Earlier we had reviewed the role of LncRNA’s in Colorectal Cancer (CRC)     besides role of different Gut Microbiota in the  generation of escalating  Obesity ,insulin resistance and type2Diabetesmellitus(T2DM).Furthermore recently describing how the part of Hydrogen Sulfide (H2S), which has been recently  acknowledged to be a gasotransmitter is implicated in various significant physiological and disease situations, inclusive of  vasodilation, stimulation of cellular   bioenergetics, anti-inflammation, and pro-angiogenesis can be used in resistant Breast Cancer inclusive of Triple-negative breast cancer (TNBC),  on reviewing therapy for Breast Cancer. Here we have tried to emphasize on the escalating incidence of Early onset Colorectal Cancer(EOCRC)(≤50yrs);this inimical EOCRC tendency partly gets reasoned out specifically by the robust impact of dietary habits  escalated intake of red as well as processed meat andhigh  fat high sugardiet .The animal- dependent    diet with high fat high sugardiet (alias Western diet ) results in    switch in dominating  Microbiota along with their metabolic  action which might aid in the interference of  homeostasis  of H2S quantities. Bacterial Sulfur metabolism has been acknowledged to be a key mode in the EOCRC pathogenesis. Here we reviewed the pathophysiological  mode by where   manner   by which diet correlated switch in Gut Microbiota alias Microbial Sulfur Diet stimulates damage as well as inflammation of the colonic mucosaalong with aids in generation of   CRC   .Stress ongreater  ingestion   of intake of fruits ,yellow vegetables, whole grain ,legumes, cruciferous vegetables were correlated with  lesser CRC occurrence which is more to be initiated right from childhood and adolescents would help in decreasing CRC imcidence. Furthermore, we have tried to clarify how H2S action might be via nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain- containing 3 (NLRP3 inflammasome). 

Colorectal Cancer (CRC) is presently the 3rd commonest malignant tumor all over world. Roughly 1.8 million new cases along with approximately 900,000 deaths GET documented worldwide every year, being the 2nd maximum   frequent etiology of mortality worldwide[1].The incidence of CRC is directly proportional  with the escalation of    socioeconmic  or the human developmental index(HDI) with time[2]. Earlier studies have pointed that the greater HDI levels  are  probably correlated with the alterations in prevalence  of lifestyle associated  with  risk factors inclusive of  escalated intake of red as well as processed meat in addition to  obesity, refined carbohydrates,   decreased physical  activity, smoking, ingestion of alcohol[3].With  the  plan to decrease CRC incidence along  with mortality numerous countries have decided to conduct   routine colonoscopy screening strategies for    early pickup as well as  avoidance by re-section of  precancerous polyps at the time of colonoscopy[4].There has been a total reduction in incidence  in numerous countries inclusive of  United States of America  (USA),Israel, along  with Japan, where early    estimation strategies have been   generated  from 1990s[4,5]. Nevertheless, an International evaluation of present  tendencies regarding CRC   incidence suggested that there has been a  significant escalation in case of young adulthood ≤50yrs observed  in the past 20yrs[6]. CRC which gets diagnosed in case of subjects≤50yrs old is   asknown as Early onset Colorectal Cancer (EOCRC). Explaination of drastic enhancement of formation of EOCRC are enigmatic. However a part from traits risk factors aiding in the generation of EOCRC are akin; however    are not restricted, to those correlated with the elderly population     inclusive of Western diet, in addition to  obesity in addition to lifestyle correlated with decreased physical  activity[2,6]. In contrast to late onset Colorectal Cancer (LOCRC), the clinical manifestation of EOCRC usually has had greater advancements apart from poor prognosis [7]. Thereby it becomes necessary to have acquisition of insight regarding modes   behind and find the risk factors along with inimitable properties of EOCRC regarding early diagnosis along with correct management. 

Escalating confirmation has pointed that diet portrays a significant factor   correlated with the Gut Microbial actions correlated with escalated EOCRC incidence [8]. The high fat high sugar   diet referred to in the form of Western diet, changes the genetic   constitution as well as the metabolic actions of the Gut Microbiome, in  particular implicated in Sulfur  Metabolism[8]. Earlier we had reviewed the role of LncRNA’s in CRC besides roles of epigenetics in DKD [9,10]. Here we review the alterations in the epidemiology   of CRC associated with worldwide food ingestion. We evaluate the actions of the  dietary constituents on inherent alterations in Gut Microbial constitution as well as the metabolic actions . Moreover, here   we emphasize the   pathophysiology of the way diet correlated switch in Gut Microbiota (GM) stimulates damages as well as inflammation to colonic mucosa in addition to aids in   the generation of CRC specifically early in life.

