C.M.
      • Reardon C.A.
      • Leone V.
      • Chang E.B.
      Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids.
      Indeed, when a HF diet microbiota was transplanted into GF mice, lipid absorption improved.
      • Martinez-Guryn K.
      • Hubert N.
      • Frazier K.
      • Urlass S.
      • Musch M.W.
      • Ojeda P.
      • Pierre J.F.
      • Miyoshi J.
      • Sontag T.J.
      • Cham C.M.
      • Reardon C.A.
      • Leone V.
      • Chang E.B.
      Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids.
      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.
      • Carmody R.N.
      • Gerber G.K.
      • Luevano Jr., J.M.
      • Gatti D.M.
      • Somes L.
      • Svenson K.L.
      • Turnbaugh P.J.
      Diet dominates host genotype in shaping the murine gut microbiota.
      • David L.A.
      • Maurice C.F.
      • Carmody R.N.
      • Gootenberg D.B.
      • Button J.E.
      • Wolfe B.E.
      • Ling A.V.
      • Devlin A.S.
      • Varma Y.
      • Fischbach M.A.
      • Biddinger S.B.
      • Dutton R.J.
      • Turnbaugh P.J.
      Diet rapidly and reproducibly alters the human gut microbiome.
      • Huang E.Y.
      • Leone V.A.
      • Devkota S.
      • Wang Y.
      • Brady M.J.
      • Chang E.B.
      Composition of dietary fat source shapes gut microbiota architecture and alters host inflammatory mediators in mouse adipose tissue.
      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.
      • Friedman E.S.
      • Li Y.
      • David Shen T.C.
      • Jiang J.
      • Chau L.
      • Adorini L.
      • Babakhani F.
      • Edwards J.
      • Shapiro D.
      • Zhao C.
      • Carr R.M.
      • Bittinger K.
      • Li H.
      • Wu G.D.
      FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid.
      • Schneider K.M.
      • Albers S.
      • Trautwein C.
      Role of bile acids in the gut-liver axis.
      They also affect bacterial growth, particularly gram-positive colonies, through oxidative stress and DNA damage,
      • Begley M.
      • Gahan C.G.
      • Hill C.
      The interaction between bacteria and bile.
      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.
      • Carr R.M.
      • Reid A.E.
      FXR agonists as therapeutic agents for non-alcoholic fatty liver disease.
      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.
      • Friedman E.S.
      • Li Y.
      • David Shen T.C.
      • Jiang J.
      • Chau L.
      • Adorini L.
      • Babakhani F.
      • Edwards J.
      • Shapiro D.
      • Zhao C.
      • Carr R.M.
      • Bittinger K.
      • Li H.
      • Wu G.D.
      FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid.
      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.
      • Begley M.
      • Gahan C.G.
      • Hill C.
      The interaction between bacteria and bile.
      Secondary BAs in turn are mediators of microbial–host communication, in part through regulation of the FXR pathway.
      • Sayin S.I.
      • Wahlstrom A.
      • Felin J.
      • Jantti S.
      • Marschall H.U.
      • Bamberg L.
      • Angelin B.
      • Hyotylainen T.
      • Oresic M.
      • Backhed F.
      Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.
      GF mice have increased conjugated BAs, such as tauro-β-muricholic acid, compared with conventionalized mice,
      • Sayin S.I.
      • Wahlstrom A.
      • Felin J.
      • Jantti S.
      • Marschall H.U.
      • Bamberg L.
      • Angelin B.
      • Hyotylainen T.
      • Oresic M.
      • Backhed F.
      Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.
      • Swann J.R.
      • Want E.J.
      • Geier F.M.
      • Spagou K.
      • Wilson I.D.
      • Sidaway J.E.
      • Nicholson J.K.
      • Holmes E.
      Systemic gut microbial modulation of bile acid metabolism in host tissue compartments.
      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.
      • Li F.
      • Jiang C.
      • Krausz K.W.
      • Li Y.
      • Albert I.
      • Hao H.
      • Fabre K.M.
      • Mitchell J.B.
      • Patterson A.D.
      • Gonzalez F.J.
      Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity.
      Separately, there is evidence that BAs can contribute to diarrhea and inflammation. A high milk-fat diet
      • Martinez-Guryn K.
      • Hubert N.
      • Frazier K.
      • Urlass S.
      • Musch M.W.
      • Ojeda P.
      • Pierre J.F.
      • Miyoshi J.
      • Sontag T.J.
      • Cham C.M.
      • Reardon C.A.
      • Leone V.
      • Chang E.B.
      Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids.
      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.
      • Devkota S.
      • Wang Y.
      • Musch M.W.
      • Leone V.
      • Fehlner-Peach H.
      • Nadimpalli A.
