The microbiome and inborn errors of metabolism: Why we should look carefully at their interplay?

Colonetti, Karina; Roesch, Luiz Fernando; Schwartz, Ida Vanessa Doederlein

doi:10.1590/1678-4685-GMB-2017-0235

Karina Colonetti Send correspondence to Karina Colonetti. Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, 90035-903 Porto Alegre, RS, Brazil. E-mail: kcolonetti@gmail.com.

Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

Laboratory of Basic Research and Advanced Investigations in Neurosciences (BRAIN), Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

Luiz Fernando Roesch

Interdisciplinary Research Center on Biotechnology-CIP-Biotec, Universidade Federal do Pampa, Bagé, RS, Brazil

Ida Vanessa Doederlein Schwartz

Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

Laboratory of Basic Research and Advanced Investigations in Neurosciences (BRAIN), Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

Send correspondence to Karina Colonetti. Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, 90035-903 Porto Alegre, RS, Brazil. E-mail: kcolonetti@gmail.com.

Figures (2)
Tables (2)

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Figure 1
Known effects of the gut microbiome on the main organs affected in an IEM. In bold are the ways by which the interactions occur. Below are the features related to the gut microbiota and the organs. The gut microbiome produces several metabolites and actively participates in the biosynthesis of vitamins and cofactors, metabolism of carbohydrates, proteins and lipids. The gut microbiota interacts with the whole body via the immune and endocrine systems. The two major organs affected in an IEM are the brain and the liver. In addition to the components of the immune and endocrine systems, the described gut-brain interactions also involve the brain-blood barrier, HPA axis, vagus nerve and the sympathetic system. This may predispose to several diseases, such as increased cardiovascular risk, multiple sclerosis, Alzheimer’s disease, depression, autism, anxiety, and also can be related to pain. Interactions with the liver can occur via the portal vein, the gut-blood barrier, and can be involved in several hepatic diseases, most of them linked to endotoxemia.

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Figure 2
Common treatments used in IEM and its effects over the microbiome. Diet is an important modulator of the microbiome, and also is a very common treatment for several IEMs. Diets with restriction or abundance of certain nutrients can cause a dysbiotic state, leading to an abnormal immune signaling (inflammation), leaking of gut-blood barrier, and breaking of the energetic balance of cells, with potential to affect the whole body. Antibiotics, on other hand, cause rapid and significant drops in taxonomic richness, diversity and evenness. This can bring benefits, as in the case of propionic/methylmalonic acidemia patients, by decreasing the levels of propionic/methylmalonic acid, or not, as in the case of organ transplants, once patients treated with antibiotics during the perioperative period had an increased risk for graft vs. host disease. Organ transplantation is a treatment for several IEMs. Other drugs used for treating this class of genetic disease can also affect the microbiome or metabolite production, like nitinisone, used in treatment of tyrosinemia type I, that raises the levels of indoles which in turn have antineoplasic effects.

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Table 1
Inborn errors of metabolism addressed in this review, main phenotypic features, and overview of management.

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Table 2
Summary of experimental studies addressing the role of the microbiome in inborn errors of metabolism.