Here we conducted a systematic review utilizing search engine pubmed, google scholar ;web of science ;embase;  Cochrane   review library  utilizing  the MeSH terms  like Colorectal Cancer; Early onset Colorectal Cancer(EOCRC); late onset Colorectal Cancer(LOCRC), Gut Microbiota(GM) ; Hydrogen Sulfide (H2S); Epigenetics; LncRNA as biomarkers ;as therapeutic targets ;mode of action  DNA methylation; Histonealterations ; biomarkers  ;  epigenetic liquid biopsy; role of tea phenols; curcumin ;nicotine  ; phosphatidylinositide 3-kinase(PI3K) /protein kinase B(AKT) ;Wnt. beta catenin signaling pathways from  2000 to 2023 till date.

We found a total of 600 articles out of which we selected 83 articles for this review. No meta-analysis was done.

2.The Bothering Trajectory in CRC incidence amongst young adults got

As per the United States Cancer Registries results   from 2013-2017,54% of CRC patients   get diagnosed in case of subjects  >65yrs old along with 34% amongst50-64yrs with a median age at 67yrs[111]. Subsequent to utilization of conducting routine colonoscopy screening strategies in addition to enhancement of  recognition of CRC risk factors, the incidence rate have undergone reduction at a fast pace  by 3% yearly in US, in  case of old  subjects[12-14] .In comparison to, that the incidence of CRC  in younger  adults ≤50yrs illustrated an  escalation of 4.3% yearly proportional alteration at the time of  2015-2019(Figure1a)[rev in 12,13]. 

Legend for Figure 1(a): Courtesy ref no-12(a). A recent trend in SEER Age-adjusted colorectal cancer incidence rate from 2000 to 2019. This figure was created by https://seer.cancer.gov/statistics-network/explorer (accessed on 15 February 2023)

Furthermore, a Global evaluation of CRCv incidence illustrated an escalation of EOCRC in men as well as women in 19 countries across 5 continents [9]. Despite maximum CRC diagnosis continues tobe in the elderly>50yrs CRC mirrors a considerably greater hurdle in younger adults<50>

Legend for Figure 1b: Courtesy ref no-12 (b) Increase in early-onset colorectal cancer incidence rate. This graph is created based on the summary of the published articles by Siegel, R.L. et al. [9].

The upward trajectory in incidence of EOCRC was initiated in the 1970’s over the continuous cohort born in as well as subsequent to 1960’s consecutively [11,15]. Dependent on CRC incidence tendencies in the United States amongst 1975-2010, the yearly proportional alteration- dependent anticipated incidence rates of colon cancer would escalate   in 2030 by 27.7% for the age of 35-49 as well as90% for the age of20-34[18]. The incidence rate of rectosigmoid in addition to    rectal cancer is anticipated to   be further greater- in contrast to colon cancer-46% of the ones amongst35-49 as well as124.2% for the age of20-34[16]. This kind of steep upward trajectory regarding incidence   of EOCRC has further been observed in countries which hunderwent or currently are going through   fast industrialization for instance Korea, Cyprus, Thailand, Taiwan etc[1-17]. Intriguingly, as illustrated in (Figure2),

Legend for Figure 2: Courtesy ref no-12-The countries demonstrate increasing colorectal cancer incidence rates in both younger and older populations. This graph is created based on the summary of the published articles by Sung, H. et al. [1] and Siegel, R.L. [11].
EOCRC enhancement in these countries takes place concurrently with the escalation of LOCRC at the time of 2008 -2012.This concurrent alteration in the CRC incidence mirrors a fast alteration in lifestyle as well as diet which has impacted elderly in addition to younger population inthe last   numerous years [11].

Unestimated exposure taking place in early life, or exposure commonly encountered by the younger generations in case of countries possessing considerably   greater  HDL might enhance the risk of EOCRC along  with can be delineated in the form of the birth cohortactions on EOCRC incidence[15]. Furthermore the elevation of CRC can be portrayed for overall ages in countries with rapid switch of generational status pointed that exposure of some risk factors at the time of a time frame in life might have the expression of CRC subsequent to a latent period[15]. The maximum fear is the susceptibility to carcinogens early in life from prenatal to adolescence might influence mutagenic injury at the time of generational period probably leading  to a postponed action on EOCRC incidence [18].The cancer trajectory might represent a substantial disease load inthe further times if immediate action  is not started  regarding theyounger  generations.

