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The genomic revolution promises to transform our approach to treat patients by individualizing treatments, reducing adverse events, and decreasing health care costs. The early advances using this have been realized primarily by optimizing preventive and therapeutic approaches in cancer using human genome sequencing. The ability to characterize the microbiome, which includes all the microbes that reside within and upon us and all their genetic elements, using next-generation sequencing allows us to now incorporate this important contributor to human disease into developing new preventive and therapeutic strategies. In this review we highlight the importance of the microbiome in all aspects of human disease, including pathogenesis, phenotype, prognosis, and response to treatment, as well as their role as diagnostic and therapeutic biomarkers. We provide a role for next-generation sequencing in both precise microbial identification of infectious diseases and characterization of microbial communities and their function. Taken together, the microbiome is emerging as an integral part of precision medicine approach as it not only contributes to interindividual variability in all aspects of a disease but also represents a potentially modifiable factor that is amenable to targeting by therapeutics.

Variability in disease presentation, progression and treatment response has been a central challenge in medicine. Although variability in host factors and genetics are important, it has become evident that the gut microbiome, with its vast genetic and metabolic diversity, must be considered in moving towards individualized treatment. In this Review, we discuss six broad disease groups: infectious disease, cancer, metabolic disease, cardiovascular disease, autoimmune or inflammatory disease, and allergic and atopic diseases. We highlight current knowledge on the gut microbiome in disease pathogenesis and prognosis, efficacy, and treatment-related adverse events and its promise for stratifying existing treatments and as a source of novel therapies. The Review is not meant to be comprehensive for each disease state but rather highlights the potential implications of the microbiome as a tool to individualize treatment strategies in clinical practice. Although early, the outlook is optimistic but challenges need to be overcome before clinical implementation, including improved understanding of underlying mechanisms, longitudinal studies with multiple data layers reflecting gut microbiome and host response, standardized approaches to testing and reporting, and validation in larger cohorts. Given progress in the microbiome field with concurrent basic and clinical studies, the microbiome will likely become an integral part of clinical care within the next decade.The gut microbiota is increasingly recognized as an important factor in disease development, progression and treatment response. This Review highlights the promise of strategies that target the gut microbiome in the treatment of disease, including cancer and infectious and metabolic diseases.

Gastrointestinal (GI) motility requires coordination among several cell types in the intestinal epithelium and the neuromuscular apparatus. A disruption in GI motility was primarily attributed to disruption of this coordinated effort among different host cells, but recent studies have begun to uncover how the products of gut microbiota can alter GI motility by modulating the function of different host cells and the interactions among them. In this issue of theJCI, Chen, Qiu, et al. used a reverse translation approach, isolating a Shigella sp.--peristaltic contraction-inhibiting bacterium (PIB) --from a cohort of patients with intractable constipation. They identified an [omega]-3 polyunsaturated fatty acid (PUFA), docosapentaenoic acid (DPA), produced by this Shigella variant, as an important driver of constipation using a series of microbiologic, biochemical, and genetic manipulations combined with in vitro and in vivo studies. This finding advances the field, given that production of DPA is rare in the human gut and appears to have a distinct effect on GI physiology.