EIM (Substrate accumulated)	Affected protein/gene	Main clinical features	Long-term management	Reference
Phenylketonuria (Phenylalanine)	Phenylalanine-4-hydroxylase (PAH)	Neurologic impairments, with physical, cognitive, and behavioral consequences, even in well-controlled PKU	Restriction of dietary phenylalanine. Phe-free medical formula. Sapropterin (BH₄) supplementation in responsive patients. Large neutral amino acids (LNAA)	Regier and Greene, 2000Regier DS and Greene CL (2000) Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1504/ (November 01, 2017). https://www.ncbi.nlm.nih.gov/books/NBK15... ; OMIM #261600
Tyrosinemia type I (Tyrosine, maleylacetoacetate, fumarylacetoacetate, and succinylacetone)	Fumarylacetoacetate hydrolase (FAH)	Hepatomegaly, acute liver failure, cirrhosis and hepatocellular carcinoma Episodic paralysis and episodic peripheral neuropathy Renal Fanconi syndrome, renal failure, glomerulosclerosis, nephromegaly, nephrocalcinosis Gastrointestinal bleeding, paralytic ileus Pancreatic islet-cell hypertrophy, splenomegaly Rickets, chronic weakness	Dietary management with reduced intake of phenylalanine and tyrosine; Nitisinone Liver transplantation	Das, 2017Das AM (2017) Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1). Appl Clin Genet 10:43–48.; Sniderman et al., 2006Sniderman King L, Trahms C and Scott CR (2006) Tyrosinemia Type I. 2006 Jul 24 [Updated 2017 May 25]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1515/ (November 01, 2017). https://www.ncbi.nlm.nih.gov/books/NBK15... ; OMIM #276700
Urea cycle disorders (Ammonia)	Carbamoylphosphate synthetase I (CPS1); Ornithine transcarbamylase deficiency (OTC); Argininosuccinate Synthase 1 (ASS1); Argininosuccinate lyase (ASL), Arginase-1 (ARG1); N-acetylglutamate synthase (NAGS); Ornithine transporter (SLC25A15); or citrin (SLC25A13)	Vomiting, lethargy, and behavioral abnormalities. Neurologic impairments. Seizures in acute hyperammonemia. Liver impairments	Dietary management with reduced intake of proteins, Essential amino acids supplementation. Vitamin and mineral supplementation, Medications to increase the nitrogen excretion. Liver transplantation,	Ah Mew et al., 2003Ah Mew N, Simpson KL, Gropman AL, Brendan ML, Lanpher C, Chapman KA and Summar ML (2003) Urea Cycle Disorders Overview. 2003 Apr 29 [Updated 2017 Jun 22]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1217/ (November 01, 2017). https://www.ncbi.nlm.nih.gov/books/NBK12... ; Häberle et al., 2012Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, et al. (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 7:32..
Alkaptonuria (Homogentisic acid and its oxidation products)	Homogentisate 1, 2-dioxygenase (HGD)	Urine that turns dark on standing, alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, arthritis (especially in the spine). Cardiovascular impairments: Aortic and/or mitral valve calcification, coronary artery calcification, aortic dilatation. Urolithiasis, ochronotic prostate stones (in males)	Nitisinone ^* * Under investigation	Introne and Gahl, 2003Introne WJ and Gahl WA (2003) Alkaptonuria. 2003 May 9 [Updated 2016 May 12]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1454/ (November 01, 2017). https://www.ncbi.nlm.nih.gov/books/NBK14... ; Mistry et al., 2013Mistry JB, Bukhari M and Taylor AM (2013) Alkaptonuria. Rare Dis 1:e27475.; OMIMOnline Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/OMIM (July 20, 2017) http://www.ncbi.nlm.nih.gov/OMIM... #203500
Propionic acidemia (Propionic acid)	Propionyl-CoA carboxylase (PCC)	Central nervous system impairments: acute encephalopathy, lethargy, axial hypotonia, limb hypertonia, coma, seizure, psychomotor retardation, cerebral atrophy, dystonia, cerebellar hemorrhage (rare), ischemic stroke in the basal ganglia (rare). Decreased appetite, feeding difficulties, vomiting, dehydration. Hepatomegaly, pancreatitis. Pancytopenia, neutropenia, anemia, thrombocytopenia. Cardiomyopathy, tachypnea, apnea. Osteoporosis, dermatitis acidemica	L-carnitine, Antibiotics, Low-protein diet, Vitamin and mineral supplementation, Precursor-free amino acid and/or isoleucine/ valine supplementation.	Baumgartner et al., 2014Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, et al. (2014) Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis 9:130.; OMIM #606054https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180313/
Methylmalonic Acidemia (Methylmalonic acid)	Methylmalonyl-CoA mutase (MUT)	Central nervous system impairments: lethargy, hypotonia, developmental delay, coma, severe involvement of globus pallidus, delay in myelination, cerebellar hemorrhage (rare), ischemic stroke in the basal ganglia (rare)}. Leukopenia, thrombocytopenia. Cardiomyopathy, hepatomegaly, pancreatitis, recurrent episodes of vomiting, interstitial nephritis, chronic renal failure	Same as in PA, plus vitamin B12 in responsive patients.	Baumgartner et al., 2014Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, et al. (2014) Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis 9:130.; OMIM #251000
Hemochromatosis type 1 (Iron)	HFE protein, Hemochromatosis gene (HFE1)	Heart involvement: cardiomyopathy, congestive heart failure, arrhythmia, cardiomegaly. Liver involvement: cirrhosis, hepatomegaly, hepatocellular carcinoma. Diabetes mellitus. Arthritis. Hypogonadotropic hypogonadism. The severe effects of the disease usually do not appear until after decades of progressive iron loading	Periodic phlebotomy	Seckington and Powell, 2000Seckington R and Powell L (2000) HFE-Associated Hereditary Hemochromatosis. 2000 Apr 3 [Updated 2015 Sep 17]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1440 (November 01, 2017) https://www.ncbi.nlm.nih.gov/books/NBK14... ; OMIM #235200
Trimethylaminuria (Amino-trimethylamine)	Flavin-containing monooxygenase 3 (FMO3)	Behavioral/psychiatric manifestations: depression, suicidal, psychosocial problems in school. In some patients: anemia, neutropenia, pulmonary infections; tachycardia and severe hypertension after eating cheese.	Dietary restriction of: Trimethylamine and its precursors including choline and lecithin Trimethylamine N-oxide; Inhibitors of FMO3 enzyme activity, such as indoles. Use of: acid soaps and body lotions, activated charcoal and copper chlorophyllin, antibiotics, riboflavin supplements.	Phillips and Shephard, 2007Phillips IR and Shephard EA (2007) Primary Trimethylaminuria. 2007 Oct 8 [Updated 2015 Oct 1]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1103/ (November 01, 2017). https://www.ncbi.nlm.nih.gov/books/NBK11... ; OMIM #602079

