Received: 27 July 2023 | Accepted: 4 September 2023

DOI: 10.1097/HC9.0000000000000295

REVIEW

Lactulose in cirrhosis: Current understanding of efficacy,

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mechanism, and practical considerations

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Patricia P. Bloom | Elliot B. Tapper

Department of Internal Medicine, Division of

Gastroenterology and Hepatology, University
of Michigan, Ann Arbor, Michigan, USA
Correspondence
Patricia P. Bloom, Division of Gastroenterology
and Hepatology, Department of Medicine,
1500 E. Medical Center Drive, Ann Arbor, MI
48104
Email: ppbloom@med.umich.edu
Abstract
HE is a complication of cirrhosis characterized by neuropsychiatric and
motor dysfunction, and results in decreased quality of life and increased
mortality. Lactulose is a synthetic disaccharide used to treat HE since 1966,
though many questions about its use remain unanswered. Lactulose
reverses minimal HE, prevents overt HE, improves quality of life, increases
the rate of recovery from overt HE, and improves survival rates. Lactulose’s
clinical effect appears to be derived from its impact on intestinal microbes,
likely a result of its enteric acidifying effect, positive pressure on beneficial
taxa, and improvement of gut barrier function. There are several practical
considerations with lactulose including (1) a need to avoid excessive bowel
movements and subsequent dehydration, (2) treatment titration protocols
need further investigation, (3) baseline or treatment-induced gastrointestinal
side effects limit adherence in some cases, and (4) the utility of monitoring
stool consistency or pH remains unknown. Further research is needed to
optimize our use of this effective treatment for HE.

INTRODUCTION in healthy adults, so lactulose makes its impact within the

HE is a complication of cirrhosis characterized by
neuropsychiatric and motor dysfunction. Manifestations
can range from subtle (minimal HE) to severe (overt HE)
and even coma. HE is associated with considerable
patient and caregiver burden, decreased quality of life,
and poor survival.[1–3] Lactulose has been used to treat
HE since 1966, yet our understanding of how to best
use lactulose in clinical treatment plans and its
mechanism remains relatively unclear.
Lactulose is a synthetic disaccharide composed of 1
molecule of galactose and 1 molecule of fructose.[4] Only
0.3% of lactulose is absorbed by the gastrointestinal tract
intestinal lumen.[5] Lactulose’s clinical effect appears to
be derived from its impact on intestinal microbes, likely a
result of its pH-lowering effect, positive pressure on
beneficial taxa, and improvement of gut barrier function.
CLINICAL EFFICACY OF
L A C T U L O S E T O TR E A T H E P A T I C H E
Lactulose is an effective treatment for HE (Figure 1). A
Cochrane review including 38 randomized controlled
trials of nonabsorbable disaccharides found a beneficial
effect on HE (RR = 0.58, 95% CI: 0.5–0.69).[6] Lactulose

Abbreviations: PEG, polyethylene glycol; SCFA, short-chain fatty acid.

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Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.

