Introduction
The high-altitude (HA) area in the Karakoram range has typical
environmental challenges, such as low oxygen pressure, temperature,
humidity, high radiation and dry weather etc., leading to series of
physiological and metabolic disorders1,2 . In
addition, change in the diet includes high fiber and low protein
products as major portion of diet, while consumption of vegetables and
fruits is significantly reduced. Such places are mainly populated with
natives, personnel on duties and researchers. Several associations
between chronic human diseases including inflammatory bowel disease
(IBD) like Crohn’s disease, some extra-intestinal disorders including
asthma, metabolic syndrome, allergies, cardiovascular disease, and
obesity 3,4,5, , altered gut microbiota
constitution and its functions have been reported in last few years6,7 . At least 30% of sojourners from low
land report adverse effects at HA including cardiac, respiratory &
neurological symptoms, joint pains, headache, nausea, vomiting, bloating
and IBD. Little work has been done on the effect of HA hypoxia on
digestive system in either patients with altitude illness or in healthy
individuals. In fact, symptoms of digestive system such as anorexia,
loss of appetite, stomach/abdominal pain, constipation, epigastralgia,
heart burn, dyspepsia, vomiting, diarrhea, hematemesis, piles and peptic
ulcers are frequently reported in mountaineers and altitude sojourners8,9,10,11,12 . Moreover, epidemiological and
clinical studies suggest that gastro Intestinal bleeding (GIB) is not
uncommon at HA, and is often
life-threatening13,14 . The problems could be
due to the release of host metabolites causing inflammation or the
interaction between the host and gut
microflora14,15,16 .
Exciting time to study the body associated microbes and the human
microbiota, consisting of 100 trillion bacteria along its
400m2 surface area, encoding 100fold more genes than
our own genome17 . The in-depth analysis of
the microbes make it to realize their influence on human physiology in
different areas to characterize the global presence of microbial
diversity under different environments and dietary habits. It is
reported that the microbial diversity in the gastrointestinal tract
plays a crucial role in host physiology, including involvement in
nutrient metabolism and gut barrier18 .
However microbiome composition driving factors are not fully understood
yet, due to several factors including limited sample size, inconsistent
DNA extraction and varied sequencing
methods19,20,21 . Various reports support the
involvement of environment, genetics, antibiotic
usage22 and lifestyle factors including
diet23,24,25 . Even short exposure to HA can
alter the composition of gut microbiota26,27 .
Li and Zhao28 and Li et
al29 , have reported contribution of HA,
genetics and dietary factors in Tibetan and Chinese Han groups in
shaping gut microbiota. Overall gut microbiome has been investigated in
some Indian tribal populations irrespective of their ethnicity and
dietary habits20 . Das et
al30 compared Indian urban and rural
population at 228m with HA population at 3500m, with respect to their
dietary habits and geographies. Study performed on western Indian
population at 153m compared to other geographies revealed a distinct
taxonomic and functional niche31 .
To the best of our knowledge there has been no study so far on genome
wide changes on human response at extreme altitude and that ours is the
first attempt as a comparative analysis on Indian sojourners belonging
to the same ethnicity ascending to extreme altitude, to compass the
complete meta genomic map and networks involved in extreme altitude
(3500 – 5800m) responses. We used 16s rRNA associations with Whole
genome sequencing (WGS) applying the same metagenomics DNA extraction &
sequencing platform and bioinformatics pipeline to yield not only
profiles of bacterial composition and diversity, but also estimate the
functional potential of the microbiome32 . For
quantifying bacterial species abundance and intra-species genomic
variation we used MIDAS, a computational pipeline, followed by novel
strain level analysis by METABET2 approach to quantify gene content of
prevalent bacterial species and identified significant intra species
population composition associated with environmental factors at extreme
altitudes. The findings revealed striking microbial dysbiosis proving
important to shed light on human acclimated processes and prevention of
the physiological changes associated with it at HA. It is expected that
besides classifying the gut microbial repertoire, particularly going
down to strain variation at nucleotide level and differences in gene
content, may provide crucial information in deciphering important
insights in correlating the structure of gut microbiome, microbial
pathogenicity, various metabolic disorders and host adaptation of
pathogens33 or other related microbial
conversions and outbreaks34,35 at high and
extreme altitudes.