Reference	EIM	Model	Experimental design	Aims	Findings
Ney et al., 2017Ney DM, Murali SG, Stroup BM, Nair N, Sawin EA, Rohr F and Levy HL (2017) Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria. Mol Genet Metab 121:96–103.	Phenylketonuria	Human	Randomized, controlled, crossover trial; Early-treated PKU subjects consumed, for 3-wk. each, their usual low-Phe diet combined with AA-Formula or GMP; Metabolomics analysis of a subset of plasma and 24-h urine samples; Dietary intake.	To assess metabolites and neurotransmitters derived from Tyr and Trp in plasma and urine samples from subjects with PKU consuming both AA-formula and GMP	Plasma metabolome: 7 of the 40 microbiome-associated compounds showed differential levels with AA-formula compared with GMP; Significant differences in the plasma profile of secondary bile acids; Associated compounds showed differential levels with AA-Formula compared with GMP; Urine metabolome: 7 of 45 microbiome; Individuals fed with AA formula had a 50% higher intake of Tyr and Trp; Differential degradation level of Tyr by intestinal microbes of individuals fed with AA-formula, potential harmful metabolites formed; Higher metabolism of Trp via the kynurenine pathway might be linked with inflammation patterns;
					Reinforces prebiotic properties of GMP.
Pinheiro de Oliveira et al., 2016Pinheiro de Oliveira F, Mendes RH, Dobbler PT, Mai V, Pylro VS, Waugh SG, Vairo F, Refosco LF, Roesch LFW and Schwartz IVD (2016) Phenylketonuria and gut microbiota: A controlled study based on next-generation sequencing. PloS One 11:e0157513.	Phenylketonuria	Human	Observational, cross-sectional study, convenience sampling strategy; Review of medical records for Plasma Phe and Tyr levels, and daily Phe intake; Questionnaire including questions on comorbidities, use of medicines, and dietary intake; V4-16S rRNA gene sequencing; Metagenome prediction.	To characterize the microbiome of PKU patients	Decreased levels of Families Clostridiaceae, Erysipelotrichaceae, and Lachnospiraceae, class Clostridiales, genera Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus, and Veillonella.
MacDonald et al., 2011MacDonald A, Cochrane B, Wopereis H and Loveridge N (2011) Specific prebiotics in a formula for infants with Phenylketonuria. Mol Genet Metab 104(Suppl):S55-S59.	Phenylketonuria	Human	8-week open-label, single-arm, pilot intervention; Infants aged between 4 weeks and 6 months; Formula Phe-free with prebiotic to replace a regular infant formula phe -free without prebiotics; Measurement of Phe levels in blood; Record of stool frequency, size, appearance, and consistency; Stool samples analyzed for pH and bacterial groups (Fluorescence in situ hybridization technique).	Influence of prebiotic scGOS/lcFOS addition to an infant Phe-free protein substitute	Bifidobacteria and lactobacilli–enterococci levels were similar to those of healthy breast-fed infants and greater than those reported for infants on infant formula without prebiotics.
Sawin et al., 2015Sawin EA, De Wolfe TJ, Aktas B, Stroup BM, Murali SG, Steele JL and Ney DM (2015) Glycomacropeptide is a prebiotic that reduces Desulfovibrio bacteria, increases cecal short-chain fatty acids, and is anti-inflammatory in mice. Am J Physiol Gastrointest Liver Physiol 309:G590-601.	Phenylketonuria	Mice C57BL6/J PKU (Pah^enu2)	PKU (Pah^enu2) and wild-type mice were fed with isoenergetic (Aminoacid, GMP, or casein) diets for 8 week; Three experiments were done; Measurement of SCFA by gas chromatography; Quantification of plasma cytokines; Analysis of splenocyte T cell populations by flow cytometry.	Prebiotic effects of GMP	Increased SCFAs levels; Decreased levels of inflammatory cytokines Decreased quantity of the Proteobacteria, genus Desulfovibrio.