3. Variations in Clinical along with molecular characteristics amongst EOCRC as well as LOCRC

The Clinical characteristics    of  EOCRC vary amongst older patients regarding in stage, tumor  placement along  with   histology at the time of the diagnosis  to start with. In case of   young adults diagnosis of CRC is in general done once maximum symptoms  like hematochezia/melena  are the manifestations[19]. In case of   80.5% patients usually  separate symptoms for instance abdominal pain, intestinal obstruction, anaemia as well as alterations in bowel habits took place [20]. Although presentation with symptoms, the degree of suspicion by the primary  clinicians is considerably less apart from their reluctance  to  send young patients for medical consultation that   might postpone the diagnosis by a median of6.2mths in  young adults under 50yrs in contrast to patients ≥ 50yrs [19,21]. Whereas at the time of diagnosis patients apparently present with advancement of stage, lymph nodes  along with distant metastasis as well as possess the  greater probability of generation of asynchronous or distant metastasis   in  time period of disease in contrast to turnover to patients ≥ 50yrs[7, 19-21]. Whereas the anatomical placement of LOCRC is organized across the colon and  rectal  at equivalent frequencies  in  case of EOCRC  an uneven  organization- maximum frequently in  rectum, next left sided Colon that is  followed by ride sided colon at 42%,31% along  with27% , respectively [22]. Moreover, in contrast to LOCRC, the histopathological properties of EOCRC possess the greater probability of  manifestation with exacerbated properties, high grade, poor differentiation of tumors possessing signet ring or mucin generating  that are  usually associated with perineural or lymphovascular invasion  of the CRC cells [7,23].

The molecular characteristics  of EOCRC  are substantially  heterogenous  composed of hereditary CRC syndromes originating from different germline mutations in addition to non hereditary or sporadic mutations without  robust  familial clubbing [15,23]. Hereditary CRC gets constituted about  5-16% of  EOCRC patients, influencing  subjects   early in   life, basically  at age of 20-30 ys[24].The pathogenesis of hereditary EOCRC is correlated with  germline genetics mutations resulting  in genetics instability, cells proliferation or decontrolled microenvironment[25]. Contrary to hereditary EOCRC molecular properties  of sporadic  EOCRC are baffling  in addition to might illustrate  distinct characteristics differentiable from those  of hereditary EOCRC[26,27]. Despite hereditary EOCRC takes place at a greater rate  in a younger population in contrast to older population sporadic  EOCRC is responsible for 80% EOCRC patients being the maximum frequent  kind[17]. In contrast to the LOCRC patients, the cancerous properties  of sporadic  EOCRC most commonly  possess microsatellite stability in addition to absence of DNA healing mode aberrations that   are variable in gene expression as well as molecular pathogenesis[24,26,].Significant variation of EOCRC which are   microsatellite stable(MSS) EOCRC with regards to  gene expression along  with molecular pathogenesis from LOCRC[26]. MSS EOCRC in stable displays over expression  of catenin- β(CTNNB1) gene in addition to correlation  with upregulation  of Wnt/β-catenin, mitogen activated protein kinase (MAPK), growth factors signaling as well as Tumor necrosis factor receptor 1 (TNFR1) pathways; in all probability impacting metastasis along with chemoradiosensitivity [42]. Other molecular abnormalities, inimitable  to EOCRC  inclusive of epigenetic change, maximum frequently line interspersed element (LINE-1) hypomethylation, correlated with escalated chromosomal instability[29]. Variations in molecular changed profiles a  represent in EOCRC which are  being actively assessed. However, in line of evidence that maximum frequent kinds of EOCRC   subjects are the with the sporadic once, the repercussion of  genetics mutations with regards to pathogenesis can’t be explained.   crosstalk amongst environmental factors in addition to genetic susceptibility would   be necessary regarding tumor   expression.

4. Lifestyle associated along with environmental risk factors correlated with EOCRC

The properties of risk factors regarding CRC have been thoroughly investigated dependent on numerous population dependent cohort as well as case control studies, basically divided into modifiable as well as nonmodifiable as illustrated in Figure3. 

Legend for Figure 3: Courtesy ref no-12-Risk factors can be categorized as modifiable and nonmodifiable.

Despite the maximum risk factors have been revealed from older populations, results regarding younger populations, suggest that,like in older populations risk factors correlated with western’’ diet along with lifestyle associated with decreased physicalactivity,  works  in the form of considerably significant escalation of CRCgeneration[30]. Western diet, possessing   greater high fat high sugardiet inclusive of escalated intake of red as well as processed meat ingestion in addition tosedentary lifestyle are pointers to human generation generation in addition to fast industrialization that are closely intertwined with Obesity apart from Obesity correlated chr diseases or malignancy[2,,31]. This tendency is well with  displayed by CRC in Asia for instance  Chinese,Singapore, Taiwan, Japan with  2-4 times enhancement etc[1,32]. Moreover, noticeable discripancies in  incidence as well as  geography of EOCRC in addition to ethnicity in the   United States (US)[33]. greater incidence are found in areas for instance southern  states like Mississipi  Delta along withAppalachia[15] . In the contextof    racial discrepancy, noticeable escalation  of EOCRC incidence  is observed in  Hispanic/Latino men as well as Whites,though CRC incidence has Earlierbeen greater in African Americanmen[33]. These discripancies partially implicate poverty,no employment,inaccessiblity  of health care facility in the younger population [33]. However  easy  acquisition of   poor quality  diets might be me implicated in the escalating incidence of EOCRC.