      • Antonopoulos D.A.
      • Jabri B.
      • Chang E.B.
      Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- 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.
      • Pitcher M.C.
      • Beatty E.R.
      • Cummings J.H.
      The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis.
      • Zinkevich V.V.
      • Beech I.B.
      Screening of sulfate-reducing bacteria in colonoscopy samples from healthy and colitic human gut mucosa.
      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
      NutrientMechanism
      Carbohydrate digestionDegradation 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 physiologyBile 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 storesVitamin 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.
      • Blaner W.S.
      • Li Y.
      • Brun P.J.
      • Yuen J.J.
      • Lee S.A.
      • Clugston R.D.
      Vitamin A absorption, storage and mobilization.
      • Goncalves A.
      • Roi S.
      • Nowicki M.
      • Dhaussy A.
      • Huertas A.
      • Amiot M.J.
      • Reboul E.
      Fat-soluble vitamin intestinal absorption: absorption sites in the intestine and interactions for absorption.
      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.
      • Shearer M.J.
      • Newman P.
      Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 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.
      • Giuliano V.
      • Bassotti G.
      • Mourvaki E.
      • Castellani D.
      • Filippucci E.
      • Sabatino G.
      • Gizzi S.
      • Palmerini F.
      • Galli F.
      • Morelli O.
      • Baldoni M.
      • Morelli A.
      • Iorio A.
      Small intestinal bacterial overgrowth and warfarin dose requirement variability.
      • Scarpellini E.
      • Gabrielli M.
      • Za T.
      • Lauritano E.C.
      • Santoliquido A.
      • Rossi E.
      • Ojetti V.
      • Cammarota G.
      • De Stefano V.
      • Gasbarrini A.
      The interaction between small intestinal bacterial overgrowth and warfarin treatment.
      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.
      • Welkos S.L.
      • Toskes P.P.
      • Baer H.
      Importance of anaerobic bacteria in the cobalamin malabsorption of the experimental rat blind loop syndrome.
      Thus, cobalamin deficiency is a complication of SIBO, likely resulting from competition between bacterial metabolism and host absorption.
      • Rowley C.A.
      • Kendall M.M.
      To B12 or not to B12: five questions on the role of cobalamin in host-microbial interactions.
      Indeed, in vitro models have shown that members of the genus Bacteroides outcompete intrinsic factor for binding to cobalamin, interfering with absorption in vivo.
      • Wexler A.G.
      • Schofield W.B.
      • Degnan P.H.
      • Folta-Stogniew E.
      • Barry N.A.
      • Goodman A.L.
      Human gut Bacteroides capture vitamin B12 via cell surface-exposed lipoproteins.
      Folate levels, by comparison, may be increased in SIBO as a result of bacterial biosynthesis.
      • Rowley C.A.
      • Kendall M.M.
      To B12 or not to B12: five questions on the role of cobalamin in host-microbial interactions.
      Iron, thiamine, and nicotinamide deficiencies also have been described in SIBO, although the mechanisms are not fully elucidated.
      • Sachdev A.H.
      • Pimentel M.
      Gastrointestinal bacterial overgrowth: pathogenesis and clinical significance.

      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,
      • Akhrass R.
      • Yaffe M.B.
      • Fischer C.
      • Ponsky J.
      • Shuck J.M.
      Small-bowel diverticulosis: perceptions and reality.
      surgically created blind loops,
      • Armbrecht U.
      • Lundell L.
      • Lindstedt G.
      • Stockbruegger R.W.
      Causes of malabsorption after total gastrectomy with Roux-en-Y reconstruction.
      strictures,
      • Swan R.W.
      Stagnant loop syndrome resulting from small-bowel irradiation injury and intestinal by-pass.
      and also dysmotility.
      • Wegener M.
      • Adamek R.J.
      • Wedmann B.
      • Jergas M.
      • Altmeyer P.
      Gastrointestinal transit through esophagus, stomach, small and large intestine in patients with progressive systemic sclerosis.
      In these disorders, there is ineffective food clearance, enhanced bacterial contact with food substrate, and subsequent bacterial colony expansion.
      • Bures J.
      • Cyrany J.
      • Kohoutova D.
      • Forstl M.
      • Rejchrt S.
      • Kvetina J.
      • Vorisek V.
      • Kopacova M.
      Small intestinal bacterial overgrowth syndrome.
      Biochemically, bacterial fermentation of carbohydrate sources leads to production of organic acids, aldehydes, alcohols, and gases.
      • Adeva-Andany M.
      • Lopez-Ojen M.
      • Funcasta-Calderon R.
      • Ameneiros-Rodriguez E.
      • Donapetry-Garcia C.
      • Vila-Altesor M.
      • Rodriguez-Seijas J.