Hepatology Communications. 2023;7:e0295. www.hepcommjournal.com | 1

 2
| HEPATOLOGY COMMUNICATIONS
also reduced mortality to 8.5% in patients with cirrhosis
and overt HE versus 14% among those with overt HE
not taking lactulose.[6] A network meta-analysis of 25
trials found that when comparing lactulose, rifaximin,
probiotics, and L-ornithine L-aspartate (an ammonia-
lowering agent) for the treatment of minimal HE,
lactulose was the only agent able to meet all 3
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endpoints: reverse minimal HE, prevent overt HE, and
improve quality of life.[7] Although many patients
experience breakthrough overt HE episodes while on
lactulose,[8] lactulose withdrawal markedly increases
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the risk of breakthrough in patients on rifaximin.[9]
Lactulose for overt HE
Lactulose is the first-line therapy for overt HE.[10] Despite
this recommendation, high-quality data are relatively
limited. Specifically, there are no controlled multicenter
trials demonstrating lactulose efficacy for overt HE
treatment or primary prevention. In the original controlled
studies of lactulose compared with sorbitol, it was
effective at inducing resolution of altered mental status
and particularly after cross-over to lactulose after
sorbitol-induced worsened cognitive function.[11,12] Com-
pared with a glucose control, lactulose also increased the
rate of mental status recovery in overt HE.[13] In a
randomized trial, lactulose delivered by means of enema
compared with tap water enemas was stopped early for
efficacy.[14] Frequent lactulose doses until improving
mental status has been associated with improved
hospital length of stay in nonrandomized trials.[15,16]
When combined with or when followed by large-volume
polyethylene glycol (PEG) colonic purges, the time to
mental status normalization is shortened.[17,18] Lactulose
is also highly effective for the secondary prevention of
overt HE episodes.[19] Breakthrough overt HE during
lactulose therapy is most often related to nonadherence
(ie, consuming no or insufficient lactulose), but
closely followed by dehydration from excessive bowel
movements.[20]
F I G U R E 1 Clinical benefits of lactulose. Lactulose has multiple
clinical benefits for patients with cirrhosis and HE.
Lactulose for minimal HE
Lactulose therapy is associated with consistent
improvements in health-related quality of life. This has
been observed using validated indices such as the
Sickness Impact Profile,[21,22] Euro-QOL,[23] and the
Modified Chinese Quality of Life Questionnaire.[24] The
impact is particularly clear for subscales involved in
social activities, home management, emotional behav-
ior, and sleep functioning.[21,22] In a randomized trial of
crystalline lactulose for patients enrolled on the basis of
high activity impairment, 28 days of lactulose did not
significantly improve health-related quality of life meas-
ured using the Short Form-8 but did improve activity
impairment, sleep quality, and cognitive function meas-
ured using the Animal Naming Test.[25]
THERAPEUTIC MECHANISM OF
LACTULOSE
Lactulose metabolism in the gut
Lactulose is a synthetic disaccharide composed of one
molecule of galactose and one molecule of fructose.[4]
Only 0.3% of lactulose is absorbed by the gastrointestinal
tract in healthy adults, so lactulose makes its impact within
the intestinal lumen.[5] Lactulose is metabolized by
bacterial enzymes into carbon dioxide and short-chain
fatty acids (SCFAs).[4] Lactulose increases fecal nitrogen
excretion in rats with gut bacteria, but not in germ-free rats,
supporting the role of bacteria in lactulose metabolism.[26]
Lactulose absorption is minimal
In 2021, it was shown in multiple experiments involving
healthy controls and patients with diarrhea-type irritable
bowel syndrome that <0.4% of lactulose is absorbed using
radiolabeled ingestions.[5] The majority of that absorption
occurs in the small bowel, based on the finding that most
urinary lactulose is collected within 8 hours of consumption.
There was no effect of age, sex, or the presence of irritable
bowel syndrome on lactulose absorption. Another study
performed a multisugar test (designed to evaluate intestinal
permeability) in patients with compensated cirrhosis and
controls.[27] While they did not report the absorption of
lactulose alone, there was no difference in the absorbed
ratio of lactulose/rhamnose between patients with cirrhosis
and controls. Likely very little lactulose is absorbed by the
intestine, unmetabolized, in patients with cirrhosis.
Location of lactulose metabolism
The geography of lactulose fermentation is challenging
to ascertain, because it is technically difficult to access
 LACTULOSE IN CIRRHOSIS