 Subsequent to  substantial  socioecomic growth ,a rapid dietary transition  to elevated ingestion   of remarkably  ,refined  wheat as well as  its  products, processed     or red meat as well as ultraprocessed    food ingestion was initiated in SouthKorea as reported  in Figure4[34].

Legend for Figure 4: Courtesy ref no-12-Dietary transition and the incidence of early-onset colorectal cancer.

There by, it is not astonishing that the prevalence escalated  from 6.8-10%  in Korean childhood in addition to  adolescents aged 6-18yrs  from 1998-2013[51]. Simultaneously Type2 Diabetes mellitus(T2 DM) amongst children≤18yrs escalated by153.5%/100,000 in 2006-205.0/100,000,a germane  escalation of 33.6%[35]. Moreover, assessment  of physical   activity , screen  time ,sleep  period,  a crossectional  study, with the  utilization of    national outcomes pointed that  just 1.6% of adolescents   were as per meeting advocated Canadian 24hour movement guidelines for children and  youth,that  implicates a minimum of 60’ of moderate- robust physical    activity,no greater than2 hrs of screen  time,8     &11hrs of  sleep  period in timespan of24 hrs of a canonical day[36].What was  greater inimical,a  separate study that analyzed  the 6year prevalence trajectory which struck to the advocated Canadian Guidelines demonstrated that<1>

5. Diet in the form of ‘’exposome’’ correlated with EOCRC

With the  propagation of   genetic   research  along with molecular epidemiology illustrated that environmental   life period exposure to risk factors possessed  an elemental part in  disease expression[39].In 2005 Wild  posited  ‘’exposome’’; implying a person’s environmental exposure right from the perinatal  prenatal period further in view ofit matching the person’s genome[40]. Exposome is comprised of  3 overlapping  domain;i) the general  external environment  ii) the particular environment iii) the  internal environment as depicted in Figure5  [26,41]. 
 

Legend for Figure 5: Courtesy ref no-12-Three components of exposomes for colorectal cancer.

Placement of a  specific exposure  in a single domain    or another is tough in addition to determination of what degree of exposure possess the capacity of resulting  in  disease in a person taking  into account the  lifespan as well as variable generation  periods[38]. Nevertheless, epidemiologic studies have tried to uravel the risk factors    at the populationlevel along with the molecular pathological epidemiology of epigenetics displayed some abnormal  epigenetic signatures in    isolating disease properties, specifically of malignant neoplasms[39]. Epigenetic changes for instance , LINE-1 hypo methylation  or CpG islands methylator phenotype   are usually correlated with EOCRC[39]. Despite particular exposomal outcomes associated with EOCRC are restricted ,an enrichment of  epidemiologic outcomes in addition to  molecular research on CRC suggested that dietary habits , antibiotics  utilization, exposure to chemicals, smoking, ingestion of alcohol in the form of exposome possess complicated crosstalk with endogenous Gut Microbiota(GM) as well as    host   factors, which stimulates inflammation ,cell   proliferation as well as genetic mutation [27].

Dietary constituents substantially impact the GM   constitution apart from which might   transfer dominant bacterial colonies amongst the Gut Microbiome, impacting  host metabolism in addition to immunity[42]. Earlier in vitro along with murine studies  illustrated that  a diet having    enrichment of animal protein escalates Bacteroides species(spp), Alistipes spp ,Bilophila spp that portray  microorganisms possessing bile tolerance , whereas resulting in reduction  of  bacterial spp which    metabolize dietary plant polysaccharides for instance Lactobacillus, Roseburia, Eubacterialis rectales along with Bacillus bifidus[[43]. Furthermore a diet having   enrichment of fat apparently escalated Firmicutes in addition to Mollicutes ; however diminishedBacteroides; escalated metabolites like lipopolysaccharide(LPS), trimethylamine-N-oxide (TMAO),but   diminishing favourable short chain fatty acids (SCFA)[44].Such metabolites usually are    the  metabolic by products of   the microorganisms from the Western diet,with high  fat, high sugar      diet are correlated with  chronic low grade Inflammation, as well as metabolic aberrations leading  to obesity, insulin resistance along with Diabetes    mellitus [43,44].

Akin observations have been demonstrated  in human studies.A study  that utilized biopsy  samples from colonic mucosa as well as faecal samples from African Americans possessing 2wks  food exchange from  a Western diet with greater fibre  diet pointed to a considerable escalation of  saccharolytic fermentation along with butyrogenesis whereas repressing   secondary    Bile Acids(BA’s) generation  that has an association with   conferring protection to the colonic mucosa in addition to  diminished CRC risk[45]. David etal. [8], performed  a study  regarding diet intervention with utilization of human  faecal samples revealed that bacterial colonization might be rapidly switched based upon kind of diet; animal  dependent or plant dependent along with changed GM   might evoke  a transcriptional  reactions  of gene enrichment of       dominant bacterial Microbiome[8]. in view of wide accessibility of ultra processed food ,the inimical actions from Microbiota which are  dominating   along with dhave formed adaptation based upon Western diet might be influencing at the time of generational  duration.This dietary exposomal actions might reason out  the sporadic EOCRC enhancement,where in terms of long time of carcinogenesis  pointed to numerous yrs of exposure in relative terms to bad dietary constituents impacting a pathogenic switch Microbiome of inimical metabolism[46].

