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Second, mechanistic insight is needed into how antibiotic- Department of Microbiology and Immunology
induced microbiota changes may affect the human host: If re- Institute for Genome Sciences
ductions in microbial diversity increase the susceptibility to University of Maryland School of Medicine
comorbidities, which part of the lost taxonomic or functional Baltimore, Maryland
microbiota repertoire needs to be replenished to avoid dis-
Reprint requests: W. Florian Fricke, PhD, Institute of Biological Chemistry and
ease? Are more easily detectable changes in the abundance Nutrition, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart,
of dominant microbiota members even relevant, or should Germany. E-mail:
they merely serve as diagnostic markers for functionally
more relevant changes affecting other rare organisms that References
we do not even know about (yet)? Animal (germ-free) model
systems seem to be our best option to confirm any hypotheses 1. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Mi-
arising from human studies by translating human findings crobiota modulate behavioral and physiological abnormalities associated
with neurodevelopmental disorders. Cell 2013;155:1451-63.
into animal experiments involving microbiota manipulation. 2. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de
Finally, where do we begin treatment, and what are our Vos WM, et al. Duodenal infusion of donor feces for recurrent Clos-
therapeutic options? If microbiota optimization is the goal, tridium difficile. N Engl J Med 2013;368:407-15.
will it be sufficient to identify 1 generic microbial cocktail 3. Storro O, Avershina E, Rudi K. Diversity of intestinal microbiota in in-
for transplantation or is a specific microbiota only good for fancy and the risk of allergic disease in childhood. Curr Opin Allergy
Clin Immunol 2013;13:257-62.
one patient but bad for another? Do we really need to 4. Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J, Li K, et al. Antibiotics in
improve our capabilities for microbiota manipulation, or early life alter the murine colonic microbiome and adiposity. Nature 2012;
can we optimize antibiotic drugs to more specifically target 488:621-6.
pathogens but not the entire microbiota? The narrow- 5. Dethlefsen L, Relman DA. Incomplete recovery and individualized
responses of the human distal gut microbiota to repeated antibi-
spectrum antibiotic drug fidaxomicin, which is used to treat
otic perturbation. Proc Natl Acad Sci U S A 2011;108(Suppl 1):
C difficile infection without grossly affecting the whole mi- 4554-61.
crobiota, could be an example of where future antibiotic 6. Greenwood C, Morrow AL, Lagomarcino AJ, Altaye M, Taft DH, Yu Z,
drug developments are leading. et al. Early Empiric Antibiotic Use in Preterm Infants Is Associated with
Overall, our knowledge of the microbiota and its func- Lower Bacterial Diversity and Higher Relative Abundance of Entero-
tional role in human health and disease remains so limited bacter. J Pediatr 2014;165:23-9.
7. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, sta-
that diagnostic rather than therapeutic applications of the bility and resilience of the human gut microbiota. Nature 2012;489:220-30.
findings by Greenwood et al and others in the field seem to 8. Song Y, Garg S, Girotra M, Maddox C, von Rosenvinge EC, Dutta A, et al.
be a more realistic goal in the near future. n Microbiota dynamics in patients treated with fecal microbiota transplan-
tation for recurrent Clostridium difficile infection. PLoS One 2013;8:
W. Florian Fricke, PhD e81330.
Institute of Biological Chemistry and Nutrition 9. Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C,
Jernberg C, et al. Decreased gut microbiota diversity, delayed Bacteroi-
University of Hohenheim
detes colonisation and reduced Th1 responses in infants delivered by
Stuttgart, Germany Caesarean section. Gut 2014;63:559-66.

Another Explanation for Breast Milk Jaundice

reast milk jaundice refers to an unconjugated hyperbi- ferase 1 (UGT1A1).2 Defects in UGT1A1 cause hereditary
lirubinemia associated with breastfeeding that de- unconjugated hyperbilirubinemiasCrigler-Najjar syn-
velops after 4-7 days of life in an otherwise-healthy drome type I (MIM #218800), in which there is complete
neonate and has no other identifiable cause.1 It is distin- deficiency of the enzyme; Crigler-Najjar syndrome type II
guished from breastfeeding jaundice, which occurs in the first (MIM #606785), where there is some limited activity of the
week of life and is the result of insufficient enzyme; and Gilbert syndrome (MIM
See related article, p 36
intake or production of breast milk. The #43500), in which there is more enzyme ac-
cause of breast milk jaundice has been the subject of tivity but less than in normal individuals.3 Polymorphic mu-
numerous investigations based on the assumption that either tations of UGT1A1, specifically G71R in the coding region
a factor in the breast milk itself or in the neonate could and A(TA)7TAA with -3279T G in the regulatory region,
contribute to the observed clinical presentation. are the most common mutations seen in Gilbert syndrome,
Bilirubin conjugation and subsequent elimination is cata-
lyzed by bilirubin uridine 50 -diphospho-glucuronosyltrans-
The author declares no conflicts of interest.

