Fig.4 Drugs with gastrointestinal toxicity modulated by gut
microbiota: methotrexate (A), irinotecan (B), 5-fluorouracil (C), and
mycophenolate mofetil (D). Red structures signify hepatotoxic drugs.
Gastrointestinal toxicity of MPA and SN-38 can be attenuated by
β-glucuronidases inhibition. Abbreviation: 5-FU, 5-fluorouracil; DPD,
dihydropyrimidine dehydrogenase; MMF, mycophenolate mofetil; MPA
mycophenolic acid; MPAG, mycophenolic acid glucuronide; MTX,
methotrexate; SN-38G, SN-38 glucuronide; UGTs,
UDP-glucuronosyltransferases.
4.1 Methotrexate
Methotrexate
(MTX) is an antifolic antineoplastic but brings about multiple side
effects including hepatotoxicity, nephrotoxicity, pulmonary toxicity,
and gastrointestinal toxicity, among which hepatotoxicity and
gastrointestinal toxicity are the most common (Wang et al., 2018). In
terms of gastrointestinal toxicity, it is characterized by
gastrointestinal mucositis. A previous study found that MTX treatment
substantially decreased gut microbial quantity and diversity of rats,
with anaerobes and streptococci significantly decreased, which is
proportionally associated with the severity of MTX-induced
gastrointestinal mucositis (Fijlstra et al., 2015). A similar study
confirmed the microbial dysbiosis caused by MTX in mice with a
significantly decreased abundance of Bacteroides fragilis , and
supplemental Bacteroides fragilis respited MTX-induced
inflammatory reactions and macrophage polarization (Zhou et al., 2018a).
Moreover, Bifidobacterium longum was also found to be a probiotic
in attenuating MTX-induced intestine damage, which was discovered in the
co-treatment of leucovorin with MTX for the sake of reducing its side
effects (Huang et al., 2020b). Supplementation with probiotics perturbed
by drugs is the most direct and explicit way in alleviating microbiota
related adverse effects, but safety remains a question for long-term
adhibition. In comparison, dietary control offers a safer alternative
herein. It was found that dietary restriction remarkably enhanced the
survival rate of mice exposed to a lethal dose of MTX and ameliorated
MTX-induced intestine inflammation with Lactobacillus rhamnosusplaying a critical role (Tang et al., 2020). In this case, dietary
restriction needless of specific diet, drug, or probiotics intervened
achieved remarkable results in reducing MTX-induced gastrointestinal
side effects, suggesting what we eat, which constitutes the major part
of gastrointestinal contents, probably determines therapeutic and toxic
outcomes of orally administered drugs somehow.
4.2 Irinotecan
Irinotecan (also called CPT-11) is
one of the most commonly applied anticancer agents for colon carcinoma
therapy but causes lethal toxicity in at least 36% of patients, most of
whom undergo diarrhea, mucositis, and other gastrointestinal reactions
(Encarnação et al., 2018). In the human body it is metabolized both by
liver and gut microbiota (Fig.4): first converted into bioactive SN-38
by liver carboxylesterases and further transforms into SN-38G by
conjugating with glucuronic acid catalyzed by hepatic
UDP-glucuronosyltransferases (UGTs), which is then subject to gut
bacterial β-glucuronidases to generate SN-38, also a toxicant that
induces damage of intestinal epithelial cells and severe diarrhea (Yang
et al., 2018b). Due to the critical role of gut bacterial
β-glucuronidases plays therein, it has been highlighted in mitigating
irinotecan-induced gastrointestinal toxicity. Intestinal bacterial
β-glucuronidases are considered to be a predictive biomarker of
irinotecan triggered diarrhea severity (Chamseddine et al., 2019) and
inhibition of it has been demonstrated to be effective in abrogating
irinotecan toxicity (Wallace et al., 2010; Roberts et al., 2013).
However, inhibition of bacterial β-glucuronidases of different origins
and structures received distinctly different outcomes: inhibition ofFirmicutes and Proteobacterium derived β-glucuronidases
alleviated irinotecan-induced diarrhea in mice while inhibition ofBacteroidetes derived one did not, suggesting functional
diversity in orthologous enzymes of gut microbiota (Wallace et al.,
2015). Additionally, probiotics such as Saccharomyces cerevisiae UFMG
A-905 (Bastos et al., 2016) and Escherichia coli Nissle 1917
(Wang et al., 2019c) treatment also has been proven to confer protective
effects against irinotecan-induced gastrointestinal side effects.