Intestinal dysbiosis might leads  to start of  chronic low grade Inflammatory situations of the colonic mucosa, generate carcinogenic metabolites or might result  in DNA  injury as well[42,47]. Earlier studies with utilization of  Metagenomic results regarding the  Microbiome correlated with a colorectal polyp or   CRC illustrated that some strains of  bacteria were  seen  more commonly  in patients with precursor adenoma or c ancer like enterotoxigenic  Bacteroides fragilis- Fusobacterium nucleatum- as well as  polyketide  synthase gene complex (pks)+bacteria along with Escherichia Coli (E.Coli)     [48]. These bacteria might result  in  direct e DNA injury, modulate   cadherin/ β-catenin , facilitate  a  tumor  permissing  microenvironment by enrollment  of myeloid obtained suppressor cells along with anti tumor immunity of NK/T cells[49]. These bacterial  modes   behind are usually  correlated with  sporadic CRC originating    from the  adenoma- carcinoma  sequence [50].

6.Sulfur metabolism of the Gut Microbiota along withits  correlation with CRC generation

Hydrogen Sulfide( (H2S)has been braoadly believed to    be a  key signaling molecule in human, that has been isolated in the  form of a gastrotransmitter   posessing various chemical  characteristics,modes    behind reactions  along with the  capacity of changing protein apart from taking part in numerous metal redox events[51]. Endogenously H2S   gets basically generated  by GM by metabolizing  inorganic  Sulfur (sulfate along with sulfite) from preservatives present in processed food on as well as     organic substances ; basically cysteine along with  taurine present in    red meat[52]. Sulfate  reducing Bacteria for instance Bilophila, Desulfovibrio, Desulfomicrobium , Fusobacterium     possess the  capacity of colonization of the Gut in the   human Gastrointestinal Tract(GIT), in addition to produce endogenous      H2S by metabolizing  inorganic  or organic Sulfur substances[47,53]. Different   microbial  enzyme inclusive of cystathione-β- synthase(CBS), cystathione-γ- Layse( CSE), as well as     3-mercapto pyruvate Sulfur transferase(3-MST) are implicated in the generation of endogenous   H2S by catabolization of cysteine along with homocysteine[53].

In view of H2S      gets generated  by microbal metabolic reactions,with ease H2S crosses the biofilms  by which  colonocytes in addition to epithelial membrane are covered possessing greater permeability[54].On gaining entry into  the colonocytes, catabolism of  H2S takes place via intracellular Oxidative metabolism  in mitochondria as well as     cytoplasm[55]. Constitution  of various mitochondrial enzyme in the colonocytes  inclusive of Sulfide quinone Oxidoreductase(SQR)ethyl malonic  encephalopathy protein 1[ ETHE1],thiosulfate as well as   thiotransferase, the Sulfide oxidation unit   is involved in H2S oxidation  to form persulfides; substantially reactive molecules whose protein   binding takes place[56].This physiological post-translational modifications of protein(S- Sulfuration) is acknowledged to along with influence   events like   cell survival as well as demise, cell  proliferation, cell differentiation in addition to hypertrophy, cellular metabolism, mitochondrial bioenergetics as well as  biogenesis,vasorelaxation, inflammation as well as Oxidative   stress( OS) [57].It is acknowledged regarding role of S- Sulfuration in controlling  DNA injury  healing  system by activation of the RAS/RAF/MEK/ERK   stepwise signaling via Sulfhydration of MEK 1, thereby impacting tumor  growth[58]. Furthermore ,persulfidation of the nuclear factor κB(NFκB) triggers metastasis facilitating gene expression apart from activating NFκB/IL-1β that might leads to propagation  of cancer as well as metastasis through activation of the vascular endothelial growth  factors(VEGF) [59].