Antibiotic treatment disturbs the commensal microbiota and is often followed by infection with enteric pathogens such as Salmonella typhimurium and Clostridium difficile; pathogen expansion is fuelled by antibiotic-driven accumulation of commensal-liberated host mucosal carbohydrates. Gut microbes support pathogen proliferation Intestinal microbiota can provide protection against invading pathogens through competition for resources and production of specific antimicrobial products. But disruption of the microbiota with antibiotics can contribute to the emergence of several enteric pathogens. Justin Sonnenburg and colleagues show here that two antibiotic-associated pathogens, Salmonella enterica serovar Typhimurium and Clostridium difficile , catabolize microbiota-liberated host sugars to fuel their growth in the mouse gut. In particular, the ability to use sialic acid cleaved from host polysaccharides by Bacteroides thetaiotaomicron is important for pathogen expansion. These findings identify a role for the gut microbiota in facilitating enteric pathogen infection and provide new options for developing therapeutics. The human intestine, colonized by a dense community of resident microbes, is a frequent target of bacterial pathogens. Undisturbed, this intestinal microbiota provides protection from bacterial infections. Conversely, disruption of the microbiota with oral antibiotics often precedes the emergence of several enteric pathogens 1 , 2 , 3 , 4 . How pathogens capitalize upon the failure of microbiota-afforded protection is largely unknown. Here we show that two antibiotic-associated pathogens, Salmonella enterica serovar Typhimurium ( S. typhimurium ) and Clostridium difficile , use a common strategy of catabolizing microbiota-liberated mucosal carbohydrates during their expansion within the gut. S. typhimurium accesses fucose and sialic acid within the lumen of the gut in a microbiota-dependent manner, and genetic ablation of the respective catabolic pathways reduces its competitiveness in vivo . Similarly, C. difficile expansion is aided by microbiota-induced elevation of sialic acid levels in vivo . Colonization of gnotobiotic mice with a sialidase-deficient mutant of Bacteroides thetaiotaomicron , a model gut symbiont, reduces free sialic acid levels resulting in C. difficile downregulating its sialic acid catabolic pathway and exhibiting impaired expansion. These effects are reversed by exogenous dietary administration of free sialic acid. Furthermore, antibiotic treatment of conventional mice induces a spike in free sialic acid and mutants of both Salmonella and C. difficile that are unable to catabolize sialic acid exhibit impaired expansion. These data show that antibiotic-induced disruption of the resident microbiota and subsequent alteration in mucosal carbohydrate availability are exploited by these two distantly related enteric pathogens in a similar manner. This insight suggests new therapeutic approaches for preventing diseases caused by antibiotic-associated pathogens.

While gut microbiome and host gene regulation independently contribute to gastrointestinal disorders, it is unclear how the two may interact to influence host pathophysiology. Here we developed a machine learning-based framework to jointly analyse paired host transcriptomic ( n  = 208) and gut microbiome ( n  = 208) profiles from colonic mucosal samples of patients with colorectal cancer, inflammatory bowel disease and irritable bowel syndrome. We identified associations between gut microbes and host genes that depict shared as well as disease-specific patterns. We found that a common set of host genes and pathways implicated in gastrointestinal inflammation, gut barrier protection and energy metabolism are associated with disease-specific gut microbes. Additionally, we also found that mucosal gut microbes that have been implicated in all three diseases, such as Streptococcus , are associated with different host pathways in each disease, suggesting that similar microbes can affect host pathophysiology in a disease-specific manner through regulation of different host genes. Our framework can be applied to other diseases for the identification of host gene–microbiome associations that may influence disease outcomes. A machine learning framework for integrating multi-omic high-dimensional datasets identified disease-specific and shared host gene–microbiome associations across three gastrointestinal diseases.

Recent studies of the human microbiome have offered new insights into how the microbiome can impact cancer development and treatment. Specifically, in pancreatic ductal adenocarcinoma (PDAC), the microbiota has been shown to modulate PDAC risk, contribute to tumorigenesis, impact the tumor microenvironment, and alter treatment response. These findings provide rationale for further investigations into leveraging the microbiome to develop new strategies to diagnose and treat PDAC patients. There is growing evidence that microbiome analyses have the potential to become easily performed, non-invasive diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. More excitingly, there is now emerging interest in developing interventions based on the modulation of microbiota. Fecal microbiota transplantation, probiotics, dietary changes, and antibiotics are all potential strategies to augment the efficacy of current therapeutics and reduce toxicities. While there are still challenges to overcome, this is a rapidly growing field that holds promise for translation into clinical practice and provides a new approach to improving patient outcomes.