      Comprehensive review on lactate metabolism in human health.
      • Halperin M.L.
      • Kamel K.S.
      D-lactic acidosis: turning sugar into acids in the gastrointestinal tract.
      • Adike A.
      • DiBaise J.K.
      Small intestinal bacterial overgrowth: nutritional implications, diagnosis, and management.
      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
      • Corazza G.R.
      • Menozzi M.G.
      • Strocchi A.
      • Rasciti L.
      • Vaira D.
      • Lecchini R.
      • Avanzini P.
      • Chezzi C.
      • Gasbarrini G.
      The diagnosis of small bowel bacterial overgrowth. Reliability of jejunal culture and inadequacy of breath hydrogen testing.
      • Hosie S.
      • Loff S.
      • Wirth H.
      • Rapp H.J.
      • von Buch C.
      • Waag K.L.
      Experience of 49 longitudinal intestinal lengthening procedures for short bowel syndrome.
      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).
      • Vitetta L.
      • Coulson S.
      • Thomsen M.
      • Nguyen T.
      • Hall S.
      Probiotics, D-lactic acidosis, oxidative stress and strain specificity.
      • Bulik-Sullivan E.C.
      • Roy S.
      • Elliott R.J.
      • Kassam Z.
      • Lichtman S.N.
      • Carroll I.M.
      • Gulati A.S.
      Intestinal microbial and metabolic alterations following successful fecal microbiota transplant for D-lactic acidosis.
      Typically, primary bile salts assist with fat absorption before deconjugation and reabsorption in the ileum.
      • Schneider K.M.
      • Albers S.
      • Trautwein C.
      Role of bile acids in the gut-liver axis.
      With bacterial overgrowth, however, steatorrhea and fat-soluble vitamin deficiency can result from premature bacterial deconjugation of primary bile salts.
      • Rana S.V.
      • Malik A.
      • Bhadada S.K.
      • Sachdeva N.
      • Morya R.K.
      • Sharma G.
      Malabsorption, orocecal transit time and small intestinal bacterial overgrowth in type 2 diabetic patients: a connection.
      • Stotzer P.O.
      • Johansson C.
      • Mellstrom D.
      • Lindstedt G.
      • Kilander A.F.
      Bone mineral density in patients with small intestinal bacterial overgrowth.
      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.
      • Khoshini R.
      • Dai S.C.
      • Lezcano S.
      • Pimentel M.
      A systematic review of diagnostic tests for small intestinal bacterial overgrowth.
      In the human gut, the majority of methanogenic archaea, classically Methanobrevibacter smithii, deplete hydrogen in the generation of methane.
      • Rezaie A.
      • Buresi M.
      • Lembo A.
      • Lin H.
      • McCallum R.
      • Rao S.
      • Schmulson M.
      • Valdovinos M.
      • Zakko S.
      • Pimentel M.
      Hydrogen and methane-based breath testing in gastrointestinal disorders: the North American consensus.
      Through scavenging hydrogen produced by neighboring microbes, termed the sink effect, methanogenic bacteria allow increased polysaccharide fermentation by neighboring microbes.
      • Krajmalnik-Brown R.
      • Ilhan Z.E.
      • Kang D.W.
      • DiBaise J.K.
      Effects of gut microbes on nutrient absorption and energy regulation.
      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.
      • Rezaie A.
      • Buresi M.
      • Lembo A.
      • Lin H.
      • McCallum R.
      • Rao S.
      • Schmulson M.
      • Valdovinos M.
      • Zakko S.
      • Pimentel M.
      Hydrogen and methane-based breath testing in gastrointestinal disorders: the North American consensus.
      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,
      • Bouhnik Y.
      • Alain S.
      • Attar A.
      • Flourie B.
      • Raskine L.
      • Sanson-Le Pors M.J.
      • Rambaud J.C.
      Bacterial populations contaminating the upper gut in patients with small intestinal bacterial overgrowth syndrome.
      • Erdogan A.
      • Rao S.S.
      • Gulley D.
      • Jacobs C.
      • Lee Y.Y.
      • Badger C.
      Small intestinal bacterial overgrowth: duodenal aspiration vs glucose breath test.
      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.
      • Goulet O.
      • Olieman J.
      • Ksiazyk J.
      • Spolidoro J.
      • Tibboe D.
      • Kohler H.
      • Yagci R.V.
      • Falconer J.
      • Grimble G.
      • Beattie R.M.
      Neonatal short bowel syndrome as a model of intestinal failure: physiological background for enteral feeding.
      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.
      • Davidovics Z.H.
      • Carter B.A.
      • Luna R.A.
      • Hollister E.B.
      • Shulman R.J.
      • Versalovic J.