The biological actions of H2S  are based upon its quantities in the lumen of the colon;   these quantities inthe lumen get decided by the endogenous  generation via  bacterial metabolism that impacts H2S   modulated tumor development. Various in vitro studies where CRC cell lines on treatment with exogenous H2S displayed a bell shaped quantity reaction in cancer which depicts the double actions of H2S[51]. CRC cells exposure to slowly   liberated H2S donors  at lesser quantities(0,2-0.3μmol) ; mitochondrial working in addition to glycolysis formation  led to escalated cancer cells proliferation  by activation of enzymes  that   form H2S amongst cancer cells; however canonically were not existent  in colonic epithelial cells[60]. Furthermore, the expression of H2S   generating enzymes were greater in CRC tissue in contrast to normal surrounding tissue probably resulting  in sustenance of ideal quantities   regarding tumor growth as well as proliferation[85]. On the other hand, CRC cells treatment with  greater quantities(1mmol)of    an H2Sdonor as isothiocyanates; which mirrors  a cruciferous plant product- resulted  in apoptosis of  CRC cells[61].The way illustrated in Figure6, exogenous H2S illustrates a  quantity based actions; sustenance of normal physiology at lower, carcinogenic  on reaching the upper 

Legend for Figure 6: Courtesy ref no-12-The action of H2S is based on its concentration. threshold,then  probably chemopreventive  at greater quantities .Thus sustenance of  proper quantities of H2S might be key regarding cell cycle  balance in addition to controlling apoptosis as well as tumor development.

H2S along with Sulfidogenic bacteria upregulation possess positive correlation with a diet  possessing high  fat high protein [47,62]. Greater quantities  of Sulfidogenic bacteria in stool is  correlated   with the risk of distalCRC[63]. Furthermore contrasting the flatus samples   from  patients with   CRC with healthy substances ,quantities  of Sulfur substances were significantly greater in the  patients with   CRC [63].An in vitro study where utilization of colon cancer  obtained epithelial cells  lines illustrated in  selective upregulation of the   of H2S   generating enzyme that quantities  of H2S in contrast to nonmalignant colonic mucosa cells[57].Mice possessing elimination of     H2S    generating enzyme working ;there was reduction of blood flow hampering tumor growth along with     angiogenesis[57].The quantity of CBS      in human samples  is lesser in healthy colonic mucosa ; however slowly escalates overtime once epithelial cells  get converted into polyps, hyperplastic polyps, tubular adenoma- carcinoma[65]. The protein CBS quantities  in human colon cancer  are  intricately associated with disease robustness in addition to tumor staging as well as tumors  with greater advancements express greater CBS protein quantities with greater expression  of VEGF[66]. Moreover,it has been illustrated that expression  of H2S detoxifying enzymes for instance TST with placement  in colonocytes lumen is substantially diminished   in  advancements of colon cancer  [67].A meta-analysis  flowchart by isolation  of  differentially expressed genes within    normal colonic mucosa, primary tumor sites in addition to metastatic samples in the liver as well as     lung  illustrated that the mitochondrial oxidation enzymes inclusive  of SQR ,ETHE1 along with TST reduced at the time of evolution   events from the normal epithelium to the primary tumor in addition to metastatic areas[68].These   observations indicated  that decontrolled expression along with    activity of detoxifying     or generating enzymes might aid in the interference of    homeostasis   of  Sulfur possessing substances. Sequentially , escalated H2S quantities might possess  a part as a tumor growth factor,triggering  tumor growth as well as proliferation apart from facilitating angiogenesis along with vasorelaxation.