the distal small bowel and proximal colon. Despite this
challenge, several studies suggest that lactulose
metabolism occurs in the colon.
In a 1965 study, Dahlqvist and Gryboski[28] took
sections of human small intestine, obtained from
surgical resections, and incubated them with lactulose
in vitro. The small intestine sections were able to
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hydrolyze lactose, but not lactulose. It is not clear if
small intestinal bacteria were included in this experi-
ment, but the authors conclude that lactulose is not
hydrolyzed by human small intestine disaccharidases.
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This study does not address the possibility that small
intestinal bacteria may metabolize lactulose, which to
our knowledge has never been studied.
The microbial breakdown of carbohydrates is fermen-
tation, which yields SCFA as the main end product. As
such, SCFA can be used as a marker of the location of
lactulose fermentation. One study performed an autopsy
of 6 adult humans within 4 hours of death and found the
following mean total SCFA levels: jejunum (< 1 mmol/kg),
ileum (13 mmol/kg), cecum (131 mmol/kg), ascending
colon (123 mmol/kg), transverse colon (117 mmol/kg),
and descending colon (80 mmol/kg).[29] While these
autopsy patients were not consuming lactulose, this
work suggests that the proximal colon is where most
carbohydrate fermentation and therefore lactulose
metabolism occurs.
Another study administered lactulose 20 g twice daily
to healthy volunteers for 8 days.[30] Four healthy
volunteers underwent colonoscopic collection of ileal
and colonic contents on days 1 and 8 of radiolabeled
(14C) lactulose. There was an increase in 14CO2 in
breath testing over the 8 days, suggesting that carbon
from lactulose breakdown products is absorbed into
systemic circulation. Over 8 days, ileal fluid did not
change in pH or SCFA concentrations. However, the
cecum had a significant drop in pH and increase in
lactate, acetate, and total volatile fatty acid concentra-
tions. Fecal pH and fatty acid concentrations did not
change. Therefore, it appears that the bulk of lactulose
metabolism in a healthy individual is occurring in the
cecum, and colonic SCFAs are used before they are
excreted in stool.
Finally, it is clear that lactulose can be metabolized by
colonic bacteria. One group anaerobically cultured 64
colonic bacterial strains in lactulose-containing media.[31]
They found that some organisms were not able to
metabolize lactulose, but many were. Lactulose metab-
olizers in vitro included Bacteroides, Bifidobacterium,
Clostridia, and Lactobacilli.
Lactulose as a prebiotic
Prebiotics are substrates selectively used by host
microorganisms that confer a health benefit.[32] Pre-
biotics are most often nonabsorbable carbohydrates,
| 3
able to be fermented by gastrointestinal bacteria,
leading to an increased abundance of beneficial taxa
and SCFA production.
Clinical reports of lactulose started in 1957 when
Petuely[33] reported that lactulose increased fecal
Lactobacillus bifidus when fed to adults and infants.
Early culture-based studies demonstrated that lactu-
lose promotes the growth of Lactobacillus and
Bifidobacteria, both microorganisms that confer a
health benefit, and the production of SCFAs butyrate,
acetate, and propionate.[34–40] Elkington et al[11] per-
formed the first double-blind clinical trial of lactulose to
treat HE, and found that lactulose consistently resulted
in the presence of lactobacilli in the stool. The
glycoside hydrolase able to hydrolyze lactulose was
found in nearly all of the 144 Bifidobacteria strains
available in the National Center for Biotechnology
Information in 2021, again highlighting the strong
relationship between lactulose and this bacteria.[41]
Based on cecal lactulose concentrations, pH, and rate
of SCFA production, it is likely that bacterial ability to
metabolize lactulose increases over 8 days.[30] While
early culture-based studies reproducibly showed an
increase in Lactobacillus and Bifidobacteria with
lactulose, it remained unclear if the prebiotic effect of
lactulose and subsequent changes in bacterial abun-
dance influence clinical outcomes in patients with
cirrhosis and HE. For example, lactulose can often
resolve overt HE within 1–2 days; however, older data
suggest that increases in probiotic bacteria are not
observed for ≥ 2 days.[42] However, these studies are
very small, confounded, and used culture-based
techniques, sometimes analyzing stool that had been
at room air temperature without DNA preservative for
24 hours.[12]
A minority (< 30%) of gut bacteria can be cultured.
Therefore, culture-based methods limit our ability to
evaluate microbiota changes with lactulose.[43] Since