      The fecal microbiome in pediatric patients with short bowel syndrome.
      • Engstrand Lilja H.
      • Wefer H.
      • Nystrom N.
      • Finkel Y.
      • Engstrand L.
      Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome.
      • Joly F.
      • Mayeur C.
      • Bruneau A.
      • Noordine M.L.
      • Meylheuc T.
      • Langella P.
      • Messing B.
      • Duee P.H.
      • Cherbuy C.
      • Thomas M.
      Drastic changes in fecal and mucosa-associated microbiota in adult patients with short bowel syndrome.
      Interestingly, longer bowel length or increased enteral nutrition over time reduced the amount of Proteobacteria.
      • Engstrand Lilja H.
      • Wefer H.
      • Nystrom N.
      • Finkel Y.
      • Engstrand L.
      Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome.
      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.
      • Joly F.
      • Mayeur C.
      • Bruneau A.
      • Noordine M.L.
      • Meylheuc T.
      • Langella P.
      • Messing B.
      • Duee P.H.
      • Cherbuy C.
      • Thomas M.
      Drastic changes in fecal and mucosa-associated microbiota in adult patients with short bowel syndrome.
      • Mayeur C.
      • Gillard L.
      • Le Beyec J.
      • Bado A.
      • Joly F.
      • Thomas M.
      Extensive intestinal resection triggers behavioral adaptation, intestinal remodeling and microbiota transition in short bowel syndrome.
      • Mayeur C.
      • Gratadoux J.J.
      • 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.
      When feces from patients with SBS are transplanted into GF rats, the SBS microbiota stimulate colonocyte proliferation and gut hormone production.
      • Gillard L.
      • Mayeur C.
      • Robert V.
      • Pingenot I.
      • Le Beyec J.
      • Bado A.
      • Lepage P.
      • Thomas M.
      • Joly F.
      Microbiota is involved in post-resection adaptation in humans with short bowel syndrome.
      However, the excess D-lactate production was not transferred, indicating that the host small intestine may be protective against this systemic acidosis.
      • Gillard L.
      • Mayeur C.
      • Robert V.
      • Pingenot I.
      • Le Beyec J.
      • Bado A.
      • Lepage P.
      • Thomas M.
      • Joly F.
      Microbiota is involved in post-resection adaptation in humans with short bowel syndrome.
      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
      • Cole C.R.
      • Frem J.C.
      • Schmotzer B.
      • Gewirtz A.T.
      • Meddings J.B.
      • Gold B.D.
      • Ziegler T.R.
      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.
      and duodenal aspirate,
      • Gutierrez I.M.
      • Kang K.H.
      • Calvert C.E.
      • Johnson V.M.
      • 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.
      • Kaufman S.S.
      • Loseke C.A.
      • Lupo J.V.
      • Young R.J.
      • Murray N.D.
      • Pinch L.W.
      • Vanderhoof J.A.
      Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with short bowel syndrome.
      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.
      • Gutierrez I.M.
      • Kang K.H.
      • Calvert C.E.
      • Johnson V.M.
      • 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.
      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
      • Cole C.R.
      • Frem J.C.
      • Schmotzer B.
      • Gewirtz A.T.
      • Meddings J.B.
      • Gold B.D.
      • Ziegler T.R.
      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.
      suspected to result from mucosal atrophy, barrier impairment, and translocation of bacteria or proinflammatory compounds.
      • Cole C.R.
      • Frem J.C.
      • Schmotzer B.
      • Gewirtz A.T.
      • Meddings J.B.
      • Gold B.D.
      • Ziegler T.R.
      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.
      • Demehri F.R.
      • Krug S.M.
      • Feng Y.
      • Lee I.F.
      • Schulzke J.D.
      • Teitelbaum D.H.
      Tight junction ultrastructure alterations in a mouse model of enteral nutrient deprivation.
      Many Proteobacteria produce lipopolysaccharide, which can induce a sepsis picture and liver damage through Toll-like receptor pathway activation.
      • Chichlowski M.
      Hale LP Bacterial-mucosal interactions in inflammatory bowel disease: an alliance gone bad.
      Proteobacteria were associated with prolonged PN and hepatitis, and Lactobacilli were associated with advanced steatosis and fibrosis, mostly after weaning off PN.
      • Korpela K.
      • Mutanen A.
      • Salonen A.
      • Savilahti E.
      • de Vos W.M.
      • Pakarinen M.P.
      Intestinal microbiota signatures associated with histological liver steatosis in pediatric-onset intestinal failure.
      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.
      • Korpela K.
      • Mutanen A.
      • Salonen A.
      • Savilahti E.
      • de Vos W.M.
      • Pakarinen M.P.
      Intestinal microbiota signatures associated with histological liver steatosis in pediatric-onset intestinal failure.
