How was cholestyramine discovered?
It is definitely synthetic, a trimethyl-ammonium derivative of polystyrene.

The first to use it as a human medication seems to be Stanley S. Bergen, Jr. et al.

See Effect of an Ion Exchange Resin on Serum Cholesterol in Man Proceedings of the Society for Experimental Biology and Medicine, Volume 102, 1959, Pages 676–679:


  It is well known that bile acids are a major
  end product of cholesterol metabolism and
  that cholesterol is probably the only precursor
  of bile acids([references]1-3 ) . Rate of oxidation of cholesterol
  to bile acids is believed to be regulated
  by need for bile acids for digestive purposes,
  cholesterol normally being oxidized at
  a rate sufficient to replace the bile acid that
  escapes reabsorption and is lost in the feces
  ([references] 4 - 5). If an agent could be found that would
  sequester bile acids and thereby promote their
  excretion in the feces, 2 consequences of clinical
  interest might be anticipated: (1) increase
  in rate of oxidative degradation of cholesterol.
  and (2) decrease in serum cholesterol level.
  Tennent ([reference] 6) described lowering of serum cholesterol
  levels in animals fed the chloride salt
  of a basic anion exchange resin. This material
  (MK-135) has marked affinity for bile
  acids in vitro and is believed to exert its serum
  cholesterol-lowering effect by virtue of this
  property( 6 ) . The present report summarizes
  results obtained when MK 135 was administered
  to 26 patients, many with elevated serum
  cholesterol levels.


Reference 6 is Tennent, D. M., Siegel, H., Zanetti, M. E., Kuron, C. W., Ott, W. H., Wolf, F. J., Circulation, 1959, v20, 996.

Even though Bergen's paper only uses the term "MK 135", according to the editor's note on the current online version, this paper is the first use of cholestyramine as a medication in humans.