the 1990s, culture-independent techniques such as
analysis of 16S rRNA amplicon sequencing have
increased the breadth and taxonomic depth of micro-
biota analysis. Analyzing 16S rRNA amplicons from
stool, a multicenter trial of lactulose in 98 patients with
minimal HE found an increase in 3 bacterial families.
Furthermore, they found that lactulose-induced fecal
microbial abundance changes differed between
patients with and without clinical response.[24] Of note,
this study reported family-level taxa (not the more
granular genus level), and did not report a change in
Lactobacillus and Bifidobacteria. Another group stud-
ied paired stool specimens in 21 patients with cirrhosis
prelactulose and postlactulose for 6 weeks.[44] Inves-
tigating bacteria found in at least 10% of samples
using 16S rRNA amplicon sequencing, they found no
taxa whose abundance differed significantly in a
paired t test (and controlling for multiple comparisons).
They found that interpatient differences in microbiota
 4
| HEPATOLOGY COMMUNICATIONS
community structure were greater than intrapatient
changes with lactulose. However, the principal coor-
dinate analysis showed that individual’s microbial
community structure did indeed change with lactulose.
This result suggests that microbial communities
change with lactulose, but may do so in a heteroge-
neous way. In a study of 7 men in whom lactulose was
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withdrawn, an amplicon-based technique similar to
16S rRNA amplicon sequencing showed that fecal
Faecalibacterium abundance dropped from 6% to 1%
with lactulose withdrawal.[45] Finally, while none of the
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amplicon-based sequencing studies in patients with
cirrhosis found an increase in Lactobacillus and
Bifidobacteria with lactulose as had been seen in
culture-based studies, a healthy human model found
that lactulose promotes re-growth of Bifidobacterium
(with amplicon sequencing methods) and butyrate
production after antibiotic administration.[46]
Techniques for microbial community analysis con-
tinue to evolve beyond amplicon-based sequencing.[47]
Metagenome approaches have several advantages
over amplicon-based techniques like 16S rRNA
sequencing, including greater taxonomic resolution
and ability to infer bacterial function. To our knowledge,
no one has investigated microbial community composi-
tion and functional changes with lactulose using these
modern metagenome analysis techniques.
Lactulose as it relates to ammonia
In the 1970s, a series of experiments performed in a fecal
incubation system characterized some fundamentals
about the relationship between lactulose, enteric bacte-
ria, and ammonia. First, Vince et al[48] found that lower
fecal pH led to less bacterial ammonia production. This is
relevant because lactulose leads to SCFA production
and stool acidification, so this acidification may diminish
bacterial ammonia production. Second, administering
lactulose significantly decreased ammonia production
from most bacteria.[49] Third, even when buffering for a
consistent pH, lactulose reduced enteric bacteria ammo-
nia production.[50] The authors concluded that the
majority of ammonia-lowering effect was attributed to
the direct lactulose effect on bacterial fermentation, and
less so from pH lowering. Lactulose fermentation by
probiotic taxa requires increased bacterial amino acid
synthesis using ammonia as the substrate, leading to
reduced luminal ammonia concentrations.[50–53]
Lactulose may reduce serum ammonia through
additional mechanisms, including trapping ammonium
ions in the colon.[54–56] Elkington et al[11] performed the
first double-blind clinical trial of lactulose to treat HE,
and found that lactulose lowered arterial ammonia
levels and stool pH in 5 of 7 patients. Here, as
elsewhere, lactulose both improved the patient’s mental
processing and lowered ammonia levels; however,
ammonia levels rarely normalize.[23] The distribution of
ammonia between colonic contents and colonic venous
blood relates to colonic pH. Above a fecal pH of 6.2,
ammonia fluxes from the colonic lumen to blood.
However, below the fecal pH of 6.2, ammonia flux
reverses and travels from the blood to the colonic
lumen.[4,12] At low fecal pH, the theory is that ammonia
diffuses from the blood into the gastrointestinal lumen,
is converted to ammonium ions, and is disposed of
through feces. Work in healthy humans supports this
possibility, as lactulose leads to an increase in total
ammonia (and nitrogen) excretion.[57]
Lactulose as a laxative agent
The first double-blind clinical trial of lactulose to treat HE
found that lactulose was more clinically effective than
sorbitol despite both inducing loose stool.[11] However,
only 1 patient had active HE symptoms at the start of