      Ongoing insult may lead to the need for liver and/or intestinal transplantation, an important cause of significant morbidity and mortality in SBS patients.
      • Mutanen A.
      • Wales P.W.
      Etiology and prognosis of pediatric short bowel syndrome.
      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.
      • Sokol H.
      • Seksik P.
      • Rigottier-Gois L.
      • Lay C.
      • Lepage P.
      • Podglajen I.
      • Marteau P.
      • Dore J.
      Specificities of the fecal microbiota in inflammatory bowel disease.
      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.
      • Dossa F.
      • Morris A.M.
      • Wilson A.R.
      • Baxter N.N.
      Life after surgery: surgeon assessments of quality of life among patients with familial adenomatous polyposis.
      Inflammation of the pouch, termed pouchitis, may manifest as tenesmus, diarrhea, and blood per rectum,
      • Cotter P.D.
      Small intestine and microbiota.
      • Coffey J.C.
      • Rowan F.
      • Burke J.
      • Dochery N.G.
      • Kirwan W.O.
      • O'Connell P.R.
      Pathogenesis of and unifying hypothesis for idiopathic pouchitis.
      • Komanduri S.
      • Gillevet P.M.
      • Sikaroodi M.
      • Mutlu E.
      • Keshavarzian A.
      Dysbiosis in pouchitis: evidence of unique microfloral patterns in pouch inflammation.
      • McLaughlin S.D.
      • Walker A.W.
      • Churcher C.
      • Clark S.K.
      • Tekkis P.P.
      • Johnson M.W.
      • Parkhill J.
      • Ciclitira P.J.
      • Dougan G.
      • Nicholls R.J.
      • Petrovska L.
      The bacteriology of pouchitis: a molecular phylogenetic analysis using 16S rRNA gene cloning and sequencing.
      and frequently is treated with antibiotics. Interestingly, pouchitis occurs in approximately half of patients with IBD pouches, but seldom in FAP patients,
      • Coffey J.C.
      • Rowan F.
      • Burke J.
      • Dochery N.G.
      • Kirwan W.O.
      • O'Connell P.R.
      Pathogenesis of and unifying hypothesis for idiopathic pouchitis.
      • Zella G.C.
      • Hait E.J.
      • Glavan T.
      • Gevers D.
      • Ward D.V.
      • Kitts C.L.
      • Korzenik J.R.
      Distinct microbiome in pouchitis compared to healthy pouches in ulcerative colitis and familial adenomatous polyposis.
      suspected to be owing in part to a higher basal epithelial turnover rate in FAP.
      • Bambury N.
      • Coffey J.C.
      • Burke J.
      • Redmond H.P.
      • Kirwan W.O.
      Sulphomucin expression in ileal pouches: emerging differences between ulcerative colitis and familial adenomatous polyposis pouches.
      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.
      • Smith F.M.
      • Coffey J.C.
      • Kell M.R.
      • O'Sullivan M.
      • Redmond H.P.
      • Kirwan W.O.
      A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch.
      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,
      • Smith F.M.
      • Coffey J.C.
      • Kell M.R.
      • O'Sullivan M.
      • Redmond H.P.
      • Kirwan W.O.
      A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch.
      • Kohyama A.
      • Ogawa H.
      • Funayama Y.
      • Takahashi K.
      • Benno Y.
      • Nagasawa K.
      • Tomita S.
      • Sasaki I.
      • Fukushima K.
      Bacterial population moves toward a colon-like community in the pouch after total proctocolectomy.
      • Young V.B.
      • Raffals L.H.
      • Huse S.M.
      • Vital M.
      • Dai D.
      • Schloss P.D.
      • Brulc J.M.
      • Antonopoulos D.A.
      • Arrieta R.L.
      • Kwon J.H.
      • Reddy K.G.
      • Hubert N.A.
      • Grim S.L.
      • Vineis J.H.
      • Dalal S.
      • Morrison H.G.
      • Eren A.M.
      • Meyer F.
      • Schmidt T.M.
      • Tiedje J.M.
      • Chang E.B.
      • Sogin M.L.
      Multiphasic analysis of the temporal development of the distal gut microbiota in patients following ileal pouch anal anastomosis.
      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.
      • de Silva H.J.
      • Millard P.R.
      • Kettlewell M.
      • Mortensen N.J.
      • Prince C.
      • Jewell D.P.
      Mucosal characteristics of pelvic ileal pouches.
      These changes do not happen in ileostomies before IPAA,
      • de Silva H.J.
      • Millard P.R.
      • Soper N.
      • Kettlewell M.
      • Mortensen N.
      • Jewell D.P.
      Effects of the faecal stream and stasis on the ileal pouch mucosa.