0 0022-3476/$ - see front matter. Copyright 2014 Elsevier Inc. All rights reserved.
UGT1A1 Uridine 5 -diphospho-glucuronosyltransferase 1


and A(TA)7TAA, with -3279T G, is the sole cause of Gilbert effect on homozygous UGT1A1*6 or the fact that with
syndrome in white patients.4 Maruo et al5,6 have shown pre- the resumption of breastfeeding the serum bilirubin con-
viously that G71R (but not A(TA)7TAA with -3279T G) is a centration and jaundice will still decrease remain unex-
cause of prolonged unconjugated hyperbilirubinemia in East plained.
Asian infants and is also a risk factor for breast milk jaundice. Breast milk jaundice remains a fascinating occurrence in
In this issue of The Journal, Maruo et al7 describe the a subset of infants who are breast-fed. Mauro et al have
causal relationship between infants with breast milk jaundice found yet another relationship for its incidence. What other
and homozygosity for UGT1A1*6. Using polymerase chain causes or relationships will be found that contribute to
reactiondirected sequencing, they analyzed UGT1A1 gene breast milk jaundice hopefully will be determined in the
allelic variation in 170 Japanese infants with breast milk near future. n
jaundice, and these genotypes were compared with serum
bilirubin concentrations. As a control group, UGT1A1 geno- Philip Rosenthal, MD
types in 55 infants without breast milk jaundice also Professor of Pediatrics & Surgery
were analyzed. The authors found that 52% of the infants University of California, San Francisco
with breast milk jaundice were homozygous UGT1A1*6. UCSF Benioff Childrens Hospital
These infants had serum bilirubin concentrations (21.8  San Francisco, California
3.65 mg/dL) that were significantly greater than in infants Reprint requests: Philip Rosenthal, MD, Pediatric Hepatology & Liver
with other genotypes (P < .0001). Homozygous UGT1A1*6 Transplant, 500 Parnassus Avenue, MU-416 East, Box 0136, San Francisco, CA
was not detected in the control group of infants without 94143-0136. E-mail:
breast milk jaundice. The authors concluded that
UGT1A1*6 is a major cause of breast milk jaundice in infants
in East Asia.
There are several additional points worthy of discussion as
1. Newman AJ, Gross S. Hyperbilirubinemia in breast-fed infants. Pediatrics
a result of this work. Although the majority (52%) of the Jap- 1963;32:995-1001.
anese infants with breast milk jaundice were homozygous 2. Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP,
UGT1A1*6, a sizeable percentage (48%) did not have this Chowdhury JR, et al. Bilirubin UDP-glucuronosyltransferase 1 is the
genotype. What was the cause of their breast milk jaundice? only relevant bilirubin glucuronidating isoform in man. J Biol Chem
Was it a factor in the mothers breast milk? Was there 1994;269:17960-4.
3. Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR.
another neonatal factor contributing to the observed jaun- Genetic lesions of bilirubin uridine-disphosphoglucuronate glucuronosyl-
dice? Furthermore, not all infants with breast milk jaundice transferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes:
are from East Asia. Will infants with breast milk jaundice correlation of genotype to phenotype. Hum Mutat 2000;16:297-306.
from other continents also be predominantly homozygous 4. Maruo Y, DAddario C, Mori A, Iwai M, Takahashi H, Sato H, et al.
UGT1A1*6? Obviously, similar investigations in breast Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of
UGT1A1 as the principal cause of Gilbert syndrome. Hum Genet
milk jaundiced infants from other areas should be under- 2004;115:525-6.
taken to confirm or refute this association in other ethnic 5. Maruo Y, Nishizawa K, Sato H, Doida Y, Shimada M. Association
groups. of neonatal hyperbilirubinemia with bilirubin UDP-
The cause of breast milk jaundice in infancy appears to glucuronosyltransferase polymorphism. Pediatrics 1999;103:1224-7.
be multifactorial. No single cause to date explains this phe- 6. Maruo Y, Nishizawa K, Sato H, Takahashi H, Shimada M. Prolonged un-
conjugated hyperbilirubinemia associated with breast milk and mutations
nomenon in all observed affected infants. Another issue of the bilirubin uridine diphosphate-glucuronosyltransferase gene. Pedi-
that the investigators did not address in this study is the atrics 2000;106:E59.
well-known improvement in breast milk jaundice when 7. Maruo Y, Morioka Y, Fujito H, Nakahara S, Yanagi T, Matsui K, et al. Bili-
breast milk feeding is temporarily suspended.8 Although rubin UDP-glucuronosyltransferase variation is a genetic basis of breast
there potentially could be a factor in the breast milk that milk jaundice. J Pediatr 2014;165:36-41.
8. Gartner LM. Breastfeeding and jaundice. J Perinatol 2001;21(Suppl 1):
inhibits UGT1A1 enzyme activity, this unknown factors S25-9.