the trial and despite resolution after cross-over from
sorbitol to lactulose, conclusions from this study are
uncertain. Magnesium sulfate was also shown to
produce diarrhea without clinical improvement in
HE.[58] Therefore, while lactulose produces a laxative
effect, it is not clear that this correlates strongly with
clinical improvement.
Lactulose and potential pathogens
Fermentation of lactulose leads to an increased
abundance of beneficial taxa that can use these
substrates, produce SCFAs, and reduce pH in the
intestinal lumen. Increased biomass of beneficial taxa
reduces available nutrients for invading microbial
pathogens.[59] In the setting of colonic acidification from
SCFAs, ammonia production from gram-negative bac-
teria decreases, likely reflecting diminished metabolic
activity as well as growth inhibition of those bacteria.[50]
A recent multicenter study of lactulose for minimal HE
found no significant change in microbial composition
(using 16s rRNA sequencing); however, those with a
clinical response experienced a significant decrease in
certain Actinobacteria, Bacteroidetes, Firmicutes, and
Proteobacteria relative to nonresponders.[24] Bacteroi-
detes and Proteobacteria produce lipopolysaccharide,
which has been implicated in the pathogenesis of
HE.[60–62]
Lactulose and barrier function
In vitro and human studies showed that prebiotics such
as galactooligosaccharides improve intestinal barrier
function by stimulating mucus-producing goblet cells,
augmenting tight junction assembly, and mitigating
 LACTULOSE IN CIRRHOSIS
inflammation.[63–66] In patients with minimal HE, lactu-
lose decreases bacterial DNA in the serum and
improves neurocognitive test scores, presumably
through changes to bacterial composition and improved
intestinal permeability—the latter of which may be a
result of increased SCFA production.[67]
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SUMMARY
While the literature is not uniform on its actions, it
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appears that lactulose’s benefits in HE are mediated
through changes in intestinal microbes, likely a result of
its pH-lowering effect, positive pressure on beneficial
taxa, and an improvement in gut barrier function
(Figure 2).
In 1969, Haemmerli and Bircher[42] wrote “the
exciting aspect of lactulose therapy, however, is its
mechanism of action. Once completely elucidated, it
may shed new light on the pathogenesis of hepatic
coma.” Nearly half a century later, we have a better
understanding of lactulose’s mechanism of action, but
the picture is still not complete.
P R A C T I C A L C O N SID E R A T I O N S
Achieving balance
The oft-repeated target for lactulose titration is to
achieve 2–3 soft bowel movements daily. In view of
F I G U R E 2 Mechanisms by which lactulose treats HE. Lactulose puts positive pressure on probiotic bacteria, which consume ammonia and
produce SCFAs as part of their metabolism. These SCFAs supply energy to the intestinal epithelia and also create an acidic environment which
place negative pressure on ammonia-producing and potentially pathogenic organisms. Figure created in biorender.com. Abbreviation: SCFA,
short-chain fatty acid.
| 5
the known mechanisms of lactulose effects, it is clear
that its benefits are facilitated in part by, but not
exclusive to, catharsis. Increased bowel movement
frequency alone is not an effective use of lactulose.
Diarrhea, for example, is a common reason for
treatment discontinuation and can lead to dehydration
or electrolyte loss, which are, themselves, triggers for
HE. For those with overt HE, early and effective
laxation in the context of euvolemia and supportive
care with additional doses is advisable.[15] However,
after the resolution of disorientation, the number of
bowel movements is no longer associated with 30-day
outcomes.[68] This finding extends to a cohort of 269
outpatients with ≥ 6 months of medication adherence,
where achieving a target of 2–3 bowel movements
daily was not associated with cognitive function on
psychometric testing.[69] In a retrospective study of
112 patients on lactulose, a Bristol Stool Scale > 4
was found to be associated with a reduced risk of
hospitalization for HE even among patients not meet-
ing the target of 2–3 bowel movements.[70]
The concept of titrating lactulose to qualitative stool
changes is attractive. However, many patients with
cirrhosis have baseline disturbances in bowel function
such as irritable bowel syndrome. Further, there was no
association between quality of life and cognitive
function and the Bristol Scale in a randomized trial of
lactulose.[25]
Moving forward, there are several areas to consider.
First, safety is paramount and closer monitoring of