      • Shepherd N.A.
      • Jass J.R.
      • Duval I.
      • Moskowitz R.L.
      • Nicholls R.J.
      • Morson B.C.
      Restorative proctocolectomy with ileal reservoir: pathological and histochemical study of mucosal biopsy specimens.
      and also are more prominent in pouches from UC patients compared with FAP patients,
      • Bambury N.
      • Coffey J.C.
      • Burke J.
      • Redmond H.P.
      • Kirwan W.O.
      Sulphomucin expression in ileal pouches: emerging differences between ulcerative colitis and familial adenomatous polyposis pouches.
      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,
      • Florin T.
      • Khalil D.
      • Lenarczyck A.
      • Moody S.
      • Cowley D.
      Re: Levine et al. Fecal hydrogen sulfide production in ulcerative colitis.
      • Levine J.
      • Ellis C.J.
      • Furne J.K.
      • Springfield J.
      • Levitt M.D.
      Fecal hydrogen sulfide production in ulcerative colitis.
      • Levine J.
      • Furne J.K.
      • Levitt M.D.
      Ashkenazi Jews, sulfur gases, and ulcerative colitis.
      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.
      • Bambury N.
      • Coffey J.C.
      • Burke J.
      • Redmond H.P.
      • Kirwan W.O.
      Sulphomucin expression in ileal pouches: emerging differences between ulcerative colitis and familial adenomatous polyposis pouches.
      • Smith F.M.
      • Coffey J.C.
      • Kell M.R.
      • O'Sullivan M.
      • Redmond H.P.
      • Kirwan W.O.
      A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch.
      • Duffy M.
      • O'Mahony L.
      • Coffey J.C.
      • Collins J.K.
      • Shanahan F.
      • Redmond H.P.
      • Kirwan W.O.
      Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis.
      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.
      • Blanton L.V.
      • Charbonneau M.R.
      • Salih T.
      • Barratt M.J.
      • Venkatesh S.
      • Ilkaveya O.
      • Subramanian S.
      • Manary M.J.
      • Trehan I.
      • Jorgensen J.M.
      • Fan Y.M.
      • Henrissat B.
      • Leyn S.A.
      • Rodionov D.A.
      • Osterman A.L.
      • Maleta K.M.
      • Newgard C.B.
      • Ashorn P.
      • Dewey K.G.
      • Gordon J.I.
      Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children.
      Adding routine antibiotic agents to nutritional interventions has been shown to decrease mortality in children with uncomplicated severe acute malnutrition,
      • Trehan I.
      • Goldbach H.S.
      • LaGrone L.N.
      • Meuli G.J.
      • Wang R.J.
      • Maleta K.M.
      • Manary M.J.
      Antibiotics as part of the management of 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.
      • Denno D.M.
      • Tarr P.I.
      • Nataro J.P.
      Environmental enteric dysfunction: a case definition for intervention trials.
      • Keusch G.T.
      • Denno D.M.
      • Black R.E.
      • Duggan C.
      • Guerrant R.L.
      • Lavery J.V.
      • Nataro J.P.
      • Rosenberg I.H.
      • Ryan E.T.
      • Tarr P.I.
      • Ward H.
      • Bhutta Z.A.
      • Coovadia H.
      • Lima A.
      • Ramakrishna B.
      • Zaidi A.K.
      • Hay Burgess D.C.
      • Brewer T.
      Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences.
      • Syed S.
      • Ali A.
      • Duggan C.
      Environmental enteric dysfunction in children.
      EED is characterized by increased inflammatory markers,
      • Guerrant R.L.
      • Leite A.M.
      • Pinkerton R.
      • Medeiros P.H.
      • Cavalcante P.A.
      • DeBoer M.
      • Kosek M.
      • Duggan C.
      • Gewirtz A.
      • Kagan J.C.
      • Gauthier A.E.
      • Swann J.
      • Mayneris-Perxachs J.
      • Bolick D.T.
      • Maier E.A.
      • Guedes M.M.
      • Moore S.R.
      • Petri W.A.
      • Havt A.
      • Lima I.F.
      • Prata M.M.
      • Michaleckyj J.C.
      • Scharf R.J.
      • Sturgeon C.
      • Fasano A.
      • Lima A.A.
      Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in northeast Brazil.
      • Syed S.
      • Manji K.P.
      • McDonald C.M.
      • Kisenge R.
      • Aboud S.
      • Sudfeld C.
      • Locks L.
      • Liu E.
      • Fawzi W.W.
      • Duggan C.P.
      Biomarkers of systemic inflammation and growth in early infancy are associated with stunting in young Tanzanian children.
      increased markers of small intestinal permeability, and bacterial protein translocation.
      • Kosek M.N.
      • Lee G.O.