Intriguingly, H2S might possess  double  actions; inimical or of advantages, based on its source along with quantities.In an earlier in vitro study where asssessment  of the modes behind the H2S actions resulting  in carcinogenesis, Sulfide at quantities equivalent to the ones in normal colonic mucosa(~ mmol) stimulate direct genomic DNA  injury     in mammalian cells. Moreover, H2S might result   in    mucosal injury by stimulating degradation of di Sulfide bonds in the  mucus layer. Sequentially , luminal bacteria in addition to their metabolites   possess the capacity of penetration of the epithelial lining, trigger apoptosis of epithelial cells in addition to stimulating  the inflammatory chain of steps[52,70].This proof is in agreement with the observation that Western diet  enhances CRC; Specifically in the  distal  intestine where Sulfur metabolizing  bacteria    are observed in greater quantities in contrast to proximal   colon[90]. Interestingly, certain studies have illustrated that H2S might be conferring  protection as well as repairing action on  the colonic epithelium . Endogenous H2S in minimal quantities(mmol)  might work in the  form of a vasorelaxant, decrease endoplasmic reticulum (ER) stress along with result  in   avoidance of  apoptosis[71]. Furthermore, exogenous H2Sis present  in garlic ,onions as well as cruciferous vegetables for instance  cabbage,  cauliflower, kali as well as broccoli  that are acknowledged  to be advantageous     for colonocytes besides enterocytes, which work in the  form of a source of energy with regards to   microbiial  metabolism. Inorganic plant obtained  H2S aids in colonocytes respiration as well as stimulation mitochondria for detoxification; thereby recover from epithelial  damage [51]. Thereby   the oral ingestion of  exogenous H2S results  in stabilization  of GM biofilm   intactness as well as avoidance of    the pathogenic switch in colonies finally hampering inflammation as well as tumor development[72]. Nevertheless, the   particular mode of  H2S effects correlated with  the crosstalk amongst dietary sources in addition to GM is required  for future assessment.The distinct biological characteristics of H2S yield  newer avenues for the treatment  of CRC, targeting modulation of H2S through administration of H2S exogenously in    escalated dosage  or  hampering endogenous  H2S expression[51]. Generation of exogenous H2S substances has already  been initiated which possess the  capacity of getting liberated in a site particular along with  time based – fashion. Different   biocompatible   polymeric in the  form of H2S donors, illustrated   their capacity of targeting  in particular  the tumorous lesions,react to the pathological milieu in addition to monitoring     the alteration in the  microenvironment subsequent  to administration[73]. H2S liberating nonsteroidal anti inflammatory drugs( H2S -NSAIDS) have been formed ; along with posited to work in the  form of anti cancer agents [74]. Subsequent  to anchoring H2S  to NSAIDS, Chattopadhya etal.[74], evaluated the growth characteristics of separate human cell lines from 6 separate tissues.Their observation was that H2S -NSAIDS hampered  the growth of all the cell lines evaluated, with robustness of 28 to>3000  times more in contrast to canonical NSAIDS[74]. HS -NSAIDS hampered cells proliferation, stimulated  apoptosis along with resulted   in G (0)  / G (1)   cell  cycle   block[74]. Furthermore, hampering of   endogenous H2S formation basically  concentrated on targeting enzymes correlated with  endogenous H2S formation[75]. Different small molecule hampering models have  got fashioned as well as generated for hampering CBS, CSE, along with 3-MST , basically stimulating antiproliferative activity[51]. Aminooxyaceticacid(AOAA) is a well acknowledged  CBS hampering agent which reacts with Vitamin B 6 converting  Vitamin B 6 into  a biologically inert kind [75].Since CBS needs a biologically active co- factor obtained from  Vitamin B 6,pyridoxal-5’ phosphate(PLP) CBS hampering takes place  in case of  AOAA’spresence. For instance assessment of  hydroxocobalamin(Vitamin B(12a)) has been  performed in the  form of a plausible   forager for H2S overdose[76].At all quantities hydroxocobalamin avoided    death of mice treated with Sodium Hydrogen Sulfide. 104]. Despite hampering agents  or    foragers decrease H2S quantities efficiently ,they  might display inimical sequelae at the time of practical     utilization in view of omnipotence of enzymes  apart from systemic influence obviously  resulting in   body  injury .For the generation of any therapeutic agent  it is a must toinvestigate the issue covering all aspects for obviating probable inimical sequelae. Future translational studies regarding getting potential therapeutics which can be practically used  clinically  that is viable.

7.  Present Status Regarding Asssessment of  the Sulfur Microbial Diet along with its Correlation with  CRC

 Scarce    clinical studies have conducted asssessment of  any dietary design correlated with Microbial Sulfur metabolism regarding CRC  generation. Nguyen etal.[105], have formed a Sulfur Microbial diet  scoring systems dependent on dietary constituents correlated with bacterial spp implicated in Sulfur metabolism. Evaluating the stool Metagenomic as well as Metatranscriptome  from CRC patients in correlation with Sulfur Microbial diet  score ;they isolated greater ingestion of low -calorie beverages,French fries, red meat, processed meat as well as lesser intake of fruits ,yellow vegetables, whole grain ,legumes, cruciferous vegetables were correlated with CRC [63,77]. Thereby implying that the Sulfur Microbial diet once long term sticking on them was  correlated with greater quantities of  Sulfur      metabolizing  bacteria in the   faeces of CRC patients in contrast to healthy subjects [90]. Moreover strictly adhering  to this Sulfur Microbial diet  was correlated with an  escalated risk of CRC in particular in the   distal part[77]. Akin to that  a large prospective cohort study of women with  full history of  adulthood, as well as adolescents  diet was correlated with an escalated risk of generating adenoma possessing malignant probability   prior to 50yrs[78]. Nguyen etal.[78], indicated  that the escalated risk might  get   initiated as early as adolescence[78].

However, the earlier studies  were dependent  on the posit with the  presumption regarding greater quantities of  Sulfur  metabolizing  bacteria might be correlated with injury   to  colonic mucosa that producing to correlated with. the generationof CRC   along with   CRC  precursors like  adenoma. In view of the complicated nature of the Gut Microbial  metabolism along with it has an intermixing with various exposomal factor ; future Clinical studies need replication in separate areas as well as culture communities with regards to      food habits. Moreover  a correct strategy for  estimating  if endogenous H2S quantities   generate by GM results in carcinogenesis by direct determination of  H2S quantities  in the  gut. Nevertheless, a direct determination of  H2S quantities  is inaccessible  in addition to possesses   technical hurdles [51]. Thereby    it becomes necessary with regards to      attempting formation of  such a diagnotic methodology regarding detection     of  association of dietary habits with bacterial metabolism .