Durrer et al., 2017Durrer KE, Allen MS and Hunt von Herbing I (2017) Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU. PLoS One 12:e0176286.	Phenylketonuria	Mice C57BL6/J (PAH^enu2 mutant)	In vitro and in vivo test of a probiotic expressing the phenylalanine lyase gene; Measurement of phe plasma pre and post-treatment; Measurement of enzyme activity; Prebiotic mixed into chow; Fecal culture and immunogenic evaluation.	Assessment of a genetically engineered probiotic (GMO)	Reduction of plasma Phe levels in the mouse model of PKU; Survival of GMO Lactobacillus reuteri 100-23C in the mouse gastrointestinal tract, but no permanent colonization; No immune response to transgenic protein.
Gertsman et al., 2015Gertsman I, Gangoiti JA, Nyhan WL and Barshop BA (2015) Perturbations of tyrosine metabolism promote the indolepyruvate pathway via tryptophan in host and microbiome. Mol Genet Metab 114:431–437.	Alkaptonuria Tyrosinemia	Human	Collection of samples from patients with alkaptonuria before and after treatment with NTBC plus samples of Tyrosinemia types I, I and transient patients; Analysis of the sera y tQ-TOF LC/ MS metabolomic platform; Untargeted metabolomics strategy; In vitro experiments with cultures of human cells and intestinal flora cultures to identify the nature of the link between 4-HPP and the elevated indoles.	Evaluate the metabolic effects of nitisinone	Increased levels of I3CHO, in patients treated with nitinisone.
Frye et al., 2016Frye RE, Rose S, Chacko J, Wynne R, Bennuri SC, Slattery JC, Tippett M, Delhey L, Melnyk S, Kahler SG, et al. (2016) Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. Transl Psychiatry 6:e927.	Propionic acidemia (PA)	Human lymphoblastoid cell lines (LCLs)	Measurement of mitochondrial function in ASD and sex-age-matched control LCLs; Incubation with PPA and reactive oxygen species.	Effects of PPA in an unfavorable redox microenvironment	PPA can have both beneficial and toxic effects on mitochondrial function, depending on concentration, exposure duration, and microenvironment redox state.
Buhnik-Rosenblau et al., 2012Buhnik-Rosenblau K, Moshe-Belizowski S, Danin-Poleg Y and Meyron-Holtz EG (2012) Genetic modification of iron metabolism in mice affects the gut microbiota. Biometals Int J Role Met Ions Biol Biochem Med 25:883–892.	Hemochromatosis type 1	Mouse	Comparison between wild-type and genetically deficient mouse; Culture followed by tRFLP and 16S rRNA gene sequencing.	Effects of iron metabolism (Irp2^-/- and Hfe^-/- genes) on microbiome	Irp2^-/- Increased levels of L. intestinalis compared to Hfe^-/- mice and L. murinus compared to both Hfe^-/-and WT mice; Hfe^-/- Increased levels of Enterococcus faecium; Increased levels of L. johnsonii to both Hfe^-/- and Irp2^-/- mice compared to WT.

[1] Send correspondence to Karina Colonetti. Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, 90035-903 Porto Alegre, RS, Brazil. E-mail: kcolonetti@gmail.com.

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The microbiome and inborn errors of metabolism: Why we should look carefully at their interplay?

Abstract