      • Guerrant R.L.
      • Haque R.
      • Kang G.
      • Ahmed T.
      • Bessong P.
      • Ali A.
      • Mduma E.
      • Penataro Yori P.
      • Faubion W.A.
      • Lima A.A.M.
      • Paredes Olortegui M.
      • Mason C.
      • Babji S.
      • Singh R.
      • Qureshi S.
      • Kosek P.S.
      • Samie A.
      • Pascal J.
      • Shrestha S.
      • McCormick B.J.J.
      • Seidman J.C.
      • Lang D.R.
      • Zaidi A.
      • Caulfield L.E.
      • Gottlieb M.
      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.
      • Campbell D.I.
      • Elia M.
      • Lunn P.G.
      Growth faltering in rural Gambian infants is associated with impaired small intestinal barrier function, leading to endotoxemia and systemic inflammation.
      • Weisz A.J.
      • Manary M.J.
      • Stephenson K.
      • Agapova S.
      • Manary F.G.
      • Thakwalakwa C.
      • Shulman R.J.
      • Manary M.J.
      Abnormal gut integrity is associated with reduced linear growth in rural Malawian children.
      • Welsh F.K.
      • Farmery S.M.
      • MacLennan K.
      • Sheridan M.B.
      • Barclay G.R.
      • Guillou P.J.
      • Reynolds J.V.
      Gut barrier function in malnourished patients.
      Dietary intervention alone is not fully effective in treating malnutrition in patients with EED,
      • Petri Jr., W.A.
      • Naylor C.
      • Haque R.
      Environmental enteropathy and malnutrition: do we know enough to intervene?.
      and a disrupted resident small intestinal microbiota is hypothesized to play a key role in the pathogenesis of EED.
      • Bartelt L.A.
      • Bolick D.T.
      • Mayneris-Perxachs J.
      • Kolling G.L.
      • Medlock G.L.
      • Zaenker E.I.
      • Donowitz J.
      • Thomas-Beckett R.V.
      • Rogala A.
      • Carroll I.M.
      • Singer S.M.
      • Papin J.
      • Swann J.R.
      • Guerrant R.L.
      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
      • Bolick D.T.
      • Kolling G.L.
      • Moore 2nd, J.H.
      • de Oliveira L.A.
      • Tung L.
      • Philipson C.
      • Viladomiu M.
      • Hontecillas R.
      • Bassaganya-Riera J.
      • Guerrant R.L.
      Zinc deficiency alters host response and pathogen virulence in a mouse model of enteroaggregative Escherichia coli-induced diarrhea.
      • Bolick D.T.
      • Medeiros P.
      • Ledwaba S.E.
      • Lima A.A.M.
      • Nataro J.P.
      • Barry E.M.
      • Guerrant R.L.
      The critical role of zinc in a new murine model of enterotoxigenic E. coli (ETEC) diarrhea.
      • Costa L.B.
      • Noronha F.J.
      • Roche J.K.
      • Sevilleja J.E.
      • Warren C.A.
      • Oria R.
      • Lima A.
      • Guerrant R.L.
      Novel in vitro and in vivo models and potential new therapeutics to break the vicious cycle of Cryptosporidium infection and malnutrition.
      and have been associated with EED. Furthermore, SIBO as diagnosed by a breath test is associated with malnutrition and poor sanitation.
      • Donowitz J.R.
      • Haque R.
      • Kirkpatrick B.D.
      • Alam M.
      • Lu M.
      • Kabir M.
      • Kakon S.H.
      • Islam B.Z.
      • Afreen S.
      • Musa A.
      • Khan S.S.
      • Colgate E.R.
      • Carmolli M.P.
      • Ma J.Z.
      • Petri Jr., W.A.
      Small intestine bacterial overgrowth and environmental enteropathy in Bangladeshi children.
      • dos Reis J.C.
      • de Morais M.B.
      • Oliva C.A.
      • Fagundes-Neto U.
      Breath hydrogen test in the diagnosis of environmental enteropathy in children living in an urban slum.
      • Mello C.S.
      • Tahan S.
      • Melli L.C.
      • Rodrigues M.S.
      • de Mello R.M.
      • Scaletsky I.C.
      • de Morais M.B.
      Methane production and small intestinal bacterial overgrowth in children living in a slum.
      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.
      • Attia S.
      • Feenstra M.
      • Swain N.
      • Cuesta M.
      • Bandsma R.H.J.
      Starved guts: morphologic and functional intestinal changes in malnutrition.
      • Brown E.M.
      • Wlodarska M.
      • Willing B.P.
      • Vonaesch P.
      • Han J.
      • Reynolds L.A.
      • Arrieta M.C.
      • Uhrig M.
      • Scholz R.