patients to avoid excessive bowel movements is
 6
| HEPATOLOGY COMMUNICATIONS
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F I G U R E 3 Use of mobile technology to titrate lactulose. Patients
taking lactulose require monitoring to avoid excessive bowel move-
ments and subsequent dehydration. Such monitoring can be achieved
with just-in-time text messages or other mobile technology.
important to avoid dehydration. This can be achieved
using just-in-time text-message-based instructions on
how to adjust doses based on the prior day’s bowel
movements as was performed in the MiKristal trial
(Figure 3).[25] Second, the method of treatment initiation
and titration has not undergone any scrutiny or
investigation. Slowly increasing the amount of lactulose
consumed by volume per dose and frequency, titrating to
bowel movement frequency and ideally patient-reported
outcomes may be advantageous. Third, further validation
of qualitative stool changes in longitudinally followed
patients is warranted. Targets include the Bristol scale,
stool pH, and even microbial composition.
Alternatives
Given the risk of bloating with and sweetness of
lactulose, there is interest in finding alternatives. In
practice, though unstudied, many will use PEG. In a
randomized trial, Rahimi et al[17] found that 4 L of PEG
hastened mental status recovery compared with lactu-
lose 30 mL thrice daily. However, 87% of PEG subjects
received lactulose before randomization, and thus, the
comparison is best framed as PEG-plus-lactulose versus
low-dose lactulose alone. In a recent small trial, 2 L of
PEG followed by lactulose was more effective than low-
dose lactulose alone.[18] Taken together, these studies
confirm the importance of early and effective laxation in
the management of overt HE while also highlighting the
role of lactulose. PEG has never been explored for the
prevention of HE. Many patients may never, or rarely,
develop recurrent HE after an episode of overt HE,
making questionable the anecdotal experiences of
success after switching to PEG. As such, it is premature
to generalize these inpatient studies to the long-term
management of outpatients. Indeed, many prior studies
conducted cross-over assessments with inert cathartics
such as sorbitol or magnesium with poor outcomes.[11,12]
Trials of PEG are needed in carefully selected patients
where equipoise exists before this strategy can be
F I G U R E 4 Aims of future lactulose research. While lactulose is
clearly effective in treating HE, there are several lingering uncertain-
ties about its mechanism and ideal use. These uncertainties should be
the focus of future research.
endorsed. Finally, given its tolerability, many patients
are started on rifaximin alone. However, patients
receiving rifaximin alone are more likely to have recurrent
hospitalizations for HE. Relative to “no therapy,” lactulose
alone was associated with a lower incidence rate ratio for
hospital-days per person-year than those receiving
rifaximin alone: 0.31 (95% CI: 0.30–0.32) versus 0.49
(95% CI: 0.45–0.53).[3]
FUTURE DIRECTIONS
Lactulose has been used to effectively treat HE for
50 years. However, some uncertainties remain about
its mechanism and ideal use. There appears to be
heterogeneous effects of lactulose clinically, as well as
on the microbiome. Future research should employ
modern metagenome analysis techniques to investi-
gate microbial community composition and functional
changes with lactulose, including analysis of diverging
subgroups (Figure 4). For example, are there certain
bacterial enterotypes that are less or more likely to
respond to lactulose clinically? What is the microbiome
community structure of lactulose nonresponders,
and could this be manipulated to lead to clinical
success? Finally, gastrointestinal side effects are
unfortunately common with lactulose use. Are there
certain microbiome composition or functional features
associated with lactulose side effects, and could they
be manipulated with other dietary, probiotic, or other
interventions?
 LACTULOSE IN CIRRHOSIS
F U N D I N G IN F O R M A T I O N
Patricia P. Bloom receives funding from the American
College of Gastroenterology (ACG Junior Faculty Award).
Elliot B. Tapper is funded by NIH U01DK130113 (Tapper).
CONFLICTS OF INTEREST
Patricia P. Bloom consults for Nexilico. She received
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grants from Vedanta. Elliot B. Tapper consults for
Allergan, Axcella, Kaleido, Mallinckrodt, Novo Nordisk,
and Takeda. He received from Gilead and Valeant.
1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 12/21/2023
ORCID
Patricia P. Bloom https://orcid.org/0000–0003–3188–
7188
Elliot B. Tapper https://orcid.org/0000–0002–0839–
1515
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