Bile acid malabsorption in patients with graft‐versus‐host disease of the gastrointestinal tract

Joshi, N; Hassan, Sandra; Jasani, Parag; Dixon, Steve; Cavenagh, Jamie; Oakervee, Heather; Smith, Matthew; Agrawal, Samir A.; Auer, Rebecca; Vos, Johannes de; Langmead, Louise; Rampton, David; Gribben, John G.; Taussig, David

doi:10.1111/j.1365-2141.2011.09014.x

Cited by 18 publications

(15 citation statements)

References 11 publications

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“…Although initially watery, the stool might turn mucoid owing to loss of transmucosal proteins and might be bloody in the setting of mucosal denudation 37 . Moreover, small intestinal mucosal injury and protein loss due to acute GVHD can lead to malabsorption and malnutrition 38 . Paradoxically, severe disease can lead to paralytic ileus, either spontaneously or as a result of analgesic and anti-motility agents such as morphine, loperamide or diphenoxylate 36 .…”

Section: Diagnosismentioning

confidence: 99%

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Naymagon

Wong

et al. 2017

Nat Rev Gastroenterol Hepatol

126

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Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.

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Section: Diagnosismentioning

confidence: 99%

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Naymagon

Wong

et al. 2017

Nat Rev Gastroenterol Hepatol

126

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“…Differences in serum bile acid levels may be caused by altered synthesis, release, or reabsorption. Bile acid malabsorption has previously been reported in GVHD ( 47 ), but an altered gut microbiome is an alternative explanation as discussed earlier. The increased levels of bile metabolites may then induce hepatic cell dysfunction and induction of pro-inflammatory mediators ( 48 ).…”

Section: Discussionmentioning

confidence: 73%

Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers

et al. 2018

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Chronic graft versus host disease (cGVHD) is a common long-term complication after allogeneic hematopoietic stem cell transplantation. The objective of our study was to compare the metabolic profiles for allotransplant recipients and thereby identify metabolic characteristics of patients with treatment-requiring cGVHD. The study included 51 consecutive patients (29 men and 22 women; median age: 44 years, range: 15–66 years) transplanted with peripheral blood stem cells derived from human leukocyte antigen-matched family donors. All serum samples investigated by global metabolomic profiling were collected approximately 1 year posttransplant (median 358 days). Thirty-one of the 51 patients (61%) had cGVHD 1 year posttransplant. The affected organs were (number of patients) liver/bile duct (23), eyes (15), gastrointestinal tract (14), skin (13), mouth (10), lungs (3), and urogenital tract (1). We compared the metabolic profile for patients with and without cGVHD, and a Random Forrest Classification Analysis then resulted in 75% accuracy in differentiating the two groups. The 30 top-ranked metabolites from this comparison included increased levels of bile acids, several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, pro-inflammatory lipid metabolites, phenylalanine and tyrosine metabolites derived from the gut microbial flora, and metabolites reflecting increased oxidative stress. However, nine of these 30 top-ranked metabolites were probably altered due to cyclosporine or steroid treatment, and we therefore did a hierarchical clustering analysis including all 51 patients but only based on the other 21 cGVHD-specific metabolites. This analysis identified three patient subsets: one cluster included mainly patients without cGVHD and had generally low metabolite levels; another cluster included mainly patients with cGVHD (most patients with at least three affected organs) and high metabolite levels, and the last intermediate group including cGVHD patients with limited organ involvement. We conclude that allotransplant recipients with cGVHD have an altered metabolic profile caused both by the disease and its immunosuppressive treatment.

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“…Secondary bile acids are mucotoxic and pro-in ammatory (41), and as such, their production may serve to amplify mucosal injury. The clinical relevance of this nding is particularly compelling with BAM reported in severe cases of GvHD-related diarrhea and even bowel perforation (36,42,43). Bile acid sequestrants (colesevelam) may offer bene ts in both the prevention of acute diarrhea (caused by motility/secretory mechanisms) as well as the prevention of MBI-LCBI.…”

Section: Discussionmentioning

confidence: 92%

Host Microbiome Dictates Infection Risk after Chemotherapy Revealing New Avenues for Antibiotic Stewardship in Oncology

Wardill¹,

Mooij²,

Ferreira³

et al. 2020

Preprint

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Background: Mucosal barrier injury (MBI) is a recognized risk factor for blood stream infection (BSI) in people undergoing chemotherapy, permitting expansion and translocation of enteric pathobionts; a phenomenon now clinically referred to as MBI-associated laboratory-confirmed BSI. Although recognized to originate from endogenous gastrointestinal sources, MBI-associated BSI continue to be treated with antibiotics; a counterintuitive approach that may increase infection risk by depletion of the host microbiome. While this point has been argued in numerous clinical studies and opinion pieces, there are few data describing mechanistic strategies to decrease MBI-associated BSI, reflecting a lack of translationally robust preclinical models. Here, we report on a new translational model of MBI caused by the chemotherapeutic drug, melphalan. We aimed to identify candidate pathways to strengthen the mucosal barrier and prevent infection, prompting new antibiotic stewardship initiatives. Results: Melphalan caused dose-dependent, systemic toxicity characterized by severe neutropenia, self-limiting intestinal injury, inflammation and biphasic fever, all of which were clinically and molecularly consistent with the dynamics of melphalan conditioning. The fecal microbiome following melphalan was depleted in richness and commensal taxa, impairing colonization resistance and the microbial metabolome and prompting expansion of enteric pathogens. Breakdown of the intestinal barrier was initiated by melphalan and exacerbated by mucotoxic bile acids.Conclusions: MBI-associated BSI is simply a form of collateral damage resulting from breakdown of the gastrointestinal microenvironment and self-perpetuating injury. Efforts to intervene early in these sequelae are therefore of great clinical significance to restrict antibiotic use and mitigate their detrimental consequences on treatment outcomes and antibiotic resistance. Our data support interventions targeting the host microbiome and metabolome due to its ubiquitous control of inflammation, mucosal injury, bile acid transformation; all of which contribute to infection risk in cancer.

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Bile acid malabsorption in patients with graft‐versus‐host disease of the gastrointestinal tract

Cited by 18 publications

References 11 publications

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers

Host Microbiome Dictates Infection Risk after Chemotherapy Revealing New Avenues for Antibiotic Stewardship in Oncology

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