      • Partida O.
      • Borchers C.H.
      • Sansonetti P.J.
      • Finlay B.B.
      Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model.
      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.
      • Brown E.M.
      • Wlodarska M.
      • Willing B.P.
      • Vonaesch P.
      • Han J.
      • Reynolds L.A.
      • Arrieta M.C.
      • Uhrig M.
      • Scholz R.
      • Partida O.
      • Borchers C.H.
      • Sansonetti P.J.
      • Finlay B.B.
      Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model.
      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,
      • Bartelt L.A.
      • Roche J.
      • Kolling G.
      • Bolick D.
      • Noronha F.
      • Naylor C.
      • Hoffman P.
      • Warren C.
      • Singer S.
      • Guerrant R.
      Persistent G. lamblia impairs growth in a murine malnutrition model.
      Cryptosporidium,
      • Costa L.B.
      • Noronha F.J.
      • Roche J.K.
      • Sevilleja J.E.
      • Warren C.A.
      • Oria R.
      • Lima A.
      • Guerrant R.L.
      Novel in vitro and in vivo models and potential new therapeutics to break the vicious cycle of Cryptosporidium infection and malnutrition.
      Enteroaggregative E coli,
      • Roche J.K.
      • Cabel A.
      • Sevilleja J.
      • Nataro J.
      • Guerrant R.L.
      Enteroaggregative Escherichia coli (EAEC) impairs growth while malnutrition worsens EAEC infection: a novel murine model of the infection malnutrition cycle.
      and a mixture of E coli and Bacteroidiales.
      • Brown E.M.
      • Wlodarska M.
      • Willing B.P.
      • Vonaesch P.
      • Han J.
      • Reynolds L.A.
      • Arrieta M.C.
      • Uhrig M.
      • Scholz R.
      • Partida O.
      • Borchers C.H.
      • Sansonetti P.J.
      • Finlay B.B.
      Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model.
      The dysbiosis induced by malnutrition, coupled with exposure to these specific microbes, makes the host more susceptible to adherent bacteria
      • Brown E.M.
      • Wlodarska M.
      • Willing B.P.
      • Vonaesch P.
      • Han J.
      • Reynolds L.A.
      • Arrieta M.C.
      • Uhrig M.
      • Scholz R.
      • Partida O.
      • Borchers C.H.
      • Sansonetti P.J.
      • Finlay B.B.
      Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model.
      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.
      • Bartelt L.A.
      • Bolick D.T.
      • Kolling G.L.
      • Roche J.K.
      • Zaenker E.I.
      • Lara A.M.
      • Noronha F.J.
      • Cowardin C.A.
      • Moore J.H.
      • Turner J.R.
      • Warren C.A.
      • Buck G.A.
      • Guerrant R.L.
      Cryptosporidium priming is more effective than vaccine for protection against cryptosporidiosis in a murine protein malnutrition model.
      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.
      • Stanghellini V.
      Functional dyspepsia and irritable bowel syndrome: beyond Rome IV.
      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.
      • Chen B.
      • Kim J.J.
      • Zhang Y.
      • Du L.
      • Dai N.
      Prevalence and predictors of small intestinal bacterial overgrowth in irritable bowel syndrome: a systematic review and meta-analysis.
      Furthermore, antibiotic treatment including rifaximin
      • Pimentel M.
      • Lembo A.
      • Chey W.D.
      • Zakko S.
      • Ringel Y.
      • Yu J.
      • Mareya S.M.
      • Shaw S.L.
      • Bortey E.
      • Forbes W.P.
      TARGET Study Group
      Rifaximin therapy for patients with irritable bowel syndrome without constipation.
      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,
      • Kerckhoffs A.P.
      • Samsom M.
      • van der Rest M.E.
      • de Vogel J.
      • Knol J.
      • Ben-Amor K.
      • Akkermans L.M.
      Lower Bifidobacteria counts in both duodenal mucosa-associated and fecal microbiota in irritable bowel syndrome patients.
      Prevotellaceae,
      • Chung C.S.
      • Chang P.F.
      • Liao C.H.
      • Lee T.H.
      • Chen Y.
      • Lee Y.C.
      • Wu M.S.
      • Wang H.P.
      • Ni Y.H.
      Differences of microbiota in small bowel and faeces between irritable bowel syndrome patients and healthy subjects.
      Escherichia, Shigella, Aeromonas, Acinetobacter, Citrobacter, and Microvirgula
      • Giamarellos-Bourboulis E.
      • Tang J.
      • Pyleris E.
      • Pistiki A.
      • Barbatzas C.
      • Brown J.
      • Lee C.C.
      • Harkins T.T.
      • Kim G.
      • Weitsman S.
      • Barlow G.M.
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      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.

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