8. Furthermore, Medici etal.[79],very  recently have revalidated the escalating incidence   of EOCRC   with reemphasizing   the earlier origination of CRC where    they have contrasted with regards to        epidemiology; countries   where EORCC is still high      while reduced in others like (see Fig 7-10]. EOCRC incident rates (IRs) keep varying from 3.5 per 100,000 in   residents from India to 12.9 in the Republic of Korea [rev in 75]. In the last10yrs , an IR enhancement  revealed was in 19 out of 36 countries, amongst  which 9 (e.g., Australia, Germany, along with  the US) illustrated reduced orhad stable or    diminishing  tendencies in older adults. Only three countries (Austria, Italy, and Lithuania) revealed a reduction in EOCRC IRs [rev in 75]. An akin organization was shown in  a further recent study [rev in 75], which further illustrated how the escalation is basically correlated with  rectal cancer, other than in the United Kingdom as well as Brazil. The   maximum incidence of EOCRC was observed in females in Switzerland (4.2/100,000) as well as in males in the Republic of Korea (4.6/100,000), with no variation in  tendency trend differences in  rectal as well as colon cancer [rev in 75].
 

Legend for Figure 7: Courtesy ref no-79-Map showing EOCRC incidence rates worldwide. Red countries are those in which an increased incidence rate of EOCRC has been documented .

Legend for Figure 8: Courtesy ref no-79-Map showing EOCRC incidence annual per cent change (APC) in the last 30 years. Red countries are those in which an increased APC has been documented. Green countries have experienced a decrease in APC .

Legend for Figure 9: Courtesy ref no-79-Associations between risk factors and anatomical sites. Red arrows are placed next to risk factors that have been shown to have a role in cancer promotion, green arrows identify protective elements, and blue arrows represent no correlations.

Legend for Figure10: Courtesy ref no-79-Mutation predominance in EOCRC in right vs. left colon. Right colon tumors have a higher rate of BRAF and MSI mutations than left colon, and left-sided and rectal showed higher mutation rates of NF1, POLE, SMAD4, and BRCA2.

Moreover, they have detailed besides part of H2S quantities on other etiologic factors are significant. However it is of utmost significance to pay heed to the importance of earlier CRC possesses greater malignant potential of young generation of CRC. They also described how left colonic tumor were correlated with greater mutation rates of NF1, POLE SMAD4  BRCA2, whereas right sided along with   rectum    displayed   BRAF MS1 mutations[79]..

The fact of the escalating incidence of EOCRC world over is depressing. Urgent need of tackling this issue  is the need of the hour. One has to give significance to ensuring that we  escalate public knowledge with regards to   inimical influencing of ultraprocessed food  or Western diet Specifically in children as well as adolescents. Nevertheless, the part of diet acting in the  form of an  exosomal factor is just a posit. The modes behind the way  dietary constituents have  a positive   or  negative crosstalk with Gut Microbiota portrays  a crucial factors  in getting  insight with regards to   tumor   generation  taking  place early in life . Sulfur metabolism that takes place in by microbiota has been   pointed to    be a key product of the Western diet that is directly associated with  carcinogenesis. Based upon its quantities, the close action of H2S yields considerable understanding with regards to avoidance efforts  with/day  dietary management regarding   tumor  targeting  therapeutic approaches.One  probability   is H2S  works   via  the nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain- containing 3 (NLRP3 inflammasome). The NLRP3 inflammasome possesses NLRP3 along with  apoptosis- correlated speck  like  proteinpossessing a caspase enrollment domain (ASC)via its N terminal PYD, as well as precursor caspase 1. NLRP3 inflammasome is implicated  in numerous diseases inclusive of DM. Recently we had reviewed howH2S represents  an  inimical  gas possessing rotten egg aroma. Recently itsisolated in the form  of a 3rd gas signal subsequent to nitric oxide (NO), as well as carbon monoxide .It possesses numerous  biological functions  possesses substantially significant part in innumerable diseases inclusive of DM. Recently it has been illustrated    that H2S controls inflammasome which aids   in  various diseases(seefig 11,12]which might work in regulation of NLRP3 inflammasome&might be the probable pathway needed to act on[80]. Further we had reviewed role of bile acid metabolism in CRC   besides role of curcumin in CRC[80-3].Thus inclusion of curcumin in diet might be more beneficial in such patients.

Legend for Figure 11: Courtesy ref no-83-Schematic diagram of the NLRP3 inflammasome activation process.

Legend of Figure 12: Courtesy ref no-83-Summary of the production of endogenous H2S. CBS: cystathionine-beta-synthase; CSE: cystathionine-gamma-lyase; 3-MST: 3-mercaptopyruvate thiotransferase; 3-MP: 3-mercaptopyruvate; CAT: cysteine aminotransferase