4.3 5-Fluorouracil
5-Fluorouracil (5-FU), used for colorectal cancer therapy, is frequently
related to mucosal side effects such as diarrhea and mucositis. 5-FU in
the human body is mainly detoxified by hepatic dihydropyrimidine
dehydrogenase (DPD), inhibition of which induces 5-FU accumulation and
consequently aggravates adverse effects. In 1993, a combination of
Sorivudine and 5-FU resulted in 18 deaths with symptoms of diarrhea and
decreased blood cells and platelets in Japan, 40 days after Sorivudine
was approved in clinical use. It was found that gut microbial metabolite
of Sorivudine, bromovinyluracil inactivated DPD and thus limited
detoxification of 5-FU (Klaassen and Cui, 2015). It is an example that
gut microbiota mediates drug-drug interactions and further studies
illustrate that gut microbiota regulates 5-FU toxicity directly. A study
relating 5-FU-induced colon inflammation to gut microbiota suggested
that 5-FU caused alterations in gut microbiota and fecal transplantation
from 5-FU treated mice to normal ones diminished functional performance
and altered colon inflammatory markers of the latter (Sougiannis et al.,
2019). Another study focusing on fecal transplantation from the
therapeutic side revealed transplantation of fecal microbiota from
health donor mice attenuated 5-FU-based chemotherapy regimen, FOLFOX
(5-FU, leucovorin, and oxaliplatin)-induced intestinal mucositis by
downregulating expression levels of toll-like receptors (TLRs), MyD88,
and serum IL-6 with verified safety (Chang et al., 2020a). Similarly,
probiotics were also found to palliate 5-FU-triggered intestinal injury,
including Lactobacillus casei rhamnosu (Chang et al., 2018),
Saccharomyces Boulardii (Justino et al., 2014), and LactobacillusGG (Holma et al., 2013), in animal experiments and human trials
respectively. The human trial also showed that methanogenic archaea made
a difference in whether patients underwent diarrhea or constipation
after 5-FU treatment (Holma et al., 2013). Additionally, prebiotics such
as the herbal pair, Atractylodes Macrocephala and Panax
Ginseng conferred a protective effect against 5-FU by restoring gut
microbiota disturbed by it and especially inhibited 5-FU-induced release
of intestinal inflammatory cytokines (Wang et al., 2019a). As we put,
strategies for tackling 5-FU-induced diarrhea and mucositis are
restricted within conventional ones, mainly including fecal microbial
transplant, probiotics, and prebiotics supplementation. The discovery of
intestinal microbial metabolism of the drug proffers different and
effective methods in coping with its toxicity, suggesting microbial
metabolism of drugs plays a significant role in determining toxic
outcomes of drugs.
4.4
Mycophenolate mofetil
Mycophenolate mofetil (MMF) is an immunosuppressive agent prescribed to
patients after transplantation and also exerts severe gastrointestinal
side effects which limit its application. As a prodrug, it is hydrolyzed
to mycophenolic acid (MPA) to confer efficacy and is converted into
glucuronidated MPA (MPAG) by hepatic enzymes. MPAG is primarily excreted
via urine but approximately 10% of it is transported into the
gastrointestinal tract and is metabolized by gut microbial
βglucuronidase back into MPA (Fig.4), whose accumulation in the colon
is associated with MMF-induced colonic inflammation (Lamba et al.,
2014). A study revealed that MMF disturbed gut microbiota of which
Proteobacteria (specifically Escherichia/Shigella ) and gene
expression of LPS biosynthesis were significantly enhanced while overall
diversity was diminished in mice, which could be reversed by
broad-spectrum antibiotics treatment (Flannigan et al., 2018).
Consistent with the metabolic pathway of MPA in the gut, it was found
that MMF induced
active
βglucuronidase expression and in turn exacerbated its gastrointestinal
adverse effect, which could be eliminated by vancomycin (Taylor et al.,
2019), suggesting that βglucuronidase also can be an efficient target
in alleviating MMF toxicity.