While the human gut microbiota are suspected to produce diffusible small molecules that modulate host signaling pathways, few of these molecules have been identified. Species of Bacteroides and their relatives, which often comprise >50% of the gut community, are unusual among bacteria in that their membrane is rich in sphingolipids, a class of signaling molecules that play a key role in inducing apoptosis and modulating the host immune response. Although known for more than three decades, the full repertoire of Bacteroides sphingolipids has not been defined. Here, we use a combination of genetics and chemistry to identify the sphingolipids produced by Bacteroides fragilis NCTC 9343. We constructed a deletion mutant of BF2461, a putative serine palmitoyltransferase whose yeast homolog catalyzes the committed step in sphingolipid biosynthesis. We show that the Δ2461 mutant is sphingolipid deficient, enabling us to purify and solve the structures of three alkaline-stable lipids present in the wild-type strain but absent from the mutant. The first compound was the known sphingolipid ceramide phosphorylethanolamine, and the second was its corresponding dihydroceramide base. Unexpectedly, the third compound was the glycosphingolipid α-galactosylceramide (α-GalCer(Bf)), which is structurally related to a sponge-derived sphingolipid (α-GalCer, KRN7000) that is the prototypical agonist of CD1d-restricted natural killer T (iNKT) cells. We demonstrate that α-GalCer(Bf) has similar immunological properties to KRN7000: it binds to CD1d and activates both mouse and human iNKT cells both in vitro and in vivo. Thus, our study reveals BF2461 as the first known member of the Bacteroides sphingolipid pathway, and it indicates that the committed steps of the Bacteroides and eukaryotic sphingolipid pathways are identical. Moreover, our data suggest that some Bacteroides sphingolipids might influence host immune homeostasis.

We investigate how host mucus glycan composition interacts with dietary carbohydrate content to influence the composition and expressed functions of a human gut community. The humanized gnotobiotic mice mimic humans with a nonsecretor phenotype due to knockout of their α1–2 fucosyltransferase (Fut2) gene. The fecal microbiota of Fut2 ⁻ mice that lack fucosylated host glycans show decreased alpha diversity relative to Fut2 ⁺ mice and exhibit significant differences in community composition. A glucose-rich plant polysaccharide-deficient (PD) diet exerted a strong effect on the microbiota membership but eliminated the effect of Fut2 genotype. Additionally fecal metabolites predicted host genotype in mice on a polysaccharide-rich standard diet but not on a PD diet. A more detailed mechanistic analysis of these interactions involved colonization of gnotobiotic Fut2 ⁺ and Fut2 ⁻ mice with Bacteroides thetaiotaomicron , a prominent member of the human gut microbiota known to adaptively forage host mucosal glycans when dietary polysaccharides are absent. Within Fut2 ⁻ mice, the B. thetaiotaomicron fucose catabolic pathway was markedly down-regulated, whereas BT4241–4247, an operon responsive to terminal β-galactose, the precursor that accumulates in the Fut2 ⁻ mice, was significantly up-regulated. These changes in B. thetaiotaomicron gene expression were only evident in mice fed a PD diet, wherein B. thetaiotaomicron relies on host mucus consumption. Furthermore, up-regulation of the BT4241–4247 operon was also seen in humanized Fut2 ⁻ mice. Together, these data demonstrate that differences in host genotype that affect the carbohydrate landscape of the distal gut interact with diet to alter the composition and function of resident microbes in a diet-dependent manner.

Abstract Background Inflammatory bowel diseases (IBDs) are a group of heterogeneous inflammatory conditions affecting the gastrointestinal tract. Although there is considerable evidence linking the gut microbiota to intestinal inflammation, there is limited knowledge on its potential role in the development of extraintestinal manifestations of IBD. Methods Four groups of patients were included: IBD-associated arthropathy (IBD-A); IBD without arthropathy (IBD-N); rheumatoid arthritis (RA); and non-IBD, nonarthritis controls. DNA from stool samples was isolated and sequenced using the Illumina platform. Paired-end reads were quality-controlled using SHI7 and processed with SHOGUN. Abundance and diversity analyses were performed using QIIME, and compositional biomarker identification was performed using LEfSe. Results One hundred eighty patients were included in the analysis. IBD-A was associated with an increased abundance of microbial tyrosine degradation pathways when compared with IBD-N (P = 0.02), whereas IBD-A and RA patients both shared an increased abundance of Clostridiaceae when compared with controls (P = 0.045). We found that history of bowel surgery was a significant source of variability (P = 0.001) among all IBD patients and was associated with decreased alpha diversity and increased abundance of Enterobacteriaceae (P = 0.004). Conclusions An increased abundance of gut microbial tyrosine degradation pathways was associated with IBD-A. An increased abundance of Clostridiaceae was shared by both IBD-A and RA patients and suggests a potentially common microbial link for inflammatory arthritis. The increased abundance of Enterobacteriaceae, previously reported in IBD, may be due to the effects of previous bowel surgery and highlights the importance of controlling for this variable in future studies.

ObjectiveThe intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS.Design39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states.ResultsPatients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota.ConclusionA subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.